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Vol 3
Vol 3
Pathology of
DOMESTIC
ANIMALS
Volume 3
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Sixth Edition
Pathology of
DOMESTIC
ANIMALS
Volume 3
EDITED BY:
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With respect to any drug or pharmaceutical products identified, readers are advised to check
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instructions, or ideas contained in the material herein.
Jubb, Kennedy, and Palmer’s pathology of domestic animals / edited by M. Grant Maxie.—Sixth
edition.
p. ; cm.
title: Pathology of domestic animals
Includes bibliographical references and index.
ISBN 978-0-7020-5322-1 (3 vol. set : alk. paper)—ISBN 978-0-7020-5317-7 (v. 1 : alk. paper)—
ISBN 978-0-7020-5318-4 (v. 2 : alk. paper)—ISBN 978-0-7020-5319-1 (v. 3 : alk. paper)
I. Maxie, M. Grant, editor. II. Title: Pathology of domestic animals.
[DNLM: 1. Pathology, Veterinary. 2. Animals, Domestic. SF 769]
SF769.P345 2016
636.089’607—dc23
2015009121
Vice President and Publisher: Loren Wilson Publishing Services Managers: Anne Altepeter and
Content Strategy Director: Penny Rudolph Patricia Tannian
Content Development Manager: Jolynn Gower Senior Project Manager: Sharon Corell
Content Development Specialist: Brandi Graham Project Manager: Louise King
Content Coordinator: Kayla Mugle Designer: Brian Salisbury
Printed in China
v
vi Contributors
†
Deceased.
Contributors vii
In this sixth edition of Pathology of Domestic Animals, we Included on the companion website are:
continue the long tradition of surveying the literature and • A complete image collection, including 325 bonus, elec-
updating the information in this reference textbook in light tronic-only figures that have been called out in the text.
of our own practical experience in the pathology of the major These figures are identified in the printed version as “eFigs.”
domestic mammals. True to the spirit of the first edition, this • An expanded list of useful references, each linked to the
text is designed to explain the pathogenesis of common and original abstract on PubMed.com.
not-so-common diseases, define the distinguishing features of I hope that we have captured significant changes and
these various conditions, and put them in a context relevant have synthesized this new knowledge to provide a balanced
to both students and working pathologists. Knowledge has overview of all topics covered. Keeping pace with evolving
been generated incrementally since the publication of the fifth agents and their changing impacts is a never-ending challenge.
edition, particularly with respect to improved understanding We have used current anatomical and microbial terminology,
of pathogenesis at the molecular level, as well as through the based on internationally accepted reference sources, such as
use of improved diagnostic tools, including the frontier of the Universal Virus Database of the International Committee
whole genome sequencing. My thanks to the contributors to on Taxonomy of Viruses (http://www.ncbi.nlm.nih.gov/
this edition for their rigorous perusal of the literature in their ICTVdb/index.htm). Microbial taxonomy is, of course, con-
areas of interest, for their addition of insightful information tinually evolving, and classifications and names of organisms
to their chapters, and for their inclusion of many new figures. can be expected to be updated as newer phylogenetic analyses
are reported. Debate continues, for example, over the
taxonomy of Chlamydophila/Chlamydia spp. And change will
NEW TO THE SIXTH EDITION
continue.
The most noticeable, and I think very welcome, change in the We have attempted to contact all contributors of figures
sixth edition is the addition of full-color figures throughout from previous editions and from various archives and apolo-
the text. Nearly all of the images from prior editions have gize to any whom we were unable to contact or who were
been replaced. These new images clearly depict the diagnostic overlooked. If any individual recognizes an image as one of
features of hundreds of conditions. his/her own or as belonging to a colleague, we would be happy
We have also added a new chapter, “Introduction to the to correct the attribution in a future printing.
Diagnostic Process,” to the usual lineup of chapters in these 3
volumes. The goal of this new chapter is to illustrate the Acknowledgments
whole-animal perspective and detail the approaches to sys- My thanks to Elsevier for their help and support throughout
temic, multi-system, and polymicrobial disease. this project, beginning in the United Kingdom with Robert
The complete index is again printed in each volume as an Edwards and Carole McMurray, and more recently in the
aid to readers. “Further reading” lists have been pruned in the United States, with Penny Rudolph, content strategy director;
print book to save space. All references are available on any Brandi Graham, content development specialist; Sharon
electronic version of the text as well as on the companion Corell, senior project manager; Louise King, project manager,
website that accompanies the purchase of any print book. and the entire behind-the-scenes production team.
These online references link to abstracts on PubMed.com.
Grant Maxie
Guelph, Ontario, 2015
COMPANION WEBSITE
In addition to updating the graphic design of these volumes,
the print version of Pathology of Domestic Animals now has a
companion website, accessible at:
PathologyofDomesticAnimals.com
ix
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These volumes are dedicated to Drs. Kenneth V.F. Jubb (1928-2013)1,
Peter C. Kennedy (1923-2006)2, and Nigel C. Palmer,
and to my family—Laura, Kevin, and Andrea.
Drs. Palmer, Jubb, and Kennedy while working on the third edition in Melbourne, 1983. (Courtesy,
University of Melbourne.)
1
http://www.vet.unimelb.edu.au/news/2013/memorial.html
2
http://senate.universityofcalifornia.edu/inmemoriam/peterckennedy.htm
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Contents
†
Deceased
xiii
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CHAP TER 1
Cardiovascular System
Wayne F. Robinson • Nicholas A. Robinson
1
2 CHAPTER 1 • Cardiovascular System General Considerations
Clinically detectable
No clinical disease,
disease (murmur,
lesion detected
arrhythmia) but no
at autopsy
evidence of failure
Heart disease
May give
rise to
Heart failure
Cranial vena cava The myocardium, the generator of the force required to
eject blood from the atria and ventricles, consists of striated
muscle cells—cardiac myocytes—embedded in a well-
SA node vascularized connective tissue framework. Individual myo-
cytes, which account for about 2 3 of the myocardial volume,
are intimately joined at intercalated discs to function as a unit.
RA Each cardiac myocyte consists of a single, central nucleus;
LA AV node
mitochondria; abundant contractile elements (myofibrils),
predominantly composed of actin, myosin, tropomyosin, and
Internodal Left bundle troponin; sarcoplasmic reticulum that stores calcium needed
pathways branch for the initiation of contraction; and the cell membrane (sar-
colemma) and T tubules needed for impulse conduction.
AV trunk
(bundle of His) Myocytes may be binucleate in some species, for instance,
dogs, and are commonly multinucleate in pigs (4-16 nuclei
LV per cell). The actin and myosin filaments comprise contractile
Right bundle RV units called sarcomeres, which are demarcated by Z lines.
branch Mitochondria occupy about 20-30% of the volume of cardiac
myocytes versus 2% in skeletal muscle, reflective of the great
dependence of cardiac muscle on aerobic metabolism. Sarco-
mere length varies from 1.6-2.2 µm; ventricular dilation
Cardiac
conducting fibers increases sarcomere length, which enhances contractility (Frank-
Starling relationship). Atrial cardiac myocytes are typically
smaller than ventricular cardiac myocytes, predominantly
Figure 1-1 The myocardial conduction system. Major species because they operate in a low-pressure system where less
differences include ramification of the cardiac conduction fibers, force is required to eject blood. There are consequently many
which can reach the subepicardium in some species (not shown). fewer myofibrils and mitochondria per cell, but they contain
AV, atrioventricular; LA, left atrium; RA, right atrium; LV, left specific granules encasing the hormone atrial natriuretic factor
ventricle; RV, right ventricle; SA, sinoatrial. (Modified from (ANF) which is released on dilation or stretching of the atria.
Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles The cardiac interstitium contains blood vessels and fibro-
for Veterinary Medicine. Cambridge, UK: Cambridge University blasts in a diverse extracellular matrix that consists of colla-
Press, 1988. Reprinted with permission.) gens, proteoglycans, noncollagenous glycoproteins, growth
factors and cytokines, and extracellular proteases. The collagen
network of the heart is arranged into 3 interconnected regions:
by the autonomic nervous system. Atrial and ventricular myo- the collagenous weave of the endomysium around individual
cytes do not normally exhibit the property of automaticity. fibers, the perimysium around groups of fibers, and the epimy-
However, when atrial or ventricular myocytes are injured, sium around the whole muscle. This fibrillar collagenous
they may repeatedly depolarize independent of a stimulus network of the myocardium prevents overstretching of myo-
from the conduction system and may become dominant pace- fibers, transmits myofiber-generated force to the chamber, and
makers. There are diseases that specifically affect the conduc- provides tensile strength and stiffness to the chamber. The
tion system producing dysrhythmias (abnormalities of rate and collagenous struts that connect adjacent myofibers provide
rhythm), but it is the dysrhythmias resulting from disease proper alignment during contraction. Struts that connect
injuring the atrial and ventricular myocytes that are most myocytes to capillaries help to maintain capillary patency
common. The cardiac wall has 3 layers: during high intraventricular pressure.
1. The epicardium, the outermost layer The endocardium lines the heart and consists of a mono-
2. The myocardium, the thick muscular middle layer layer of endothelium on a continuous basement membrane,
3. The endocardium, the innermost layer, which is continu- covering the inner subendothelial layer of dense collagen, and
ous with the tunica intima of the great vessels entering and the outer subendothelial layer composed of collagen, elastin,
leaving the heart and blood and lymph vessels. The atrioventricular (AV) valves
The epicardium, or visceral pericardium, consists of a thin are endocardial infoldings with a layer rich in elastin on the
layer of mesothelium resting on elastic fiber-rich connective atrial side (atrialis); a central layer (fibrosa) of dense irregular
tissue that merges with that of the myocardium. The epicar- connective tissue covered by layers of elastic fibers; and, on
dium is continuous with the parietal pericardium, which con- the ventricular side, loose connective tissue (spongiosa). The
sists of an inner mesothelial layer and a thick layer of collagen central collagen of the AV valves is continuous with the dense
and elastic fibers. The cavity between the visceral and parietal collagen of the chordae tendineae, which are attached to the
pericardium contains serous fluid that lubricates the surfaces ventricular papillary muscles. The aortic and pulmonic semi-
and reduces friction between the epicardium and pericardium lunar valves consist of a ventricularis layer of collagen and
during cardiac motion. Although the pericardial sac is not a radially aligned elastin on the ventricular side, a central spon-
vital organ, its proper function includes prevention of sudden giosa layer of water and glycosaminoglycans, and a fibrosa layer
cardiac dilation, assurance of equal end-diastolic transmural of collagen and elastin arranged in a circumferential direction
pressures throughout the ventricles, limitation of right ven- on the great vessel side of the valves to resist back-pressure of
tricular stroke work, hydrostatic compensation for gravita- blood. Valve cusps are predominantly avascular.
tional or inertial forces, reduction of friction, and maintenance The coronary arteries feed a dense capillary network that
of cardiac alignment and streamlined cardiac flow. supplies the myocardium, endocardium, epicardium, cardiac
4 CHAPTER 1 • Cardiovascular System General Considerations
skeleton, and bases of the cardiac valves. Blood collected by original state and is often left thickened, shrunken, and dis-
venules and veins is drained into the right atrium via the coro- torted. Affected valves may be either insufficient or stenotic
nary sinus. Lymphatic capillaries draining the cardiac connec- or both, but one or the other usually predominates. Distor-
tive tissue are continuous with larger lymph vessels in the tions of the structure of heart valves in the absence of vegeta-
endocardium and epicardium. Sympathetic and parasympa- tions and with an intact valvular endothelium are commonly
thetic innervation is extensive in the atria, and particularly encountered. Valves can be effaced, displaced, shrunken,
around the SA and AV nodes. thickened, or, in the case of the AV valves, no longer firmly
anchored to the papillary muscles. All result, to a greater or
Morphologic patterns of heart disease lesser extent, in a diminution of effective unidirectional blood
The 3 broad anatomic divisions of the heart—the mural and flow. Probably the best examples of distortions in architecture
valvular endocardium, the myocardium, and the pericardium— are those seen in congenital heart disease, such as valvular
exhibit differing features in the face of disease. It is not that aortic and pulmonic stenosis, left and right AV valvular steno-
the usual suspects that affect all organs are not in play. Inher- sis or insufficiency. Similar lesions can be seen in acute or
ited disease, infectious agents, toxins, nutritional deficiencies, healed valvular endocarditis and degenerative diseases of the
and neoplasia all affect the heart, but it is the combination of AV valves, such as endocardiosis in dogs. Abnormal chamber
the structure of the heart, the biological characteristics of the or great vessel communication is of special interest because
cells comprising the heart, and their response to injury, in of the altered hemodynamics that ensue in the transition from
concert with the host’s general response to injury, that results fetal to postnatal life. Predominantly congenital in origin, it is
in the display of the particular features of heart disease. It often the result of incomplete closure of fetal communications
should be remembered that the heart may also show evidence between the atria, ventricles, and great vessels following birth.
of disease as an integral part of diseases of another organ Acquired arteriovenous communication can also occur.
system or systemic disease.
The myocardium
The mural and valvular endocardium and The myocardium may be primarily and specifically affected
the heart valves proper by a particular disease, but it may also be just another organ
Valvular abnormality from any cause can lead to disturbances involved in systemic disease. The morphologic manifestations
of blood flow through the heart either by altering the normal of myocardial disease reflect some of the characteristics of the
unidirectional pattern of flow, or by impeding blood flow into myocardium, such as the predominance of contractile proteins
or out of the chambers. Alterations in hemodynamics reflect in each cardiac myocyte; the exquisite compartmentalization
changes in systolic workloads characterized by changed pres- of calcium required for regular and orderly contraction; its
sure loading during contraction (afterload), or changed volume high requirement for energy for regular contraction; its end-
loading during diastole (preload). Most valvular disorders arterial blood supply, predisposing the myocardium to infarc-
impose only a single preload or afterload on the heart. This tion; and the very limited capacity of cardiac myocytes for
encompasses those valvular disorders that cause either insuf- regeneration. Cardiac myocytes, however, have a remarkable
ficiency (failure to close) or stenosis (narrowing, failure to open). capacity to increase in mass (hypertrophy) in response to an
Some of the congenital heart abnormalities, such as patent increase in either physiologic or pathologic workload.
ductus arteriosus and tetralogy of Fallot, have multiple preload As do all tissues, the myocardium has a limited set of reac-
and afterload effects. The general rules are (eFig. 1-2): tions to injury, but the pattern and distribution of lesions may
1. Valvular insufficiency increases the preload on the aid in arriving at a morphologic and etiologic diagnosis. The
ventricle. stage of irreversible damage to a myocyte, at least in ischemia,
2. Semilunar valvular stenosis, outflow tract stenosis, and is determined by structural and functional changes in the
hypertension increase the afterload on the ventricle. mitochondria. Irreversible damage occurs after only 30
3. AV valvular stenoses and pericardial disorders decrease the minutes of ischemia, whether or not flow is restored.
preload on the ventricles. Shortly after birth, most cardiac myocytes lose their ability
Subendocardial hemorrhage is a frequent accompaniment to regenerate. Once the neonatal period passes and a particular
to a myriad of diseases of the heart, but more particularly, myocyte or group of myocytes is lost, there is usually no
with systemic disease, where the heart is just another surface replacement. There is, however, recent evidence to show that
where hemorrhage can be observed. Subendocardial mineral- there is a low level of cardiac myocyte turnover throughout
ization occurs as either a dystrophic or metastatic phenome- life. On the death of myocytes, there is progressive scavenging
non. Additions to valves and/or the mural endocardium result of the necrotic or apoptotic remnants of the myocytes and
from disturbances to the health of the endothelial lining of replacement by fibrosis. Remaining myocytes do have the
the mural and valvular endocardium, and because of the loca- capacity for compensatory hypertrophy.
tion, can have wide-ranging consequences. The most severe Myocardial injury may be functionally manifest as either
and extensive occurs with microorganisms, particularly bacte- irregularities in the rate or rhythm of impulse formation and
ria, that arrive via the systemic circulation that adhere to conduction (dysrhythmias), or as depression in the force of
endothelium and/or subendocardium after the endothelium myocardial contraction. Dysrhythmias are usually associated
has been damaged or eroded. The cascade of events that with acute, nonlethal, often focal injury to cardiac myocytes.
follow, especially the incitement of thrombosis, results in a Contractility disturbances occur when there are either insuf-
mass of platelets, fibrin, and inflammatory cells (vegetations) ficient numbers of ventricular myocytes for effective contrac-
accumulating on the exposed surfaces, impeding blood flow tion, as occurs in massive ischemic necrosis of ventricular
through the heart and predisposing to thrombotic emboli myocytes following blockage of a major coronary artery, or
lodging in end-arteries in organs throughout the host. Although when there is generalized ineffective contraction of normal
healing may occur, the healed valve is rarely returned to its numbers of myocytes. Generalized, ineffective myocardial
4.e1
Semilunar Stenoses
Supra/subvalvular and
valvular stenosis
Increased ventricular
afterload
Concentric hypertrophy
Hemodynamic
effects of
valvular
abnormalities
Insufficiencies AV stenoses
[Both AV and SL valves] Decreased ventricular
Increased ventricular preload
preload Increased atrial afterload
Eccentric hypertrophy
eFigure 1-2 Hemodynamic effects of valvular abnormalities. AV, atrioventricular; SL, semilunar.
(Courtesy Vasileios Psychas.)
Diseases of the Heart General Considerations 5
Abnormal pattern of blood flow Increased cardiac work demands on one or both ventricles
(shunted blood flow) result from disturbed hemodynamics, in the form of sustained
Although these can be acquired, they are much more com- pressure overload (e.g., obstructed flow in aortic valvular
monly congenital in origin. They can be simple communica- stenosis) or volume overload (e.g., regurgitant flow in mitral
tions between the great vessels (patent ductus arteriosus), the valvular regurgitation).
atria (patent foramen ovale/atrial septal defect), or the ven- Congestive heart failure is characterized by vascular conges-
tricles (ventricular septal defect). The pathophysiology can be tion and edema fluid within the interstitium of tissues and body
complicated where the defect results in increases in both cavities. Not all cases of heart failure are of the congestive type.
preload and afterload on particular chambers. A special case Although in congestive heart failure the clinical manifesta-
of shunted blood flow occurs with the transposition of the tions are more or less constant, in acute heart failure, there
great vessels. may be intermittent weakness and syncope caused by a sub-
stantial change in heart rate or rhythm, resulting in a precipi-
Restricted atrial/ventricular filling tous drop in cardiac output. The effect of acute heart failure
Pericardial disease, either acute or chronic, can restrict chamber is often sudden unexpected death, often with minimal lesions.
filling during diastole, as can some of the hypertrophic cardio- Circulatory failure, or shock, denotes a state of inadequate
myopathies. In essence, the compliance of either the pericar- peripheral vascular perfusion and is used to describe a state that
dium or the myocardium is reduced, which prevents full may or may not be the result of heart failure. It is character-
diastolic relaxation of the ventricles. The major pathologic ized by a drop in effective circulating blood volume. Common
effect is one of increased central venous pressure leading to causes are acute internal or external hemorrhage, dehydration,
congestive heart failure, which can be predominantly right- or endotoxic shock. Shock can of course lead to acute heart
sided or left-sided, depending on which chamber is most failure.
affected. Based on clinical manifestations, heart failure may be pre-
dominantly either left-sided failure or right-sided failure. Left-
sided failure results in left atrial dilation, pulmonary congestion
Further reading and edema, and clinical signs of dyspnea and cough. A promi-
Bergmann O, et al. Evidence for cardiomyocytes renewal in humans. nent feature of chronic left-sided heart failure is the presence
Science 2009;324:98-102. of hemosiderin-laden macrophages (“heart failure cells”) in
Bonow RO, et al., editors. Braunwald’s Heart Disease. A Textbook of pulmonary alveoli, the result of diapedesis of red cells into
Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders; the alveoli. Right-sided failure results in excessive right atrial
2012. pressure and systemic venous congestion, expressed as jugular
Ettinger SJ, Feldman EC, editors. Textbook of Internal Veterinary Med- distension, hepatic and splenic enlargement, ascites, and
icine: Diseases of the Dog and Cat. 7th ed. Philadelphia: Saunders peripheral edema. Cor pulmonale is defined as right heart
Elsevier; 2010. failure secondary to pulmonary disease, such as chronic obstruc-
Hurst JW, et al. The Heart. 13th ed. New York: McGraw-Hill; 2011. tive pulmonary disease, dirofilariasis, or pulmonary thrombo-
Miller LM, et al. Cardiovascular System and Lymphatics. In: Zachary JF, embolism. Because the cardiovascular system is closed, failure
McGavin MD, editors. Pathologic Basis of Veterinary Disease. of one ventricle will ultimately lead to failure of the other,
5th ed. St Louis: Elsevier; 2012. culminating in global or biventricular failure.
Orton EC. The Heart. In: Bojrab MJ, Monnet E, editors. Mechanisms of Although there are many causes that lead to intermittent
Disease in Small Animal Surgery. Boca Raton, Fla: CRC Press; 2010. or permanent lowering of effective cardiac output, there is a
Plendl J. Cardiovascular System. In: Eurell JO, Frappier BL, editors. Dell- limited set of responses to this by the animal. The major
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley compensatory mechanisms include the intrinsic cardiac
Blackwell; 2007. p. 117-133. responses of dilation and hypertrophy, and the systemic
Schoen FJ, Mitchell RN. The heart. In: Kumar V, et al., editors. Robbins responses, which include increased heart rate and peripheral
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia: resistance, redistribution of blood flow, venular constriction, and
Saunders; 2010. p. 529-587. increased blood volume. In each case, the compensatory
responses are at least temporarily beneficial and are directed
toward increasing cardiac output to meet the metabolic needs
of the animal. The range within which the compensatory
HEART FAILURE
mechanisms result in an increase in cardiac output is wide.
Heart failure is the end point of a number of causes, rather than Indeed, the increase may be up to 5 times the basal rate. As
a specific disease, and denotes a situation in which all compen- cardiac output falls below the requirements of the animal,
satory mechanisms have been exhausted, and the heart is signs of congestive heart failure appear. These may be inter-
unable to meet the demands of the animal. The syndrome is mittent or prolonged, depending on the nature of the defect.
characterized by diminished cardiac output (“forward failure”), An untoward side effect of the systemic responses is
or damming back of blood in the venous system (“backward increased capillary hydrostatic pressure that leads to the accu-
failure”), or both. The heart can fail because of impaired pump mulation of edema fluid. This can involve the systemic or
function or because of increased cardiac work demands; both pulmonary veins. Right-sided lesions, such as right atrioven-
mechanisms may be operative in some cases. The heart can tricular (AV) valvular insufficiency, pulmonic stenosis, or pul-
fail as a pump because of monary hypertension, result in peripheral-dependent edema
1. Decreased myocardial contractility, or loss or replacement (e.g., submandibular edema [“bottle-jaw”], brisket edema),
of myofibers, or ascites, hydrothorax, and hydropericardium. Left-sided defects,
2. Decreased distensibility (compliance), or such as left AV or aortic valvular insufficiency, cause pulmo-
3. Dysrhythmia (abnormal heart rate and/or rhythm) nary edema as the predominant finding.
6.e1
Further reading
Borg TK, et al. The cell biology of the cardiac interstitium. Trends Car-
diovasc Med 1996;6:65-70.
Darke PGG, et al. Color Atlas of Veterinary Cardiology. London: Mosby-
Wolfe; 1996.
Fox PR, et al. Textbook of Canine and Feline Cardiology. Principles and
Clinical Practice. 2nd ed. Philadelphia: WB Saunders; 1999.
Robinson TF, et al. Skeletal framework of mammalian heart muscle.
Arrangement of inter- and pericellular connective tissue structures.
Lab Invest 1983;49:482-498.
Tilley LP, Goodwin J-K. Manual of Canine and Feline Cardiology.
Philadelphia: WB Saunders; 2001.
Ware WA. Cardiovascular Disease in Small Animal Medicine. London:
Manson Publishing; 2011.
Diseases of the Heart Heart Failure 7
apoptotic loss of myocytes; excessive apoptosis can contribute size of the papillary muscles and the trabeculae carneae (Fig.
to failure of a hypertrophic heart. This postulate is supported 1-6). Although the hypertrophy may emphasize one or other
by experimental work with receptor-mediated Gαq signaling chamber, the whole heart is involved. When the right ventricle
of cultured rat cardiac myocytes (Gαq is the α subunit of the is involved, the moderator band (trabecula septomarginalis)
Gq family of G proteins, guanine nucleotide–binding proteins, may be much thickened. Extreme hypertrophy of one chamber
which transduce signals); moderate levels of Gq signaling
stimulate cardiac hypertrophy, whereas high-level Gq activa-
tion results in cardiac myocyte apoptosis. Increased ventricular afterload (Pressure overload)
There are distinctive anatomic patterns of hypertrophy that
accompany the increase in workload. Concentric cardiac
hypertrophy, that is, an increase in mass of the ventricle without Increased
accompanying increase in end-diastolic volume, characterizes ventricular
increased systolic loads (increased afterloads), such as aortic systolic
stenosis, pulmonic stenosis, and pulmonary hypertension in Increased resistance pressure
patent ductus arteriosus. There is often a decrease in the to ventricular ejection
volume of the ventricular lumen (Fig. 1-3). An increase in
diastolic load (increased preload), typically produced by AV or
semilunar valvular insufficiencies or by arteriovenous shunts,
results in eccentric cardiac hypertrophy, which is an increase
in myocardial mass accompanied by increased end-diastolic
volume (dilated chamber). Because of dilation, the thickness of
the involved ventricular wall is usually no more than normal
and may be less (Fig. 1-4).
Ventricle undergoes
In relation to altered hemodynamic loads placed on the compensatory
heart, AV valvular stenosis or pericardial fibrosis restrict ven- hypertrophy
tricular filling, leading to a decrease of the load on the myo- (concentric)
cardium (Fig. 1-5).
The gross appearance of the hypertrophic heart depends
on the chamber affected and the nature of the insult. In Figure 1-3 Increased ventricular afterload. The involved ventri-
general, hypertrophy of the right side of the heart makes the cle undergoes concentric hypertrophy following increased resis-
heart broader at its base; hypertrophy of the left side increases tance to ventricular ejection. End-diastolic volume may be
the organ length; bilateral hypertrophy produces a more reduced. The shaded area shows the outline of a normal ventricle.
rounded shape than normal. (Modified from Robinson WF, Huxtable CRR, eds. Clinicopatho-
In concentric hypertrophy, there is increased thickness of the logic Principles for Veterinary Medicine. Cambridge, UK:
wall of the affected chamber, and a marked increase in the Cambridge University Press, 1988. Reprinted with permission.)
Increased venous
return from AV
shunt such as PDA
Increased end
diastolic volume
Ventricle undergoes
Increased ventricular compensatory
contractility following hypertrophy (eccentric)
stretching of myofibers
Figure 1-4 Increased ventricular preload. Increased ventricular preload may result from (1) bidi-
rectional flow from insufficient atrioventricular (AV) or semilunar valves, or (2) increased volume
of blood from intracardiac or extracardiac arteriovenous shunts. The ventricle dilates and under-
goes eccentric hypertrophy. The shaded area shows the outline of a normal ventricle. PDA, patent
ductus arteriosus. (Modified from Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
for Veterinary Medicine. Cambridge, UK: Cambridge University Press, 1988. Reprinted with
permission.)
Diseases of the Heart Heart Failure 9
Decreased preload
AV valve
stenosis or
pericardial
disease
Decreased
cardiac output
Decreased end
diastolic volume
Restriction of blood flow Figure 1-7 Eccentric left ventricular hypertrophy in dilated car-
into the ventricle diomyopathy in a dog. The lumen of the left ventricle is increased
Figure 1-5 Decreased ventricular preload. Decreased ventricular relative to the thickness of the walls of the ventricle.
preload follows atrioventricular (AV) valvular stenosis or myocar-
dial restriction, such as pericardial fibrosis. End-diastolic volume
In both types of hypertrophy, the endocardium may be
decreases because of restricted inflow. (Modified from Robinson
diffusely opaque as a result of subendocardial fibrosis, and
WF, Huxtable CRR, eds. Clinicopathologic Principles for Veteri-
this alteration may be the best indication of dilation in the
nary Medicine. Cambridge, UK: Cambridge University Press,
atria, in which dilation and hypertrophy can be difficult
1988. Reprinted with permission.)
to assess.
An example of concentric cardiac hypertrophy occurs
in cats with hyperthyroidism (thyrotoxicosis), a condition
usually resulting from the presence of thyroid hyperplasia or
adenoma. The thyroid glands in these cases are unilaterally or
bilaterally enlarged, nodular, pink to dark brown, and may
contain cysts. Microscopically, the thyroids usually exhibit a
mixture of hyperplastic areas, adenomatous nodules, and
normal follicles (see also disorders of the thyroid gland in Vol.
3, Endocrine glands). The pathogenesis of ventricular hyper-
trophy in this disease is not clear, but may involve the direct
action of thyroid hormones on myocardium, enhanced myo-
cardial adrenergic receptor number or affinity, peripheral
vasodilation, and work hypertrophy in response to increased
peripheral tissue demands for oxygen and dissipation of heat.
The hearts in most cases are symmetrically hypertrophied;
however, some exhibit asymmetric hypertrophy. The left
ventricular lumen is usually reduced in size. Affected myofi-
bers are enlarged, but are not in disarray in the great
majority of cases. The hypertrophy is reversible on return
to euthyroidism.
Figure 1-6 Concentric left ventricular hypertrophy. The ven-
tricular free wall and interventricular septum are thickened, and Systemic responses in heart failure
the lumen of the ventricle is reduced, in this cross-section of The extracardiac features of heart failure stem from 2 basic
ventricles from a dog. pathophysiologic changes: fluid accumulation and tissue or
organ ischemia. Depending on the cause of the heart failure,
both effects may be present, but it is more usual for one to
may encroach on the diastolic capacity of its opposite number. predominate.
Microscopically, the myocytes are enlarged, but the increase Fluid accumulation results from the retention of sodium
in the size of fibers is not uniform and is not always easy to and water, which primarily involves the kidneys, and also
discern on routine microscopy. involves atrial natriuretic factor released from the heart (eFig.
In eccentric hypertrophy and dilation, the heart tends to be 1-3A). The influence of the failing heart on the kidneys stems
globose, and even though the mass is increased, the wall is from its inability to supply them with an adequate flow of
usually thin. The papillary muscles may also be attenuated blood. Blood flow through different parts of the kidneys
(Fig. 1-7). depends on the vasomotor tone of blood vessels within the
9.e1
Depression in
cardiac output
Redistributed/decreased
Increased ADH
renal blood flow
Increased retention
of water
Increased filtration fraction:
Increased renin/
Proportionally more sodium
angiotensin/aldosterone
delivered to tubules
Increase in
blood volume
Increased retention
of sodium
A
Pathologic features of CHF
Histopathology Histopathology
Pulmonary venous congestion; Dilated congested hepatic sinusiods;
alveolar edema; alveolar macrophages parenchymal atrophy
contain RBCs/hemosiderin
B
eFigure 1-3 Congestive heart failure. A. Pathogenesis of heart failure. This involves sodium and
water retention by the kidney following reduced blood flow/redistribution of blood flow to the
kidney. Increased antidiuretic hormone (ADH) activity also contributes to the retention of water.
All lead to an increase in blood volume. (Modified from Robinson WF, Huxtable CRR, eds. Clini-
copathologic Principles for Veterinary Medicine. Cambridge, UK: Cambridge University Press,
1988. Reprinted with permission.) B. Pathologic features of congestive heart failure (CHF).
RBCs, red blood cells.
10 CHAPTER 1 • Cardiovascular System Heart Failure
parenchyma. It is considered that many, if not all, of the intra- Syndromes of circulatory failure
renal blood flow changes in heart failure follow increased Circulatory failure, the term implying severe systemic conse-
activity of the sympathetic nervous system. quences, falls into 3 general categories: cardiac syncope, periph-
The kidneys receive approximately 20% of the output of eral circulatory failure, and congestive heart failure.
the left ventricle, almost all of which flows through the renal
cortices. One of the earliest changes following a drop in Cardiac syncope
cardiac output is redistribution of blood flow within the Cardiac syncope is characterized clinically by profound
kidney. There is reduced flow through the outer renal cortex changes in blood pressure and heart rate with bradycardia or
and increased flow within the outer renal medulla. This results tachycardia, either of which may result in inadequate output
in readjustment of the filtration fraction, which is the ratio of of blood. Both may occur in the presence or absence of organic
glomerular filtration rate (GFR) to renal blood flow. Contrary heart disease.
to expectations, there is a less than proportionate drop in GFR In one form of cardiac syncope, hypersensitive or hyperac-
compared with renal blood flow, resulting in an increased tive reflexes, for which the vagus nerve is the efferent limb,
filtration fraction. As a consequence, proportionally more may result in reflex inhibition of the heart rate, manifest as
sodium moves through the glomerular filter, leading to pro- extreme bradycardia or as asystole. The sudden deaths that
portionally more sodium being delivered into the proximal result from acute pleural irritation or the tracheal irritation of
convoluted tubule. Because the rate of sodium resorption aspirated vomitus fall into this group, and obviously there may
remains constant, a greater number of sodium ions are be no organic heart lesion.
resorbed. Also, because of the increased filtration fraction, In a second form of cardiac syncope, the heart rate is
local plasma osmotic pressure in the efferent arteriole increases, extremely rapid, and the cardiac output severely reduced.
causing greater resorption of sodium and water. Such may occur in paroxysmal tachycardia, atrial flutter or
The alteration in renal blood flow in heart failure also fibrillation, and ventricular fibrillation.
increases the activity of the renin-angiotensin-aldosterone Third, in organic heart disease with complete obstruction
system, producing more sodium resorption from the distal of impulse conduction from the atrium to the ventricle
convoluted tubule. There is also increased water-retaining (complete heart block), syncope may occur if there is suffi-
activity by antidiuretic hormone. cient delay before the ventricle assumes an independent
A mechanism within the heart also regulates blood volume, rhythm.
blunting the activity of aldosterone and the renin-angiotensin Finally, cardiac syncope may terminate a syndrome of con-
system. Atrial natriuretic factor (ANF), with natriuretic and gestive cardiac failure when the cardiac reserve is depleted
diuretic properties, is present in granules in some of the atrial and the heart cannot increase its output sufficiently to meet
myocytes. If the atrial pressure is elevated or the atria are sudden increases in peripheral needs.
distended, ANF is released and causes natriuresis, vasodilation,
suppression of the renin-angiotensin-aldosterone axis, and Peripheral circulatory failure
decreased arterial blood pressure. In terms of homeostasis, ANF Peripheral circulatory failure is characterized by reduction in
has effects opposite to those of aldosterone, thus providing a the effective circulating blood volume with insufficient venous
balance to fluid regulation. Although plasma ANF is signifi- return and reduced cardiac output. Acute hemorrhage and
cantly increased in dogs with chronic left AV valvular insuf- shock are examples of this form of circulatory failure.
ficiency, it is not clear whether the metabolic effects of
aldosterone or ANF predominate, but it would appear that Congestive heart failure
the effects of aldosterone over-ride those of ANF. The combination of compensatory mechanisms, brought into
It should be noted that none of the hormones mentioned play to maintain cardiac output, is in general successful.
produce the edema of congestive heart failure if administered However, there is also the planting of the seeds of destruction.
alone. In addition, once a new steady state has been reached, Both the local increase in venous hydrostatic pressure and the
the hormonal state returns to relatively normal limits. Last, increased sodium and water retention by the kidneys tend to
the mechanisms that are brought into play are not exclusive to promote the development of interstitial edema. Depending on
the syndrome of heart failure. Any situation that leads to a the inciting abnormality, it is usual for one side of the heart
drop in effective circulating blood volume will activate the to fail before the other, but it must be remembered that the
sodium- and water-retaining mechanism. The fundamental cardiovascular system is a closed circuit and that failure of one
difference between these states and congestive heart failure is side will eventually embarrass the other (eFig. 1-3B).
that the total blood volume in heart failure is already more Left-sided heart failure is ushered in by progressive dilation
than adequate, but the effective blood volume is much dimin- of the left ventricle and atrium, although this progression may
ished because of the poor cardiac output. The volume be marked by exacerbations and remissions if hypertrophy is
changes in heart failure should be viewed as an integrated given time to develop. The major extracardiac manifestations
response by the body to compensate for the inability of the of left-sided failure arise from the damming back of blood in
heart to respond to the normal hemodynamic needs of the lungs and the diminution in cardiac output. The pulmo-
the body. nary venous congestion is transmitted back to the capillaries of
The expansion of blood volume has both a beneficial and the alveolar wall, and edema fluid accumulates in the inter-
a detrimental effect. By increasing blood volume, venous stitial tissue and the alveolar spaces. The consequent reduction
return is enhanced and, in turn, cardiac output and tissue in pulmonary vital capacity and impaired gaseous exchange
perfusion are improved. However, this is to the detriment of of cardiogenic pulmonary edema result in hypoxic stimulation
the balance between capillary hydrostatic pressure and plasma of the carotid sinus and medullary respiratory centers so that
osmotic pressure. This leads to an increase in the amount of reflex dyspnea occurs. A wheezing bronchial cough is common
fluid in the interstitial spaces and body cavities. and is presumed to be due to irritation of the respiratory
Diseases of the Heart Heart Failure 11
A B
C
Figure 1-8 Congestive heart failure. A. Left-sided congestive heart failure in a dog. Pulmonary
alveolar capillaries are congested, and there is hemorrhage into alveoli that contain hemosiderin-
laden macrophages (“heart-failure cells”). H&E. B. Same section as (A) stained with Prussian blue
to highlight the abundance of iron derived from hemosiderin in alveolar macrophages. C. Chronic
passive congestion of the liver, leading to zonal hepatocyte atrophy, in right-sided congestive heart
failure in a dog. H&E.
mucosae by the edema fluid. Cyanosis may be present but is There is some species difference in the distribution of
more often the rule in right ventricular failure. edema in congestive heart failure. In ruminants and horses,
At postmortem, the lungs are usually of normal color, but dependent subcutaneous edema is expected; in the other species,
may be light brown, and are heavy and wet. Stable, white froth excess subcutaneous fluid is scant or absent. In dogs, the pre-
is present in the airways, and fluid exudes from the cut surface. dominant accumulation of fluid is in the peritoneal cavity. In
Because of its low protein content, there is little evidence of cats, it is in the thorax.
the abundant fluid on microscopic examination. The alveoli Grossly, the liver is enlarged and congested and has a
contain erythrocytes and a scattering of macrophages, some of “nutmeg” appearance on section because of chronic passive
which contain hemosiderin. It may be necessary to use a dif- congestion (Fig. 1-8C). Microscopically, the sinusoids are
ferential stain for iron to confirm the presence of these dilated, with atrophy of the parenchyma about the central
so-called “heart-failure cells” or siderophages (Fig. 1-8A, B). veins. In more severe or acute cases, the parenchyma in this
They are more numerous in chronic disease, and hemosiderin location may undergo degeneration or necrosis. It is excep-
within their cytoplasm may be sufficient to produce tawny tional for an animal with congestive failure to live long enough
discoloration of the lungs. for severe fibrosis and nodularity to occur. Impaired hepatic
In right-sided heart failure, the major extracardiac mani- function is not usually a significant part of the clinical course,
festations depend on increased hydrostatic pressure in the although jaundice may be observed.
systemic and portal venous systems, and the reduction of flow Congestion of the stomach and intestines is evident, and
from the lungs to the left ventricle. Renal complications occur this may impair their function, which is manifest usually as
more frequently in right-sided than in left-sided heart failure, diarrhea. In horses, the subserosal lymphatics, particularly of
leading to increased blood volume, peripheral edema, and the large bowel, are often readily discernible, dilated, and filled
more marked azotemia. with edema fluid. The systemic and portal veins are distended,
12 CHAPTER 1 • Cardiovascular System Examination of the Heart
and the spleen is enlarged and congested. However, this latter useful system is to follow the route of blood flow through the
finding is masked if the animal in question has been eutha- heart, that is, an inflow-outflow method of dissection (Fig.
nized using barbiturates. 1-9A, eFig. 1-4). This technique may require modification in
the case of cardiac anomalies. Examination of the heart in the
planes used for echocardiographic examination could be
EXAMINATION OF THE HEART
beneficial.
In a gross postmortem examination of the heart, it is impor- • The initial examination of the heart and great vessels is
tant to examine 4 major areas: pericardium, myocardium, best made with the organs in situ to assess abnormalities
mural and valvular endocardium, and the great vessels. A of size and position.
i ii iii iv
A v vi vii viii
Caudal
AV node vena cava 1 Sinus
node
2
Septum
Coronary sinus
AV node
AV bundle RV
Bundle branches free wall
3 Ventricular septum
B
Figure 1-9 Examination of the heart. A. Gross examination. (i) Heart oriented to show right
atrium/ventricle facing. (ii) Incision made transversely from caudal vena cava to right auricular
appendage. (iii) Incision commenced in right atrium into junction between right ventricle and
interventricular septum. (iv) Right ventricle opened to display right atrioventricular valve. (v)
Incision continued to display right ventricular outflow tract and pulmonic valve. (vi) Heart oriented
to display left atrium (transversely incised from pulmonary vein to left auricular appendage) and
left ventricular free wall. (vii) Left ventricle free wall incised from base to apex displaying the left
atrioventricular valve. (viii) Left ventricular outflow tract and aortic valve displayed by incision
through left atrioventricular valve. Goat. B. Microscopic examination of the heart. The cardiac
conduction system can be assessed via block 1, in which the sinus node is located subepicardially
in the terminal groove at the junction of the cranial vena cava and right auricular appendage, and
block 2, in which the atrioventricular (AV) node is located subendocardially on the right side of
the interatrial septum, just cranial to the coronary sinus: Serial sections through this block will
reveal the AV node, the common bundle, and the origins of the bundle branches. A block through
the left ventricular free wall, including papillary muscle, or block 3, through the ventricular septum,
is the minimal representative sample to take from a grossly normal heart. RV, right ventricle.
12.e1
free wall/papillary muscle and AV valve, great vessels, plus any Jacob M, Wilson Tang WH. Pathophysiology of congestive heart failure.
grossly evident lesions. In: Griffen BP, et al., editors. The Cleveland Clinic Cardiology
The selection of sections to study the specialized conduc- Board Review. Philadelphia: Lippincott Williams & Wilkins.; 2013.
tion system should include the sinus node, the AV node, the p. 155-163.
common bundle (bundle of His), left and right crura (bundle Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc
branches), and conducting fibers. The sinus node lies subepi- Pathol 2012;21:365-371.
cardially in the terminal groove (sulcus terminalis) at the King JM, et al. The Necropsy Book. Gurnee, Ill: CL Davis DVM Founda-
junction of the cranial vena cava and the right atrium. Sections tion; 1999.
should include either side of that site, to incorporate tissue in Lymperopoulos A, et al. Adrenergic nervous system in heart failure:
the sulcus terminalis region. The AV node is obtained by pathophysiology and therapy. Circ Res 2013;113:739-753.
removing a block of tissue from the coronary sinus to the Maillet M, et al. Molecular basis of physiologic heart growth: funda-
cranial edge of the septal leaflet of the right AV valve. The mental concepts and new players. Nature Rev Mol Cell Biol
block includes interatrial septum and dorsal ventricular 2013;14:38-48.
septum, and will then contain the AV node, which is located Schoning P, et al. Body weight, heart weight, and heart-to-body weight
subendocardially on the right side of the interatrial septum, ratio in greyhounds. Am J Vet Res 1995;56:420-422.
the common bundle, and the left and right crura. The speci- Souders CA, et al. Pressure overload induces early morphological
men should be serially sectioned into samples 3 mm thick, changes in the heart. Am J Pathol 2012;181:1226-1235.
and all samples should be processed. Towbin JA. Molecular genetic basis of sudden cardiac death. Cardio-
In routine cases, there are no special requirements for fixa- vasc Pathol 2001;10:283-295.
tion. Stains of particular use are hematoxylin and eosin,
Masson trichrome, phosphotungstic acid hematoxylin, Luxol
fast blue, and Gomori aldehyde fuchsin. CONGENITAL ABNORMALITIES OF
Note that rigor mortis begins earlier in myocardial than in THE HEART AND LARGE VESSELS
skeletal musculature, and reaches greater development in the
more powerful left ventricle. Rigor should completely express In the transition from fetal to neonatal life, substantial adjust-
the blood from the left ventricle; rigor of the right ventricle ments occur within the cardiovascular system. There are altera-
is less efficient, and emptying is incomplete. The presence of tions in the pressures in cardiac chambers and great vessels, the
some clotted blood in the right ventricle is normal, whereas pattern of blood flow, and the volume of blood flow. Because
if present in the left ventricle, it is indicative of incomplete of these changes, the retention postnatally of fetal vascular
rigor and therefore perhaps of severe myocardial degenera- communications, such as the ductus arteriosus, may place an
tion. The presence of unclotted blood in the left ventricle excessive load on the heart in the postnatal period and beyond.
some hours after death is more difficult to interpret. Unclot- There are also congenital heart defects, such as pulmonic ste-
ted blood, the result of fibrinolysis, may flow back into the nosis, which compromise the fetus, the newborn, and the adult.
ventricle when rigor passes. It is typically only those defects that allow adequate in utero
Blood usually clots slowly after death and permits eryth- development and a reasonably successful perinatal life that are
rocytes to sediment. Where blood is present in volume, as in recognized; anomalies sufficiently severe to cause death in
the heart and arterial trunks, sedimentation and subsequent utero, or in the neonatal period, often are not.
clotting leads to the formation of “currant jelly” and “chicken As with most diseases, there is a spectrum of change. The
fat” clots, the former containing erythrocytes, and the latter variation in severity of a particular lesion may be wide and will
largely devoid of them. Chicken fat clots are to be expected necessarily influence whether clinical signs are observed. As such,
in horses, which normally have a rapid erythrocyte sedimenta- there is a higher incidence of congenital heart disease than is
tion rate, and are in relative excess in anemia. Postmortem recognized clinically. There is also a group of congenital heart
clots are to be distinguished from thrombi; clots are not diseases that do not produce clinical signs of heart failure, but
attached to the endocardium. which are manifested by upper alimentary dysfunction.
Biopsy of the heart in not commonly undertaken in vivo, Although little is known of the causes of many cardiac mal-
but is possible via transvenous endomyocardial biopsy. Mul- formations in domestic mammals, there is no doubt that,
tiple biopsy samples of the right ventricular myocardium may especially in dogs, some are genetically determined. The dem-
be obtained by this means, and may be used, for example, to onstration that some congenital heart diseases are genetically
monitor the cardiotoxic effects of anthracycline therapy. determined arose from the observation that the incidence of
defects was higher in purebred populations. It has been
thought that both patent ductus arteriosus (PDA) and
Further reading conotruncal defects have a polygenic inheritance pattern,
Abel ED, Doenst T. Mitochondrial adaptations to physiological versus where the full expression of these diseases depends on the
pathological hypertrophy. Cardiovasc Res 2011;90:234-242. inheritance of a number of genes from different loci. However,
Bernardo B, et al. Molecular distinction between physiological and studies on Keeshonds with conotruncal defects indicate that
pathological cardiac hypertrophy: experimental findings and thera- the inheritance pattern is most compatible with a single auto-
peutic strategies. Pharmacol Ther 2010;128:191-227. somal locus. The data suggest the presence of a mutant allele
Bourlaug BA, Redfield MM. Are systolic and diastolic heart failure that is partially penetrant in heterozygotes and fully penetrant
overlapping or distinct phenotypes within the heart failure spec- in homozygotes. Congenital subaortic stenosis in the New-
trum? Circulation 2011;123:2006-2014. foundland dog is also genetically determined; it may either be
Falk T, et al. Associations between cardiac pathology and clinical, echo- polygenic or a single dominant gene that is variably expressed.
cardiographic and electrocardiographic findings in dogs with con- Table 1-3 outlines the breed-specific predisposition to con-
gestive heart failure. Vet J 2010;185:68-74. genital heart disease in the dog.
14.e1
Further reading
Adams JW, et al. Enhanced Gαq signaling: a common pathway medi-
ates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad
Sci U S A 1998;95:10140-10145.
Brand T, et al. Expression of nuclear proto-oncogenes in isoproterenol-
induced cardiac hypertrophy. J Mol Cell Cardiol 1993;25:1325-
1337.
Edwards WD. Cardiovascular system. In: Ludwig J, editor. Handbook
of Autopsy Practice. 3rd ed. New Jersey: Humana Press; 2002.
p. 21-43.
Gerdes AM, Capasso JM. Structural remodeling and mechanical dys-
function of cardiac myocytes in heart failure. J Mol Cell Cardiol
1995;27:849-856.
Hardt SE, Sadoshima J. Negative regulators of cardiac hypertrophy.
Cardiovasc Res 2004;63:500-509.
Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008;358:1370-
1380.
Horban A, et al. Correlation between function and proto-oncogene
expression in isolated working rat hearts under various overload
conditions. J Mol Cell Cardiol 1997;29:2903-2914.
Keene BW, et al. Modified transvenous endomyocardial biopsy tech-
nique in dogs. Am J Vet Res 1990;51:1769-1772.
Matsuo T, et al. Mechanisms of cardiac hypertrophy in canine volume
overload. Am J Physiol 1998;275:H65-H74.
McMullen JR, et al. Phosphoinositide 3-kinase (p110α) plays a critical
role for the induction of physiological, but not pathological, cardiac
hypertrophy. Proc Natl Acad Sci U S A 2003;100:12355-12360.
Miller PJ, Holmes JR. Observations on structure and functions of the
equine mitral valve. Equine Vet J 1984;16:457-460.
Parmley WW. Neuroendocrine changes in heart failure and their clinical
relevance. Clin Cardiol 1995;18:440-445.
Sheaff MT, Hopster DJ. Post Mortem Technique Handbook. London:
Springer; 2001. p. 87-116.
Sugden PH, Clerk A. Cellular mechanisms of cardiac hypertrophy. J Mol
Med 1998;76:725-746.
Takemura N, et al. Atrial natriuretic peptide in the dog with mitral
regurgitation. Res Vet Sci 1991;50:86-88.
Tamamori M, et al. Endotheün-3 induces hypertrophy of cardiomyo-
cytes by the endogenous endothelin-1-mediated mechanism. J Clin
Invest 1996;97:366-372.
Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992;327:94-
98.
Yamazaki T, et al. Molecular mechanism of cardiac cellular hypertrophy
by mechanical stress. J Mol Cell Cardiol 1995;27:133-140.
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 15
Table • 1-3
Breed-specific predispositions to congenital heart disease in dogs
Defect Breed
Patent ductus arteriosus Bichon Frise, Chihuahua, Cocker Spaniel, Collie, English Springer Spaniel, German Shepherd, Keeshond,
Kerry Blue Terrier, Maltese Terrier, Pomeranian, Poodle, Shetland Sheepdog, Yorkshire Terrier
Pulmonic stenosis Airedale Terrier, Beagle, Chihuahua, English Bulldog, Fox Terrier, Mastiff, Miniature Schnauzer,
Samoyed, Scottish Terrier, West Highland White Terrier
Subaortic stenosis Boxer, English Bulldog, German Shepherd, German Shorthaired Pointer, Golden Retriever, Great
Dane, Newfoundland, Rottweiler, Samoyed
Persistent right aortic arch German Shepherd, Great Dane, Irish Setter
Tetralogy of Fallot English Bulldog, Keeshond
Atrial septal defect Doberman Pinscher, Samoyed
Ventricular septal defect English Bulldog
Tricuspid insufficiency or dysplasia German Shepherd, Golden Retriever, Great Dane, Labrador Retriever, Weimaraner
Mitral insufficiency or dysplasia Bull Terrier English Bulldog, Chihuahua, German Shepherd, Great Dane
Table • 1-4
Proportions (%) of canine congenital cardiac anomalies in 4 surveys
Patterson Mulvihill, Priester Hunt et al. Tidholm
Anomaly* (1953-1965), n = 248 (1964-1971), n = 700 (1977-1989), n = 100 (1989-1996), n = 151
In humans, increasing attention has been focused on muta- The pattern and incidence of congenital cardiac disease varies
tions in transcription modulators, signal transduction, and with the species examined. In dogs, PDA, pulmonic stenosis,
structural protein genes as causes of inherited congenital and subaortic stenosis are common (Table 1-4). In cattle, atrial
heart disease. This includes the transcription factors Nkx2-5, and ventricular septal defects (VSDs) and transpositions of
GATA4, and TBX-5, and the NOTCH pathway genes the main vessels are most frequently diagnosed. Subaortic
JAGGED1, NOTCH1, and NOTCH2. The NOTCH pathway stenosis and endocardial cushion defects are the most frequent
genes have been associated with valvular defects and tetralogy anomalies in pigs. In cats, endocardial cushion defects and
of Fallot. Further insights into the normal and abnormal devel- congenital left AV valve insufficiency appear to be common.
opment of the heart and great vessels have come from the Congenital cardiovascular disease is quite uncommon in
effects of targeted gene mutations and deletions using the horses.
zebrafish, Danio rerio, as an experimental model. In cases of suspected cardiac abnormality, it is essential to
There may be other as yet undefined factors that contrib- examine the heart and large vessels in situ because relations
ute to the development of congenital heart disease in domestic are difficult to trace once the organ is removed. Some animals
animals. In humans, cardiac and vascular anomalies are are born with hearts that, although of normal arrangement,
common features of several syndromes produced by chromo- are very small. In the majority of cases of cardiac abnormality,
somal abnormalities and viral infections such as rubella. There the anomaly is reflected in gross enlargement of the organ and
is little evidence to suggest the presence of similar abnormali- in alteration of the size or disposition of the large vessels.
ties or infections associated with congenital heart disease in Cardiac malformations are extremely variable, and their analy-
domestic animals. sis can be perplexing if it is not remembered that they do
16 CHAPTER 1 • Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels
follow fairly simple basic patterns. The recognition of the The consequence of an ASD in the neonate is excessive flow
primary abnormality is an essential first step. This then assists from the left to right atrium, with resultant volume overload on
in the recognition of secondary abnormalities, which develop the right ventricle and elevated central venous pressure (Figs.
as adjustments to allow blood to circulate through the heart. 1-10, 1-11). In some cases, following the development of
An understanding of the mechanics of abnormal development pulmonary hypertension, the flow through the defect is
is necessarily based on an understanding of the normal devel- reversed, leading to cyanosis.
opment of the organ, for which reference should be made to
a standard text of embryology. Aorta
There is no completely satisfactory system for classifying
congenital heart defects, as they may be complex or may
Cranial vena cava PA
overlap as part of a spectrum. Based on a combination of ana-
tomic defects and functional effects, they may be classified as
PV
• Malformations causing systemic to pulmonary (left-to-
right) shunting PV
• Malformations of cardiac valves RA
• Transposition complexes LA
• Miscellaneous cardiac anomalies
• Vascular anomalies Caudal
vena cava
Malformations causing systemic to pulmonary
(left-to-right) shunting
In the development of the heart, there are 3 major arteriove-
nous communications: between the atria, the ventricles, and RV
LV
the great vessels. These connections are necessary for shunting
of blood in the fetus. The atrial and ventricular septa close in
utero; the foramen ovale and the ductus arteriosus close early
in the neonatal period. Failure of closure results in atrial septal
defect (ASD), VSD, or PDA, 3 of the more common congenital
cardiac defects in domestic animals. Less common defects in Figure 1-10 Atrial septal defect (ASD). An ASD usually results
this group include AV septal defect, persistent truncus arteriosus, in increased blood flow from the left (LA) to the right (RA)
aorticopulmonary window, and anomalous pulmonary venous atrium. The right ventricle (RV) dilates under this increased
return. volume load. Also, a mild increase in afterload develops from the
increased volume load within the right ventricle. LV, left ventricle;
Atrial septal defect PA, pulmonary artery; PV, pulmonary vein. (Modified from Rob-
In the fetus, separation of the left and right atria commences inson WF, Huxtable CRR, eds. Clinicopathologic Principles for
with the downgrowth of the septum primum, which grows Veterinary Medicine. Cambridge, UK: Cambridge University
toward the AV junction, where the developing endocardial Press, 1988. Reprinted with permission.)
cushions begin to form the AV valves and separate the ven-
tricles. The septum fuses with the endocardial cushions, oblit-
erating the ostium primum, and then begins to fenestrate in its
middle. The fenestration is destined to become the ostium
secundum. A second septum (septum secundum) develops
downward and to the right of the septum primum. With its
semilunar edge, the septum secundum and the remains of the
septum primum form the foramen ovale. Within the left
atrium, the septum primum forms the flap valve of the
foramen ovale that allows blood flow from right atrium to left
atrium in the fetus. In the majority of animals, anatomic
closure of the foramen ovale follows functional closure post-
natally. A probe-patent foramen ovale postnatally is not an ASD, *
for although the foramen ovale may not be anatomically
closed, it is functionally closed (valvular competent) because
left atrial pressure exceeds right atrial pressure.
An ASD can result from
• Defects of the septum between the right upper pulmonary
veins and the cranial vena cava (sinus venosus defect)
• Failure of fusion of septum primum with the endocardial
cushions (ostium primum defect, low in the atrial septum
adjacent to the AV valves, a form of AV septal defect)
• An excessively large ostium secundum or inadequate
development of the septum secundum (ostium secundum Figure 1-11 Atrial septal defect (arrow) in a 3-week-old lamb. A
defect, in mid-septum at the site of the fossa ovalis, the high ventricular septal defect is also evident (asterisk). (Courtesy
most common type) M.J.M. Sula.)
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 17
A B
Figure 1-12 Ventricular septal defect. A. High ventricular septal defect (arrow) in a dog, involving
the pars membranacea. The chamber of the left ventricle is enlarged (volume overload) and is
accompanied by mild subendocardial fibrosis following chronic dilation. (Courtesy D. Hayden.)
B. Large ventricular septal defect of the muscular part of the interventricular septum in a calf.
Atrioventricular (AV) septal defect 1-12B). Although occurring most commonly as an isolated
Also known as endocardial cushion defects or AV canal defects, defect, VSD is also seen as part of a number of other defects,
these malformations arise from deficiency of the AV septum such as tetralogy of Fallot or persistent truncus arteriosus.
that separates the left ventricular inlet from the right atrium. There appears to be a high incidence of spontaneous postnatal
The atrial septum primum must fuse with the endocardial closure of small VSDs in humans, and a similar phenomenon
cushions, which in turn contribute to the development of the has been reported in dogs.
atrial and ventricular septa, and to the medial leaflets of the The presence of a VSD has no deleterious effect on the
left and right AV valves. Anomalous development may result fetus because left and right ventricular pressures are equal,
in a range of anatomic defects, including ostium primum defect and there is therefore little flow across the defect. Postnatally,
(partial AV canal), VSD with a cleft in the right AV valve, or the effects of VSDs are related to the size of the defect and the
common AV canal. The common or complete AV septal defect level of pulmonic vascular resistance relative to the systemic resis-
consists of an ostium primum defect, a VSD, and a common tance. Pulmonary vascular resistance normally drops postna-
AV orifice. tally, leading to a left-to-right shunt. Left ventricular output is
Defects of the AV canal are among the most common defects maintained by an increase in end-diastolic volume and aug-
in the pig. In the largest series examined, 40% of pigs with mentation of contractility by the Frank-Starling mechanism.
congenital heart disease had this defect. It is also a frequent Because right ventricular pressure equals left ventricular pres-
finding in cats. sure, the right ventricle is confronted with a large systolic and
diastolic load. Both ventricles undergo hypertrophy, the left
Ventricular septal defect being more obviously eccentric in nature (Fig. 1-13).
Ventricular septal defect is one of the most common defects Eventually, pulmonary hypertension can lead to shunt
encountered in domestic animals. The separation of the left and reversal (right-to-left), cyanosis, and death. The term Eisen-
right ventricles is completed by 3 parts of the embryonic menger complex is applied to VSD cases in which, instead
heart: the muscular portion of the septum, the downward of the usual left-to-right shunt, flow has been reversed to a
growth of the conotruncal ridges, and the membranous portion right-to-left shunt through the VSD as a consequence of
of the septum derived from the endocardial cushions. Defects severe pulmonary hypertension that is, in turn, due to high
can be related to defective development of any of the 3 parts. pulmonary vascular resistance. The more general term
VSDs are usually single but may be multiple, and most com- of Eisenmenger syndrome is applied to any anomalous
monly involve the membranous septum (Fig. 1-12A). This type circulatory communication (e.g., ASD, VSD, PDA) that leads
of VSD is termed paramembranous or perimembranous, as they to obliterative pulmonary vascular disease, with resulting
exceed the bounds of the membranous septum and involve a reversal of the left-to-right shunt across the pulmonary-
muscular defect at their periphery; they may also be referred systemic communication.
to as subaortic or infracristal. Less common sites of VSD are
subpulmonary (infundibular, conal, supracristal), below the Patent ductus arteriosus
septal leaflet of the right AV valve, or in the muscular portion of Patent ductus arteriosus (PDA) is one of the more common
the ventricular septum toward the apex of the heart (Fig. defects, and it is recorded in all species (Fig. 1-14). In the dog
18 CHAPTER 1 • Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels
Aorta
PDA
Cranial vena cava
PV
PV
RA
PA LA Left atrial
dilation
Caudal
vena cava
Increased RV
afterload LV Figure 1-16 Pulmonic stenosis in a dog. The pulmonary artery
has been opened showing the poststenotic dilation and the thick-
ened, distorted pulmonary valves fixed in a closed position.
(Courtesy A. G. Armien.)
Increased
preload
Aorta
Figure 1-15 Patent ductus arteriosus (PDA). In most cases,
blood flow through a PDA occurs during both systole and diastole
from the aorta into the pulmonary artery. The right ventricle Cranial vena cava PA
hypertrophies concentrically because of the increased afterload
(pulmonary arterial hypertension). The left atrium and ventricle PV
hypertrophy eccentrically because of the increased preload
(increased volume of blood returning from the pulmonary circuit). PV
For abbreviations, see Figure 1-10. (Modified from Robinson WF,
RA
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary LA
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.) Caudal
vena cava
Malformation of semilunar or
atrioventricular valves
Failure of adequate development of the semilunar valves
RV
usually results in valvular or subvalvular stenosis. Anomalous LV
AV valves may be insufficient or stenotic or both.
Pulmonic stenosis
Pulmonic stenosis is a relatively common congenital anomaly in
dogs, but an unusual finding in other domestic species. It is
inherited in Beagles, and is suspected to be so in English Bull- Figure 1-17 Pulmonic stenosis is usually valvular and places an
dogs, Bull Mastiffs, Chihuahuas, and terrier types. The term increased afterload on the right ventricle which undergoes con-
pulmonic stenosis encompasses 3 anatomic variations: supraval- centric hypertrophy. There is poststenotic dilation of the pulmo-
vular, valvular, and subvalvular or infundibular stenosis. Valvu- nary artery. For abbreviations, see Figure 1-10. (Modified from
lar stenosis, the most common form in dogs, is probably due Robinson WF, Huxtable CRR, eds. Clinicopathologic Principles
to disordered fusion of the valve cushions and their failure to for Veterinary Medicine. Cambridge, UK: Cambridge University
hollow out properly. The valve, which is then more or less Press, 1988. Reprinted with permission.)
dome shaped with an irregular central perforation, is sur-
rounded by 3 recognizable sinuses of Valsalva that are small
and irregular in form (Fig. 1-16). Subvalvular or infundibular hypertrophy is always present because of the increased afterload
stenosis is produced by a ring of connective tissue that encir- placed on the right ventricle (Fig. 1-17).
cles the upper portion of the outflow tract of the right ven- In English Bulldogs, the breed most commonly affected by
tricle, or by hypertrophy of the crista supraventricularis pulmonic stenosis, the stenosis is frequently caused by a cir-
muscle ridge. With each form, the pulmonary trunk is dilated cumpulmonary left coronary artery that originates from a single
and thin walled. This is probably due to a combination of right coronary artery. The cause of this syndrome appears to
turbulent flow and a drop in pressure, creating a venturi be malformation of the left aortic sinus of Valsalva and inver-
effect in the pulmonary artery. Concentric right ventricular sion of the proximal segment of the left main coronary artery.
20 CHAPTER 1 • Cardiovascular System Congenital Abnormalities of the Heart and Large Vessels
Aorta
PA
Aorta
RV
tal
LV ep
l a rs
t
icu ec
e ntr def
V
A
B
Aorta PA
LV
RV
C
Figure 1-18 Tetralogy of Fallot. A. Over-riding aorta and right ventricular hypertrophy can be
seen. B. High ventricular septal defect and over-riding aorta evident. C. Pulmonic stenosis and
right ventricular hypertrophy are evident. (Arrows—red for left side and blue for right side—on
white plastic tubes show direction of blood flow). LV, left ventricle; PA, pulmonary artery;
RV, right ventricle. (Courtesy V. Psychas.)
Tetralogy of Fallot dextroposed aorta does not depend on the degree of overrid-
The primary lesion in tetralogy of Fallot is obstruction to right ing, but on the severity of the pulmonic stenosis (Fig. 1-19).
ventricular outflow, either through pulmonic stenosis or infun-
dibular stenosis that results from abnormal conotruncal par- Aortic and subaortic stenosis
titioning. The other lesions in the tetrad are ventricular septal Isolated congenital aortic valvular stenosis is distinctly uncom-
defect (VSD), overriding aorta, and secondary right ventricular mon. Subvalvular aortic (subaortic) stenosis is, in contrast, a
hypertrophy (Fig. 1-18A-C). Tetralogy is one of the congenital common defect in pigs and often occurs in conjunction with
heart diseases that invariably results in clinical signs. Affected what has been termed endocardiosis of the left AV valve. In one
animals fatigue easily and are usually cyanotic and polycythemic. study of 321 pigs that had left AV valvular abnormalities
The latter is a response to hypoxia. Growth rate is usually (endocardiosis), 258 had accompanying subaortic stenosis.
retarded. At least in Keeshonds, the condition is inherited as a Subaortic stenosis is among the more frequently encountered
defect at a single autosomal locus, in which there is partial anomalies in dogs, and often occurs in association with left
penetrance in heterozygotes and complete penetrance in AV valvular disease. Dog breeds commonly affected include
homozygotes. Analysis of affected Keeshonds has revealed the German Shepherd dog, Weimaraner, Golden Retriever,
various grades of malformation. The spectrum of anomalies German Shorthaired Pointer, Saint Bernard, Newfoundland,
included subclinical defects of the crista supraventricularis, Dogue de Bordeaux, and English Bull Terrier.
VSD, pulmonic stenosis with abnormal nonpatent interven- The anatomic appearance of the subvalvular lesion ranges
tricular septum, and tetralogy of Fallot. Closure of the inter- from a number of small fibrous plaques on the endocardial
ventricular septum is contributed to by the conotruncal surface of the left ventricular outflow tract on the interven-
septum. The flow of blood from the right ventricle into the tricular septal aspect, to a completely encircling fibrous band
Diseases of the Heart Congenital Abnormalities of the Heart and Large Vessels 21
Aorta Aorta
PA PA
Cranial vena cava Cranial vena cava
PV PV
PV PV
RA RA
LA
LA
Caudal Caudal
vena cava vena cava
RV RV LV
LV
Figure 1-19 Tetralogy of Fallot. The severity of the pulmonic Figure 1-21 Aortic and subaortic stenosis place an increased
stenosis determines the predominant direction of flow. If severe afterload on the left ventricle, which hypertrophies concentrically.
pulmonic stenosis is present, the flow is into the aorta via the There is poststenotic dilation of the aorta. For abbreviations
ventricular septal defect. The right ventricle hypertrophies con- see Figure 1-10. (Modified from Robinson WF, Huxtable CRR,
centrically because of the increased afterload placed on it. For eds. Clinicopathologic Principles for Veterinary Medicine.
abbreviations see Figure 1-10. (Modified from Robinson WF, Cambridge, UK: Cambridge University Press, 1988. Reprinted
Huxtable CRR, eds. Clinicopathologic Principles for Veterinary with permission.)
Medicine. Cambridge, UK: Cambridge University Press, 1988.
Reprinted with permission.)
the affected valve with the ventricular wall. In right AV dys- process, termed valvular telangiectasis in the septal cusp of the
plasia, the valve is insufficient, the right atrium is enlarged, and right AV valve in Beagles, has been reported to progress from
the right ventricle is eccentrically hypertrophied. The anomaly telangiectasis through scarring and osseous metaplasia.
may be associated with malformation of the left AV valve Primary endocardial fibroelastosis is characterized by
complex or VSD. In Ebstein’s anomaly of the right AV valve, diffuse endocardial thickening by collagen and elastic fibers,
there is downward displacement of the basal portions of the and left ventricular hypertrophy and dilation in the absence
valve into the right ventricle. The morphologically similar of any associated cardiac malformation. The fact that diffuse
canine right AV valve malformation has been mapped to a endocardial thickening occurs when any chamber of the heart
susceptibility locus on chromosome 9 in several kindreds of remains dilated for a prolonged period has probably led to the
purebred Labrador Retriever dogs. Right AV atresia—absence confusion that exists about endocardial fibroelastosis. There
of the right AV orifice—is accompanied by an interatrial com- have been reports in the literature describing the existence of
munication, right ventricular hypoplasia, and usually a VSD. this condition in a number of species, but the primary disease
has only been well documented in cats and, to a lesser extent,
Left atrioventricular valvular insufficiency or stenosis dogs. The disease in affected Burmese kittens commences with
A mixed-frequency holosystolic murmur, with its point of localized endocardial lymphedema. This is detectable micro-
maximum intensity on the left caudal sternal border, is indica- scopically, but not grossly, at 1 day of age. Progressive deposi-
tive of left AV valve insufficiency. Commonly heard in old tion of endocardial collagen and elastin follows and allows
dogs with endocardiosis, it may also be associated with moder- macroscopic detection from 20 days of age. The left atrium is
ate to severe left-sided failure in young dogs and cats. Malfor- dilated, and the left ventricle is hypertrophied and dilated.
mation of the left AV valve complex is probably the most common The endocardial fibrosis progressively involves cardiac con-
congenital cardiac anomaly in the cat. The lesion has a relatively ducting fibers, which exhibit some degenerative change.
wide spectrum of severity, and may result in either an insuffi- Although not definitely established, there appears to be little
cient or a stenotic valve. Anatomically, there is an enlarged doubt of the inherited nature of the disease.
annulus, short thick leaflets, short thickened chordae tendin- False tendons are thin, often branching, structures that
eae, upward malposition of atrophic or hypertrophic papillary traverse the cavity of the left ventricle and are not connected
muscles, and enlargement of the left atrium and ventricle. to the valve cusps; they are common in domestic mammals.
There is also diffuse endocardial fibrosis. In dogs, the lesion They are composed of cardiac muscle, blood vessels, fibrous
has been most commonly seen in Cavalier King Charles tissue, and Purkinje cells. False tendons are of debatable sig-
Spaniels, Great Danes, English Bull Terriers, and, to a lesser nificance, but may play a role in innocent murmurs and
extent, German Shepherd dogs. cardiac dysrhythmia.
Cor triatriatum (triple atria) is a rare lesion in cats and dogs
Transposition complexes resulting from failure of incorporation of the common pulmo-
Some of the more severe cardiac anomalies are a combination nary vein into the left atrium. A membrane separates the left
of defects of the aorta and pulmonary artery. Malposition or atrium into 2 compartments, which can impede pulmonary
transposition of arterial trunks is a condition in which the drainage and lead to pulmonary edema. Cor triatriatum dexter
aorta lies in relation to the pulmonary artery such that it (right atrium) can cause ascites.
receives blood from the right ventricle, the basic defect being Epithelial inclusions are found occasionally in ventricular
dextroposition of the aorta. There are 4 degrees, or types, of this myocardium in well-defined areas of discoloration or spongi-
anomaly: ness. The inclusions are present as acinar or ductular structures
• Overriding aorta—(the most common type), the aorta lined by a simple layer of cuboidal epithelial cells on a base-
straddles the interventricular septum, which is defective, ment membrane. The inclusions are possibly of endodermal
and receives blood from both ventricles, and the pulmo- origin from the foregut and represent displacements arising
nary artery leaves the right ventricle; very early in embryogenesis, when the heart rudiment is adja-
• Partial transposition—both vessels leave the right ventricle; cent to the developing foregut.
• Overriding pulmonary artery—the pulmonary artery strad- Myocardial bridges are anatomic variants that are superfi-
dles a defective ventricular septum and the aorta emerges cial myocardial bands that run across short segments of a
from the right ventricle; coronary artery located epicardially in the dog, cat, goat,
• Complete transposition—the aorta emerges from the right sheep, and human. The bridges appear to be of little functional
ventricle and the pulmonary artery emerges from the left significance.
(eFig. 1-5). Congenital absence of the pericardium occurs in dogs.
It is usual in these transposition complexes for either the Affected animals are usually asymptomatic.
pulmonary artery or the aorta to be hypoplastic. Double-chambered right ventricle is a rare cardiac anomaly
in cats and dogs.
Miscellaneous cardiac anomalies Variations in the position of the heart are not cardiac mal-
Congenital hematomas (hemocysts) on the margins of the AV formations but, instead, malformations of adjacent structures:
valves are common, especially in calves, but appear to be of little • In ectopia cordis, the heart may lie in extrathoracic, prester-
consequence. These are usually blood-filled cysts lined by nal, or intra-abdominal positions (Fig. 1-22). Dislocations
endothelium; they originate in the clefts normally present in within the thorax are the result of asymmetrical pressure,
the substance of the valves in intrauterine life. The cysts may as for example, in congenital diaphragmatic hernia or
measure up to 1.0 cm in diameter and be multiple. There is pleural effusion.
some question as to whether the cysts involute within a few • In peritoneopericardial diaphragmatic hernia, which
months of birth, or whether they persist for a year or more, occurs in dogs and cats, intestine and/or liver are present
by which time the content is changed to serous fluid. A similar in the pericardial sac.
22.e1
from the ascending aorta. The right arch, which is usually the
larger of the 2, follows the course given above. It is joined
above the esophagus by the small left arch. The significant end
result is constriction of the esophagus.
Aorticopulmonary septal defect, or window, is a rare defect
in dogs that results from incomplete division of the truncus
arteriosus. Pulmonary hypertension develops, leading to right-
to-left shunting of blood.
Coarctation of the aorta is another rare defect in dogs, and
is seen as narrowing of the aorta adjacent to the ductus
arteriosus/ligamentum arteriosum. Left ventricular pressure
overload can result in left heart failure. Additional malforma-
Figure 1-23 The persistent right aortic arch traverses the esopha-
tions of the aorta reported in dogs include interruption of the
gus and the trachea, resulting in marked dilation of the esophagus
aorta and tubular hypoplasia of the ascending aorta (Fig. 1-24).
cranial to the persistent arch. (Courtesy P. Nation.)
Congenital aneurysm of the aorta or of the pulmonary
artery, involves, for either vessel, the trunk and arch, but may
• Dextrocardia is a rare condition in dogs in which the apex not extend beyond the insertion of the ligamentum arterio-
of the heart, which normally points to the left (levocardia), sum. Aortic aneurysm may be associated with aneurysm of
points to the right. Dextrocardia may be part of situs inver- one or more of the aortic sinuses of Valsalva.
sus, in which the heart and other internal organs are trans-
posed in a mirror-image fashion. Kartagener’s syndrome, a
rare condition in dogs, includes dextrocardia, sinusitis, and Further reading
bronchiectasis, the last 2 features as a result of ciliary Bakkers J. Zebrafish as a model to study cardiac development and
dyskinesia. human cardiac disease. Cardiovasc Res 2011;93:279-288.
Buchanan JW, Patterson DF. Etiology of patent ductus arteriosus in
Vascular anomalies dogs. J Vet Intern Med 2003;17:167-171.
Persistence of the right aortic arch is a well-known anomaly Campbell FE, Thomas WP. Congenital supravalvular mitral stenosis in
in dogs and has been observed in cattle. It is due to persistence 14 cats. J Vet Cardiol 2012;14:281-292.
of the right fourth aortic arch instead of, as is normal, the left Clark KL, et al. Transcription factors and congenital heart defects. Ann
fourth aortic arch. A right aorta descends to the right of the Rev Physiol 2006;68:97-121.
midline, arches over the origin of the right bronchus, and French AT, et al. Genome-wide analysis of mitral valve disease in cava-
descends either to the left or right of the vertebral column. lier King Charles spaniels. Vet J 2012;193:283-286.
With the aorta in this position, the ductus arteriosus (ligamen- Fukushima R, et al. Epidemiological and morphological studies of
tum arteriosum), passing from the aorta to the pulmonary double-chambered right ventricle in dogs. J Vet Med Sci
artery, encloses the esophagus and compresses it against the 2011;73:1287-1293.
trachea. Obstruction of the esophagus at this point leads to Granados-Riveron JT, et al. Combined mutation screening of NKX2-5,
dysphagia and, shortly, to dilation of the cervical portion of GATA4, and TBX5 in congenital heart disease: multiple heterozy-
the esophagus (Fig. 1-23). gosity and novel mutations. Congenit Heart Dis 2012;7:151-159.
A double aortic arch is a variation of the foregoing in Hall TL, et al. Congential cardiac defects in neonatal foals: 18 cases
which the left arch persists as well as the right. Both arches arise (1992-2007). J Vet Intern Med 2010;24:206-212.
23.e1
Matic SE. Congenital heart disease in the dog. J Small Anim Pract
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1999. p. 457-470. onic development: studies in the CTD line of keeshond dogs. Am
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Deutsch Tierarzt Wochen 1993;100:443-445. aorta and ventricular septal defect in three Arabian foals. Vet Pathol
Guglielmini C, et al. Atrial septal defect in five dogs. J Small Anim Pract 1982;19:160-168.
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Hsu FS, Du SJ. Congenital heart diseases in swine. Vet Pathol
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24 CHAPTER 1 • Cardiovascular System Pericardial Disease
Further reading
Aronsohn MG, Carpenter JL. Surgical treatment of idiopathic pericar-
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Bouvy BM, Bjorling DE. Pericardial effusion in dogs and cats: 1. Normal
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Bradley GA, et al. Hemopericardium in a dog due to hemorrhage
originating in a heart base thymic remnant. J Vet Diagn Invest
1992;4:211-212.
Gwatkin R, Moynihan W. Valvular lesion in swine: rupture of heart in
two cases. Can J Comp Med Vet Sci 1942;6:213-214.
Mansfield CS, et al. Intra-atrial rhabdomyoma causing chylopericar-
dium and right-sided congestive heart failure in a dog. Vet Rec
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Mesfin GM. Spontaneous epicardial fibrous fronds on the atria of
Beagle dogs. Vet Pathol 1990;27:458-461.
Petrus DJ, Henik RA. Pericardial effusion and cardiac tamponade sec-
ondary to brodifacoum toxicosis in a dog. J Am Vet Med Assoc
1999;215:647-648.
26 CHAPTER 1 • Cardiovascular System Pericardial Disease
pneumonia (infection with Mycoplasma hyopneumoniae and organization and scarring will result in focal or diffuse fibrous
other agents), and is occasionally observed in salmonellosis adhesions between the pericardial surfaces, with partial or
and in streptococcal infection of piglets. Fibrinous pericarditis complete obliteration of the sac.
in adult sheep is usually part of pasteurellosis; in lambs, it is The residual lesions of fibrinous pericarditis occur as more
usually part of pasteurellosis or caused by streptococci. In or less distinct variants. Focal, patchy thickenings of the epi-
horses, Mycoplasma felis causes pericarditis and pleuritis; strep- cardium without adhesions form minimal residue and are
tococcal pericarditis may coexist with polyarthritis. Fibrinous usually more distinct on the ventricles than on the atria, where
pericarditis in horses may also be associated with the mare they may be obscured by normal fat. The original scar tissue
reproductive loss syndrome. Pericarditis is rare in cats, but it may undergo fatty metaplasia or be edematous. (The same
is seen as part of feline infectious peritonitis. lesion also occurs covering healed foci of superficial myocar-
In fibrinous pericarditis, there is seldom significant exuda- ditis.) Focal or diffuse adhesive pericarditis varies in extent
tion of fluid, so distension of the pericardial sac is not to be from a few “violin strings” across the sac to complete oblitera-
expected. The exudation of fibrin usually begins about the tion of the sac. Inclusion cysts lined by mesothelium are often
base of the heart and extends from there to cover, more or present in fibrous adhesions, and there tends to be excess fluid
less completely, both the pericardium and epicardium. The present in non-obliterated portions of the sac. The pericar-
fibrin is gray-white, but it may be flecked with blood, or dium is separable from the epicardium by blunt dissection. As
yellow if a large number of leukocytes are added to the the connective tissue is not dense, there is usually no embar-
exudate. Except for small pools of serum or serous exudate, rassment of cardiac function.
the pericardium and epicardium are in apposition. When the Purulent pericarditis almost invariably denotes the presence
leaves are drawn apart, the exudate is drawn out into villus- of pyogenic bacteria, either as primary pathogens or as oppor-
like projections to give an appearance responsible for the tunists in fibrinous pericarditis. It occurs almost solely in cattle
names “cor villosum,” “shaggy heart,” and “bread-and-butter as a result of traumatic perforation by a foreign body originat-
pericarditis” (Fig. 1-28). ing in the reticulum, but it is observed in cats and horses in
The completeness of resolution depends upon how quickly association with empyema (pyothorax). Migrating grass awns
the fibrinous exudate can be removed, which is a function of (“foxtail,” Hordeum glaucum, and H. leparinum) have been
the amount of fibrin, and how quickly the mesothelium can identified as causes of suppurative pericarditis in dogs in the
be regenerated, which is a function of the amount of meso- western United States.
thelium that has been destroyed. Restorative processes compete The suppurative pericardial fluid may appear as thin,
with the processes of organization. Within a week or so, there cloudy exudate; as frank, creamy pus; or as a mixture of pus
will be well-formed fibrous tissue in the deepest parts. Imme- and masses of fibrin. The color depends on the organisms
diately superficial to this, there will be young granulation present, but usually varies from yellow to green, being irregu-
tissue and then a stratum of fibroblasts mixed with leukocytes, larly dirty gray when putrefactive bacteria are present. The
and on the surface, there remains the fibrin clot infiltrated exudate is usually foul smelling. The volume of exudate varies
with numerous leukocytes. If the course is prolonged, from a thin layer on the serosal surface to 4 L or more. In the
early stages, it can be wiped or washed off to reveal the vas-
cular injection and granularity of the membranes. Soon, the
whole of the epicardium is covered with coagulum; the pari-
etal layer of the pericardium is less severely affected, and
separation of the 2 reveals a shaggy appearance of the heart
(cor villosum).
Microscopically, the subjacent tissues are densely infiltrated
with leukocytes, the reaction extending more deeply than in
fibrinous pericarditis, the formation of new blood vessels and
connective tissue is prominent, and the overlying coagulated
exudate is densely infiltrated with leukocytes.
Resolution probably never occurs. Because of the severity of
the inflammatory reaction, healing is by organization, as is
characteristic of all suppurative inflammations. Although the
course of suppurative pericarditis may be prolonged, the per-
sistence of the inciting agent, or more usually agents, prevents
complete organization.
Constrictive pericarditis resulting from progressive organi-
zation can be so severe and diffuse that it leads to impaired
diastolic filling and the development of right-sided heart
failure (Fig. 1-29). The adhesions cannot be broken down by
blunt dissection and may be mineralized. They obliterate the
pericardial cavity, but they may also extend beyond it to
involve the mediastinum. The heart, which is confined by scar
tissue, may be smaller than normal, or it may be greatly
enlarged and hypertrophic, especially when there are also
Figure 1-28 Fibrinous pericarditis in a foal. Greatly thickened extrapericardial adhesions present. There is always severe
pericardial sac and extensive fibrinous exudate loosely attached cardiac dysfunction, and death occurs from congestive heart
to the epicardium, accompanied by epicardial hemorrhage. failure.
Diseases of the Heart Endocardial Disease 27
Degenerative lesions
Further reading Myxomatous valvular degeneration
Bolin DC, et al. Microbiologic and pathologic findings in an epidemic (“endocardiosis”) in dogs
of equine pericarditis. J Vet Diagn Invest 2005;17:38-44. Myxomatous valvular degeneration, commonly termed endo-
Braun U. Traumatic pericarditis in cattle: clinical, radiographic and cardiosis, is the most common cardiovascular lesion in dogs. It is
ultrasonographic findings. Vet J 2009;182:176-186. a significant cause of clinically apparent left-sided heart failure,
Perkins SL, et al. Pericarditis and pleuritis caused by Corynebacterium but is also frequently encountered as an incidental finding at
pseudotuberculosis in a horse. J Am Vet Med Assoc 2004;224:1133- postmortem. Advanced endocardiosis of the left atrioventricu-
1138. lar (AV) (mitral) valve leads to mitral insufficiency and regur-
Shubitz LF, et al. Constrictive pericarditis secondary to Coccidioides gitant flow into the left atrium, noted clinically as a systolic
immitis infection in a dog. J Am Vet Med Assoc 2001;218: murmur, and culminates in left-sided heart failure. The
537-540. shrunken, distorted AV valves are seen with greatest frequency
Veloso GF, et al. Septic pericarditis and myocardial abscess in an English in toy, small, and medium breeds of dogs, especially in
Springer spaniel. J Vet Cardiol 2014;16:39-44. males of breeds such as the Poodle, Pomeranian, Schnauzer,
Chihuahua, Doberman Pinscher, Whippet, Fox Terrier, Boston
Terrier, Cavalier King Charles Spaniel, Dachshund, and the
English Cocker Spaniel. There are significant negative associa-
ENDOCARDIAL DISEASE
tions for the Labrador Retriever and the German Shepherd
The most clinically significant endocardial lesions affect the dog. The prevalence of the disease increases with age, from 5%
heart valves rather than the mural endocardium. Lesions may at <1 year of age to >75% at 16 years of age. Endocardiosis is
cause valvular stenosis, or valvular insufficiency, or both. Ste- also reported in the left AV valves of normal market-weight
nosis of a valve, or failure to open completely, impedes the forward pigs, but appears to be clinically inconsequential.
flow of blood. Valvular insufficiency, alternatively termed regur- Endocardiosis affects chiefly the left AV valve (Fig. 1-30A-C).
gitation, or incompetence results in reversed flow of blood. Valvu- The right AV valve is less severely and less frequently affected.
lar dysfunction may produce abnormal heart sounds that are The aortic and pulmonic semilunar cusps are only occasionally
detectable clinically as murmurs. The consequences of valvular involved. Grossly, the affected AV cusps are shortened and
disease depend upon the rapidity of onset, type, and duration thickened. The thickening of the leaflet may be more or less
of the lesion, and may be ameliorated by cardiac compensa- uniform with a rounded edge, or with prominent nodular
tory mechanisms. thickenings on the free margin. The valves are opaque and
The propensity of thrombi to form on the free margins of white, but the surface is smooth and glistening, without any evi-
valves is well known, but the factors leading to it are not. It dence of inflammation. The chordae tendineae may also be
may be related to the continual movement and the resulting thickened and occasionally are ruptured, allowing eversion of
apposition of the surfaces of the free margins of the valves. the leaflet into the atrium and leading to acute ventricular
There are also ill-defined factors, such as intercurrent disease failure. The left AV valvular annulus may be enlarged.
or increased workload, which promote the development of The least severe gross change consists of a few small, dis-
thrombi. The lack of an internal blood supply to the valve may crete nodules at the line of closure of the valve. These progress
also be a contributing factor, and in common with other vas- to multiple larger nodules that tend to coalesce in the area of
cular structures, injured endothelial cells release inflammatory contact. There may be irregular areas of opacity in the proxi-
mediators, such as prostaglandins, and other substances, such mal portions of the leaflet. The nodules may coalesce to form
as adenosine diphosphate, which are potent stimulators of plaque-like deformities in the area of cusp contact. The
platelet aggregation. Once the endothelium is removed, the chordae tendineae are thickened at their points of insertion
exposed collagen also stimulates the aggregation of platelets. into the valve, and there are clearly defined areas of opacity
The presence of the initial thrombus leads to further clotting. on the basal portions of the leaflet. The most severe change is
In contrast to cardiac myocytes, endothelial cells have a great characterized by a gross distortion of the valve by gray-white
capacity for regeneration and for covering any breach in their nodules and elevated plaques. The cusps are contracted,
27.e1
Further reading
Buttenschon J, et al. Microbiology and pathology of fibrinous pericar-
ditis in Danish slaughter pigs. J Vet Med A 1997;44:271-280.
Day MJ, Martin MW. Immunohistochemical characterisation of the
lesions of canine idiopathic pericarditis. J Small Anim Pract
2002;43:382-387.
Seahorn JL, et al. Case-control study of factors associated with fibrin-
ous pericarditis among horses in central Kentucky during spring
2001. J Am Vet Med Assoc 2003;223:832-838.
Stafford Johnson JM, et al. Septic fibrinous pericarditis in a cocker
spaniel. J Small Anim Pract 2003;44:117-120.
Wood JLN, Chanter N. Mycoplasma infections in horses: a fresh look
using modern methods may reveal an elusive “virus.” Equine Vet J
1996;28:177-179.
Worth LT, Reef VB. Pericarditis in horses: 18 cases (1986-1995). J Am
Vet Med Assoc 1998;212:248-253.
28 CHAPTER 1 • Cardiovascular System Endocardial Disease
C
Figure 1-30 Endocardiosis in a dog. A. Smooth, glistening, nodular thickening of the left atrio-
ventricular (AV) valve. The left atrium also shows the presence of “jet lesions,” which are irregular
raised areas of subendocardial fibrosis. B. Close-up endocardiosis left AV valve. Cusps are thickened
and shrunken. (Courtesy E. Olson.) C. Dilated left atrium resulting from volume overload of the
atrium. There are also tears of the atrial wall, which led to hemopericardium.
thickened, and irregular. There may also be fixed upward diffusely thickened by fibrosis following prolonged dilation.
displacement of the free margin of the valve. Enlargement and There may also be evidence of regurgitation in the form of
redundancy of the valve may be seen as doming or hooding focal elevated streaks and plaques of subendocardial fibrosis
of the body of the valve toward the atrium; this prolapse of in the atria (“jet lesions”). Left atrial tears may also be seen in
the body of the redundant left AV valve into the atrium advanced cases, and these tears may rupture and lead to hemo-
(“mitral valve prolapse”) may be seen both echocardiographi- pericardium. Mural thrombi can form in the dilated left
cally and at postmortem. Chordae tendineae may be ruptured, atrium; dislodgement of the thrombi can result in thrombo-
in which case the free edge of the valve may prolapse as a flail embolism, for instance, of coronary arteries leading to myo-
leaflet. Care should be taken in the assessment of the valves, cardial infarction.
because both the left and right AV valve leaflets thicken with Microscopically, the earliest changes are present on the
increasing age, and the free margin of the septal leaflet of the atrial side of the valves. There is proliferation of the endothe-
right AV valve is normally distinctly thicker than the free lium, increased numbers of subendothelial fibroblasts and
leaflets. macrophages, and splitting and separation of elastic fibers
Changes secondary to AV valvular insufficiency are dilation between the atrialis and spongiosa. However, it is the thickening
of the atria, particularly the left atrium, and dilation of the of the spongiosa and degeneration of the fibrosa that are the most
ventricles. The ventricles may be eccentrically hypertrophied. prominent features of endocardiosis. The spongiosa is greatly
The left atrial and ventricular subendocardium may be thickened by the proliferation of loose fibroblastic tissue and
Diseases of the Heart Endocardial Disease 29
A B
C
Figure 1-31 Microscopy of endocardiosis in a dog. A. Normal valve leaflet. H&E. (Courtesy C.
Foutz.) B. Affected leaflet. Myxomatous degeneration of the stratum spongiosum of the atrioven-
tricular valve. H&E. C. The increase in glycosaminoglycans in the affected valve leaflet is high-
lighted by staining with Alcian blue.
the deposition of the proteoglycans, hyaluronic acid, and ventricles themselves. This increased tensile strain leads to
chondroitin sulfate (Fig. 1-31A-C). In a few cases, amyloid increased serotonin levels in the valve itself, in turn activating
may be deposited. There is no increase in collagen or elastic the transforming growth factor-β (TGF-β) group of pro-
tissue in the spongiosa. The changes in the fibrosa are also teins. TGF-β proteins in turn promote the activation of
marked. Collagen bundles become swollen and hyalinized, myofibroblasts/mesenchymal cell phenotypes. Whether the
fragment, and disappear. In advanced cases, only scattered increased production of proteoglycans is initiated by the same
remnants of the fibrosa remain. Similar changes are seen in mechanism remains to be seen. Activation of matrix metal-
chordae tendineae. Intramural coronary arteriosclerosis and loproteinases also appears to contribute to the destruction of
focal myocardial necrosis and fibrosis are commonly seen in collagen and other fibrillar proteins in the valve.
the left ventricular myocardium, especially the papillary There is a striking similarity of endocardiosis to the pro-
muscle, if the ventricle is hypertrophic. lapsed mitral valve syndrome of humans, in which there is
The cause of endocardiosis is not known, but there is clearly deposition of glycosaminoglycans in the spongiosa secondary
a genetically influenced degeneration of connective tissue at its to an as yet undefined abnormality of collagen metabolism.
center. This suggestion is supported by the observation that the Mitral valve prolapse also occurs in humans in association
most frequently affected breeds are of the chondrodystro- with connective-tissue disorders, such as Marfan syndrome,
phoid type. Endocardiosis is inherited in Dachshunds and Ehlers-Danlos syndrome, osteogenesis imperfecta, and a
Cavalier King Charles Spaniels; a polygenic mode of inheri- variety of muscular dystrophies.
tance is suggested. Mitral insufficiency in the horse can result from endocardio-
Recent research suggests that alteration in tensile strain on sis, endocarditis, flail valve leaflets, rupture of chordae tendin-
the valves is involved in the initial phases of the disease. Given eae, and left AV valve prolapse. Clinical signs of exercise
the genetic nature in some breeds and the familial nature intolerance, poor performance, or congestive heart failure
in others, the origin of the increased tensile strain on the result. Dilation of the pulmonary artery may also ensue, indi-
valves may be the result of abnormal architecture of the AV cating pulmonary hypertension, and may presage pulmonary
valvular complex and possibly abnormal conformation of the artery rupture.
30 CHAPTER 1 • Cardiovascular System Endocardial Disease
Valvular cysts
Congenital hematomas (hemocysts) on the margins of the AV
valves are common, especially in calves (see previously, Mis-
cellaneous cardiac anomalies). Blood cysts and serous cysts have
been reported in the AV valves in 11% of the hearts in a series
of 30,000 slaughter cattle, with a higher incidence in cows
than calves. Blood-filled cysts were often present on both AV
valves, whereas serous cysts occurred more frequently on the
left AV valve. This suggests that cysts do not regress with age;
indeed their incidence and size may increase with age. The
endothelium lining the blood-filled cysts was positive for
factor VIII–related antigen. The cysts may represent ectasias
of blood vessels and lymphatics.
Subendocardial fibrosis
Subendocardial fibrosis may be diffuse or focal, congenital, or
acquired. The congenital lesions are discussed under Congeni-
tal abnormalities of the heart and large vessels. Diffuse suben-
docardial fibrosis is seen whenever a ventricle or atrium is dilated
for a prolonged period. It is probably best exemplified by the
dilated cardiomyopathy of large-breed dogs.
Subendocardial fibrosis in localized areas is observed
chiefly in the atria and is regarded as a reaction of the endo- Figure 1-32 Extensive subendocardial mineralization in the left
cardium to abnormal jets of blood or to turbulence following atrium and ventricle of a horse following ingestion of Solanum
congenital or acquired valvular disorders (see Fig. 1-30A). glaucophyllum (vitamin D analogue toxicosis). (Courtesy A. P.
They are loosely termed jet lesions, but are probably areas Loretti.)
subject to increased static pressure in turbulent flow.
Subendocardial mineralization Lacerda CM, et al. Static and cyclic tensile strain induce myxomatous
Subendocardial mineralization is associated with a variety of effector proteins and serotonin in canine mitral valves. J Vet Cardiol.
disorders. It occurs commonly in opaque plaques or as small 2012;14:223-230.
grains in the left atrium, and occasionally in the trunk of the Marcato PS, et al. Blood and serous cysts in the atrioventricular valves
aorta in dogs that have recovered from ulcerative endocarditis of the bovine heart. Vet Pathol 1996;33:14-21.
of renal insufficiency (see Mineralization, later). Prominent Orton EC, et al. Signaling pathways in mitral valve degeneration. J Vet
white plaques of mineralization also occur beneath the endo- Cardiol 2012;14:7-17.
cardium of the right ventricle in nutritional myopathy of lambs.
Subendocardial mineralization in the atria and left ventricle
may accompany endocardial fibrosis when these cavities are
Endocarditis
acutely dilated, either as congenital or acquired defects, and Endocarditis is one of the more significant of the endocardial
in a variety of prolonged debilitating diseases in cattle (Fig. 1-32). alterations. It is usually bacterial in cause, the exceptions being
Calcium and phosphorus are deposited in degenerate suben- occasional parasitic or mycotic lesions. Any portion of the
docardial muscle, but more commonly in fibroelastic tissue. endocardium may become inflamed, but the lesions are usually
The fibroelastic tissue is modified either by chronic disease primary on the valves, from which there may be some encroach-
or elevated serum levels of calcium and phosphorus, as in ment on the adjacent mural endocardium (Fig. 1-33A, B). The
vitamin D intoxication, or following the ingestion of plants left AV valve is most commonly affected in most species, fol-
containing vitamin D analogues (see Vol. 3, Endocrine glands). lowed by aortic, right AV valve, and pulmonic, except in cattle,
Proprietary rodenticides based on calciferols cause this lesion in which the right AV valve is more commonly affected.
in dogs. Many bacterial species are capable of causing acute valvu-
lar endocarditis, and the larger the number of cases examined,
the wider the variety of pathogens recognized. In cattle, True-
perella pyogenes is probably the most common pathogen, and
Further reading a primary focus of infection can often be found in some other
Aupperle H, et al. N-linked glycans of proteins from mitral valves of site, such as a traumatic peritoneal abscess, hepatic abscess,
normal pigs and pigs affected by endocardiosis. Eur J Biochem metritis, or mastitis. Streptococci of enteric origin are also of
2000;267:1299-1306. some importance in cattle, although the manner of their sys-
Aupperle H, et al. Immunohistochemical characterization of the extra- temic invasion is not clear. Erysipelothrix rhusiopathiae causes
cellular matrix in normal mitral valves and in chronic valve disease endocarditis in a variety of animals, most commonly in the
(endocardiosis) in dogs. Res Vet Sci 2009;87:277-283. pig; however, streptococci are more commonly isolated from
Disatian S, Orton EC. Autocrine serotonin and transforming growth cases of acute bacterial endocarditis of swine. Mature horses
factor beta 1 signaling mediates spontaneous myxomatous mitral seldom develop bacterial endocarditis, but the lesion has been
valve disease. J Heart Valve Dis 2009;18:44-51. observed in association with Streptococcus equi, Actinobacillus
Fox PR. Pathology of myxomatous mitral valve disease in the dog. J Vet equuli, Escherichia coli, Pseudomonas aeruginosa, and Candida
Cardiol. 2012;14:103-126. parapsilosis. A number of cases in horses have originated from
30.e1
Further reading
Aupperle H, et al. Expression of transforming growth factor-beta1,
-beta2 and -beta3 in normal and diseased canine mitral valves.
J Comp Pathol 2008;139:97-107.
Castagnaro M, et al. Morphological and biochemical investigations of
mitral valve endocardiosis in pigs. Res Vet Sci 1997;62:121-125.
Corcoran BM, et al. Identification of surface morphologic changes in
the mitral valve leaflets and chordae tendineae of dogs with myxo-
matous degeneration. Am J Vet Res 2004;65:198-206.
Gagna C, et al. Pathology of mitral valve in regularly slaughtered pigs:
an abattoir survey on the occurrence of myxoid degeneration
(endocardiosis), fibrosis and valvulitis. Zentralbl Veterinarmed A
1998;45:383-395.
Lester WM. Myxomatous mitral valve disease and related entities: the
role of matrix in valvular heart disease. Cardiovasc Pathol
1995;4:257-264.
McCarthy KP, et al. Anatomy of the mitral valve: understanding the
mitral valve complex in mitral regurgitation. Eur J Echocardiogr
2010;11:13-19.
Olsen LH, et al. Epidemiology and inheritance of mitral valve prolapse
in Dachshunds. J Vet Intern Med 1999;13:448-456.
Reef VB, et al. Severe mitral regurgitation in horses: clinical, echocar-
diographic, and pathological findings. Equine Vet J 1998;30:18-27.
Seki Y, et al. Transmural myocardial infarction caused by thromboem-
bolism associated with mitral insufficiency in a dog. J Vet Med Sci
1998;60:741-743.
Diseases of the Heart Endocardial Disease 31
A B
Figure 1-33 Endocarditis. A. Vegetative endocarditis of the right atrioventricular valve of a cow,
caused by Trueperella pyogenes. (Courtesy J. Schefers.) B. Ulcerative, destructive endocarditis of
the aortic valve of a dog. (Courtesy M. Bouljihad.)
Infectious in origin
Valvular
Sustained or intermittent Healing of the
endocarditis
lesion occurs from
Bacteremia/fungemia the base by fibrosis
Parasitic [rarely]
mastitis and enterotoxigenic coliforms in colibacillosis. There do not produce pulmonary infarcts in the absence of pre-
is also an immunologic cross-reaction between E. rhusiopath- existing pulmonary congestion. Emboli arising in the left heart
iae antigens and valvular and myocardial antigens. Various produce their most obvious effects in the kidney and spleen
Streptococcus spp. have been shown to adhere to exposed base- as septic or aseptic infarcts and embolic glomerulitis, and in
ment membrane of porcine valves. the myocardium as myocardial abscesses or interstitial myo-
The lesion of acute bacterial endocarditis is usually carditis. Arthritis is commonly observed in association with
observed as irregular vegetations on the affected valve. It is endocarditis in the dog. Cerebral embolism is rare in animals.
quite exceptional to find the earliest lesion, which consists of Unless the valvular lesions are very slight, there is, with
irregular ulcerations on the swollen leaflet. The composition of healing, some degree of permanent damage, especially if the
vegetations is similar to that of thrombi with, however, few inflammation is recurrent. Shrinkage or adhesion of leaflets
platelets. Numerous bacterial colonies are present in the vegeta- may cause narrowing of the orifice (stenosis), or insufficiency
tions, almost always in pure populations. It is wise to make as a result of failure of the distorted valves to close the orifice.
preliminary identification of the organisms by smears, because Stenosis and insufficiency may coexist. The usual outcome is
although they persist in colonies buried in the vegetations, congestive heart failure.
they may not be cultivable. With the current techniques of Mural endocarditis may be merely an extension to the
molecular biology, such as PCR, it should be possible to iden- walls of the cardiac chambers of a process originating on the
tify at least the genus of the noncultivable organisms embed- valves. This is almost invariably true of endocarditis caused by
ded in the thrombus. The bacteria that initiate the lesion are Trueperella pyogenes. Small foci of mural endocarditis may be
enmeshed in the early layers of thrombi and are buried deeply found adjacent to foci of myocarditis, especially myocardial
as new layers are formed on the surface. With continued abscesses. Right or biventricular thrombosis in alpacas has
multiplication, many microscopic colonies are formed, and been associated with mural endocarditis and inconsistent iso-
without appropriate antimicrobial treatment, it is their per- lation of a causative agent. This suggests the possibility of a
sistence in the protected environment that is the reason fastidious organism as the cause, such as Bartonella spp. or the
healed bacterial endocarditis is seldom seen. Even though the possibility of an underlying cardiomyopathy.
bacteria in the thrombi may lose their vitality, as indicated by Parasitic endocarditis caused by the larvae of Strongylus
lack of cultivability, they are persistently antigenic. vulgaris occurs in horses acutely in the form of vegetative
Grossly, the vegetations are yellow-red or yellow-gray and valvular endocarditis and chronically as caseous and calcare-
usually covered by a thin clot of blood, which can be easily ous nodules attached to the endocardium at various sites,
peeled off. The surface of the vegetation is friable, and small including the apex of the left ventricle and protruding into
vegetations can be easily removed to leave a granular, eroded the cavity. There is, in the same cases, parasitic aortitis of the
surface on the valve. The ulcerations are especially common bulb. With the advent of effective anthelmintics, parasitic
in the commissures and at the free margins of the valves, endocarditis in horses is rare.
imparting to them a rough, serrated appearance. The primary An acute form of ulcerative mural endocarditis occurs in
valvular lesion frequently extends to the adjacent mural endo- cattle dying from blackleg, as red thrombotic masses attached
cardium and, in the cases of aortic valvular endocarditis, to to the free wall of the right ventricle and, less often and less
the adjacent aortic intima in the sinuses of Valsalva, which extensively, on the right atrial and valvular endocardium.
may involve an orifice of a coronary artery, predisposing to Various unique intracardiac fistulae or shunts have been
myocardial embolism. Endocarditis of the AV valves tends to reported as sequelae to endocarditis in dogs, including exten-
spread along the chordae tendineae, causing some of them sion of aortic valvulitis into the right coronary artery and fis-
to rupture. Acute swelling and inflammatory change take tulation into the right atrium; perforation of the membranous
place in the substance of the valve itself, often with necrosis, interventricular septum, leading to a left ventricular outflow
which obscures the line of partition between the valve and its tract–right atrial shunt (Gerbode defect) in a dog with severe
surface vegetation. mural endocarditis caused by a Bordetella-like organism; and a
Organization of the thrombus proceeds from the base fistula between the left ventricular outflow tract and the left
by the usual process of granulation, which is likely to be atrium adjacent to the mitral valve annulus in a dog with
impeded or destroyed by bacterial growth. Early scarification Staphylococcus intermedius endocarditis.
in the deepest layers separates the thrombus from the One of the more common forms of mural endocarditis
underlying myocardium and is frequently accompanied occurs in renal failure in dogs. The lesion is confined, within
by mineralization. the heart, to the left atrium, but similar lesions occur in the
Valvular endocarditis is commonly fatal, although resolution large elastic arteries, being more frequent in the pulmonary
may be complete if lesions are only minor. Clinical signs in and aortic trunks immediately proximal to the valves, and less
animals with endocarditis may only be detected late in the frequently in the descending aorta and its major branches.
disease, with the most common being pyrexia, lameness, and (The vascular lesions associated with renal failure are dis-
cardiac murmurs. The frequency with which clinical signs are cussed under Diseases of the vascular system.) The endocar-
observed is dependent on the husbandry conditions under dial and major-arterial lesions are more common in acute
which the animal is kept. Other sequelae are those resulting than in chronic renal failure, insofar as these syndromes are
from valvular damage or embolism. Portions of the vegetations distinguishable.
may become detached and carried as emboli, to become The ulcerative atrial lesion, which is identical to the arterial
impacted in the vessels of other organs. Such emboli may be lesion, begins as a swelling of the interstitial spaces of the
either bland, that is, consist of thrombotic material only, or subendocardium or intima of the arteries, with deposition of
septic, consisting of thrombotic material together with the enmeshed glycosaminoglycans. Initially, the endothelium is intact and,
infectious agent. Emboli arising in the right heart may produce when viewed grossly in this stage, the endothelial surface is
pulmonary abscesses or pulmonary thrombosis. These latter seen to be raised slightly, finely wrinkled, and slightly opaque
Diseases of the Heart Myocardial Disease 33
Table • 1-5
Causes of myocardial dysfunction in
domestic animals
Infectious Viruses, chlamydiae, rickettsiae, bacteria, fungi,
protozoa, helminths
Toxic Ionophores (monensin, salinomycin,
maduramicin), catecholamines, antineoplastics
(cyclophosphamide, doxorubicin,
daunorubicin), doxycycline, gossypol,
saccharated iron, thallium, toxic plants
(many), insects (blister beetle [Epicauta])
Metabolic Hyperthyroidism, hypocalcemia
Nutritional Vitamin E-selenium, taurine (cats), copper,
deficiency thiamine
Genetic Porcine stress syndrome
Figure 1-35 Ulcerative atrial mural endocarditis of uremia in a Neuromuscular Muscular dystrophy
dog. (Courtesy Vasileios Psychas.)
Storage Glycogen storage disease, amyloidosis
disorders,
other
but still shiny. The lesion may not progress farther than this depositions
but, instead, heals with some fibrosis, which leaves areas of
Infiltrative Neoplasia (lymphoma, hemangiosarcoma)
uneven opacity. More usually, however, there is progression to
necrosis involving the cellular elements as well as collagen, Idiopathic Cardiomyopathy
elastic, and reticulin fibers. The necrotic tissue ulcerates, and
the margin is densely infiltrated by leukocytes (Fig. 1-35). The
ulcerations may perforate the wall of the atrium. Thrombi, in and myocarditis, through idiopathic myocardial disease (cardio-
greater or lesser amounts, form on the ulcerated surface. myopathy). The reaction of myocardium to insults is limited, and
Heavy deposits of calcium salts often form in the degenerate includes the usual expressions of degeneration, necrosis,
tissue. If renal sufficiency is re-established, the endocardial inflammation, and healing. Acute changes, such as necrosis and
lesion may heal leaving irregular patches of fibrosis with an hemorrhage, will be discussed first. Given time to adapt to an
intact endothelium, often covering persistent white plaques insult, a diseased myocardium may grossly take one of 2 con-
of mineralization. Other extrarenal lesions of uremia are con- formations: dilated or hypertrophic. This classification is useful
sidered in Vol. 2, Urinary system. conceptually, but is somewhat arbitrary, and individual cases
will often have features of more than one form, for instance,
the heart in a cat with hyperthyroidism will hypertrophy, but
Further reading it may eventually dilate and fail.
Erol E, et al. Bartonella bovis isolated from a cow with endocarditis.
J Vet Diagn Invest 2013;25:288-290. Hemorrhage of the heart and its membranes
Firshman AM, et al. Thrombotic endocarditis in 10 alpacas. J Vet Intern Petechial and larger subepicardial hemorrhages are so common
Med 2008;22:456-461. in horses that die naturally that they are almost to be regarded
Jarplid B, et al. Observations of apparent early valvular endocarditis in as normal. The incidence of hemorrhages in sheep and cattle
swine. J Vet Diagn Invest 1997;9:449-451. is somewhat lower; they are seldom seen in dogs and cats.
Malik R, et al. Vegetative endocarditis in six cats. J Feline Med Surg Subepicardial hemorrhages are common in instances of asphyxia
1999;1:171-180. or death in anoxia, and in many acute infectious fevers. Larger
Ohad DG, et al. Molecular detection of Bartonella henselae and Bar- ecchymotic hemorrhages that may involve most of the epicar-
tonella koehlerae from aortic valves of Boxer dogs with infective dium occur in the hemorrhagic diatheses.
endocarditis. Vet Microbiol 2010;141:182-185. Subendocardial hemorrhages have the same pathogenesis
Porter SR, et al. Vegetative endocarditis in equids (1994-2006). J Vet but are considerably less common. Ecchymotic hemorrhages
Intern Med 2008;22:1411-1416. beneath the endocardium of the left ventricle occur in
Sykes JE, et al. Evaluation of the relationship between causative organ- instances of acute cerebral injury and are useful as a diagnostic
isms and clinical characteristics of infective endocarditis in dogs: 71 indication of clostridial enterotoxemia in lambs and calves,
cases (1992-2005). J Am Vet Med Assoc 2006;228:1723-1734. being present in a considerable proportion of cases.
Small interstitial capillary hemorrhages within the myocar-
dium accompany those within the subserosa. Deep myocardial
hemorrhages that do not extend to the serosa are commonly
MYOCARDIAL DISEASE
present in pigs that die of asphyxia; they are distributed in the
Myocardial dysfunction can be the product of a wide variety wall of the right ventricle in the vicinity of the descending
of agents and conditions (Table 1-5). This section deals with coronary grooves. A remarkable degree of myocardial hemor-
the range of myocardial disease, from the more-or-less specific rhage occurs in mulberry heart disease of swine (see Mulberry
myocardial conditions of degeneration, necrosis, hemorrhage, heart disease of swine, later).
33.e1
Further reading
Allen BL, et al. Streptococcus anginosus adheres to vascular endothe-
lium basement membrane and purified extracellular matrix pro-
teins. Microb Pathog 2002;32:191-204.
Bennett D, Taylor DJ. Bacterial endocarditis and inflammatory joint
disease in the dog. J Small Anim Pract 1987;29:347-365.
Bratberg AM. Immunological cross reactions of antigens of E. rhusio-
pathiae and heart tissue from swine. Acta Vet Scand 1981;22:46-
54.
Chomel BB, et al. Fatal case of endocarditis associated with Bartonella
henselae type I infection in a domestic cat. J Clin Microbiol
2003;41:5337-5339.
MacDonald KA, et al. A prospective study of canine infective endocar-
ditis in northern California (1999-2001): emergence of Bartonella
as a prevalent etiologic agent. J Vet Intern Med 2004;18:56-64.
Maxson AD, Reef VB. Bacterial endocarditis in horses: ten cases (1984-
1995). Equine Vet J 1997;29:394-399.
Pesavento PA, et al. Pathology of Bartonella endocarditis in six dogs.
Vet Pathol 2005;42:370-373.
Ramirez GA, et al. Left ventricular outflow tract-right atrial communi-
cation (Gerbode type defect) associated with bacterial endocarditis
in a dog. Vet Pathol 2003;40:579-582.
Smith AN, et al. Left ventricular outflow tract to left atrial fistula asso-
ciated with endocarditis in a dog. J Am Anim Hosp Assoc
2000;36:133-136.
Takahasi T, et al. Taxonomic evidence that serovar 7 of Erysipelothrix
strains isolated from dogs with endocarditis are Erysipelothrix ton-
sillarum. J Vet Med B Infect Dis Vet Public Health 2000;47:311-313.
Vasconcelos D, et al. Lesions caused by natural infection with Strepto-
coccus suis type 9 in weaned pigs. J Vet Diagn Invest 1994;6:
335-341.
34 CHAPTER 1 • Cardiovascular System Myocardial Disease
Myocardial degeneration
Cardiac muscle is structurally similar to skeletal muscle and
is subject to the same anatomic types of degeneration. There
is, however, a greater liability for cardiac muscle to undergo
degeneration as a response to many nonspecific causes, prob-
ably related to its continuous activity. Diffuse nonspecific myo-
cardial degeneration occurs secondarily in a variety of systemic
diseases, especially infectious fevers, anemia, and toxemia.
Hydropic change, or vacuolar degeneration, of the myocar-
dium is characterized grossly by a dull gray appearance and
increased friability so that the myocardium is easily torn. On
cut surface, the muscle is smoother than normal, the outlines
of individual muscle bundles obscured.
Fatty change—the appearance of lipid vacuoles in myocyte
cytoplasm—is a more severe event than hydropic change, and
may be recognized grossly as uneven patches of pale yellow
myocardium. The process of fatty change is not uniform, and
it is sometimes possible to recognize, beneath the endocar- Figure 1-36 Osteocartilaginous metaplasia of the right atrium in
dium, alternating bundles of fibers or strips of myocardium a sheep. The central aspect of the atrial free wall contains large
more yellow than the remainder (“thrush-breast heart”). Both areas of mature lamellar bone and cartilage. H&E.
hydropic change and fatty change are reversible forms of cel-
lular injury.
Atrophy of the heart occurs in chronic wasting diseases and quite varied and part of a number of disease syndromes
malnutrition. In some cases, the atrophy is accompanied by described elsewhere in these volumes.
dark pigmentation, and it is then called “brown atrophy.” It In infectious disease, the distinction between myocardial
should be recognized, however, that atrophy can occur without necrosis and myocarditis with myofiber necrosis is somewhat
pigmentation, and pigmentation can occur without atrophy. arbitrary—inflammatory cells will invade necrotic myocar-
Ruminants are principally affected by atrophy, brown or not, dium; in acute myocarditis, inflammatory cells should be inti-
and rarely does the atrophic heart produce clinical distur- mately associated with necrotic myocardial cells, and adjacent
bance. The epicardial fat may be gelatinous, the endocardium myocytes may appear normal. Necrosis predominates in
wrinkled, and myocardium brown and friable. Histologically, highly fatal foot-and-mouth disease in neonatal lambs, piglets,
the muscle fibers are thin, the nuclei small and dark, and and calves, whereas the residual lesions in older cattle qualify
masses of brown pigment granules are present within second- as myocarditis with a significant inflammatory response. Ful-
ary lysosomes at the nuclear poles. The pigment is lipofuscin minating infection by canine distemper virus in young puppies
(“wear-and-tear pigment”), an oxidation product of unsatu- is purely degenerative, whereas parvoviral and herpesviral
rated lipids. infections in the same age group contain elements of an
Xanthosis (xanthomatosis) refers to the abnormal lipofuscin inflammatory response. Of the bacterial diseases, and except-
pigmentation of the myocardium and skeletal muscles seen in ing blackleg, Histophilus somni appears to be responsible for a
cattle, particularly mature Ayrshire cows (see Vol. 1, Muscle residual syndrome of sudden death in cattle with myocardial
and tendon). Microscopically, lipofuscin is commonly seen at necrosis or infarction, although in some cases myocardial
the nuclear poles of cardiac myocytes in aged dogs and cats. abscesses may be present.
Mineralization occurs quite commonly in the myocardium, Severe, often fatal, myocardial necrosis is typically part of
and is to be expected whenever there is necrosis of fibers. the important vitamin E and selenium-responsive syndromes
Calcium salts are selectively deposited in the Purkinje network of nutritional myopathy of lambs, calves (Fig. 1-37A, B),
in organomercurial poisoning in cattle, in which the mineral- swine, and horses, and in mulberry heart disease of swine.
ization is preceded by hyaline necrosis of the Purkinje fibers It may also be seen as part of equine rhabdomyolysis and
and is followed by surrounding fibrosis. of capture myopathy and other exertional syndromes (see
Osteocartilaginous metaplasia of the right atrial myocar- Vol. 1, Muscle and tendon).
dium in sheep is a common incidental finding in adults, and Deficiency disease, additional to those that respond to
has been reported at a prevalence of ~10%. The foci of meta- vitamin E and selenium, may include myocardial necrosis. It
plasia are often palpable grossly, but may only be detectable occurs, although not invariably, in thiamine deficiency in car-
by radiography or microscopy. Histologically, the myocardium nivores, always as a single acute episode. Falling disease of
of the atrial free wall contains trabeculae of lamellar bone that cattle in Australia and Florida is a syndrome of sudden death
are bordered by cartilage and chondroid matrix (Fig. 1-36). believed to result from prolonged copper deficiency. Myocar-
The metaplastic regions are not associated with the os cordis dial scars accompany acute lesions, suggesting repetitive epi-
at the heart base. sodes and resembling the lesions of fluoroacetate poisoning in
cattle eating the gidgee plant, Acacia georginae, which is to be
Myocardial necrosis* distinguished from the nontoxic Acacia cambadgei (gidyea,
Focal to massive myocardial necrosis, or residual scars thereof, gidgee). In cats, taurine deficiency causes myocardial failure.
is a common lesion in postmortem material. The causes are Toxic myocardial degeneration is common, and although
some examples are accompanied by degeneration of skeletal
muscle, they are described here. Injectable saccharated iron
*Contribution to the Myocardial necrosis section by Dr. R. McKenzie compounds, by virtue of the capacity of iron to generate free
is gratefully acknowledged. radicals in ferric/ferrous translations, cause fatal myocardial
Diseases of the Heart Myocardial Disease 35
B
A
Figure 1-37 Nutritional myopathy. A. Pale areas of myocardial necrosis in a lamb. (Courtesy
Vasileios Psychas.) B. Myocardial necrosis and mineralization of necrotic myocytes in a calf. H&E.
area. In cases dying within 24 hours, the pericardial reaction the affected area, and the nuclei of the myocytes become
may be the only indication grossly of infarction, the necrotic pyknotic. At this stage, macrophages are evident. Granulation
muscle at this stage not being clearly altered or merely pale. tissue appears at the periphery of the lesion toward the end
The necrotic area becomes more sharply defined by hyper- of the first week and usually predominates by the end of the
emia by the second to fourth days. By the tenth day, there is sixth week.
beginning replacement of the necrotic zone by fibrous There are variations in the microscopic appearance of
ingrowth. Replacement fibrosis is well established by the end myocyte necrosis, and some attempt has been made to associ-
of the sixth week. A substantial, often transmural loss of myo- ate the differing microscopic patterns with particular causes,
cardium and replacement by fibrous tissue may lead to the but these associations are not definitive. The first variant is
development of aneurysms of the ventricular wall. coagulative necrosis characterized by cellular swelling, nuclear
Microscopically, lesions are not usually detectable for the hyperchromasia, early loss of striations, and a “granular”
first 6-12 hours. However, ultrastructural changes are observed appearance of the myocyte. This type of change is observed
within 1 hour. Recognition as early as 2 hours may be possible primarily in ischemic states. Coagulative myocytolysis is typi-
using special stains, such as hematoxylin-basic fuchsin-picric fied by the presence of thick, irregular, eosinophilic bands,
acid. Necrosis becomes apparent by routine stains after 12 with an accompanying loss of striations and lightly staining
hours (Figs. 1-40, 1-41). Subsequently, neutrophils infiltrate granular areas in myocytes. The bands are hypercontracted
sarcomeres (“contraction bands”) (see Fig. 1-41) and the light
granular areas are mitochondria. Evidence from experimental
models suggests that the alteration is the result of the excessive
release of endogenous catecholamines. However, this change
may be observed in normal myocardium if it is fixed imme-
diately after death. Colliquative myocytolysis appears as a loss
of striations, and homogeneous, weakly eosinophilic cyto-
plasm. The ultrastructural appearance is characterized by
intracellular edema, with disintegration of fibrils and other
organelles. Waviness of myocardial fibers is claimed by some to
be one of the earliest changes observed in myocardial infarc-
tion in humans. The affected fibers are not necrotic, but are
thinner and undulating in appearance. It is thought that the
waviness is due to irreversible stretching followed by compres-
sion of ischemic fibers by the surrounding viable myocardium.
Attenuated wavy fibers (<6 µm diameter, wavy appearance)
have been noted to be common in the myocardium of dogs
with dilated cardiomyopathy.
Anichkov (Anitschkow) cells, also known as “caterpillar
Figure 1-40 Myocardial necrosis in a calf. Focal necrosis of
cells,” have been observed in myocarditis and a variety of natu-
cardiac myocytes showing eosinophilia, loss of cross striations, and
rally occurring and experimentally induced myocardial necro-
absence of nuclei (arrowhead). Extensively mineralized necrotic
ses. They are also seen in rheumatic fever in humans in
cardiac myocytes (arrow). Some normal cardiac myocytes remain
association with Aschoff bodies. Anichkov cells appear as large
in lower portion. H&E.
mononuclear cells in which the nuclear chromatin is present
in an undulating wavy ribbon with slender processes radiating
from it (Fig. 1-42). The origin of these cells is in dispute. Sug-
gestions include a fibroblastic, pericytic, endothelial, or myo-
cytic origin. Depending on the theory accepted, the function
is either that of a macrophage or an abortive attempt at
cardiac myocyte regeneration.
A few of the more interesting examples of myocardial
degeneration and necrosis follow.
Fluoroacetate poisoning
Sodium fluoroacetate (compound 1080) is used extensively
in some parts of the world as a vertebrate pesticide, and espe-
cially as a rodenticide. It is also highly toxic for most domestic
mammals. The median lethal dose for most species is ~0.25-
1.00 mg/kg of body weight. Fluoroacetate is not directly toxic,
but becomes so when converted to fluoroacetyl–coenzyme A.
This compound is then combined with oxaloacetic acid to
form fluorocitrate. The citric acid cycle enzymes cis-aconitase
Figure 1-41 Myocardial necrosis in a calf. Phosphotungstic acid and succinic dehydrogenase are inhibited by fluorocitrate,
hematoxylin (PTAH) stain emphasizes the contraction bands effectively inhibiting the production of adequate amounts of
(collapsed sarcomeres) in the necrotic cardiac myocytes (arrow). adenosine triphosphate (ATP). Accidental poisoning by fluo-
Normal cardiac myocytes (above and below arrow) have fine cross roacetate occurs either by direct ingestion of the poison, or
striations of normal sarcomeres. indirectly, as when dogs eat poisoned rabbits.
38 CHAPTER 1 • Cardiovascular System Myocardial Disease
Gousiekte
Gousiekte (“quick” disease) is a plant poisoning of ruminants in
southern Africa that is of great economic importance in that
region. The disease is characterized by acute heart failure 5-8
weeks after the ingestion of certain plants in the family Rubia-
ceae. Clinical signs are seldom seen in natural cases; animals
are usually found dead. A number of plants can cause the
disease, including Pachystigma pygmaeum, P. thamnus, P. latifo-
lium, Fadogia homblei, Pavetta harborii, and Pavetta schuman-
niana. Pavetamine is the water-soluble, heat-stable toxin
responsible for causing gousiekte.
Gross pathologic changes include generalized congestion,
ascites, hydropericardium, hydrothorax, and pulmonary edema.
Ventricular dilation is an inconsistent feature. However, the
ventricular walls are thinner and have a tough consistency. In
a small proportion of cases, the heart is macroscopically
normal. Microscopically, there is focal-to-extensive myofiber loss
Figure 1-42 Focal myocarditis (Aschoff body) characterised by with replacement fibrosis. The surviving myofibers may be atro-
multinucleated giant cells (long arrow), lymphocytes, and some phied, and groups of lymphocytes and macrophages may be
cells with caterpillar nuclei (Anichkov cells, short arrow) in a dog. present in areas of fibrosis.
H&E.
Avocado poisoning
Sheep and goats may die following the ingestion of fresh leaves
Fluoroacetate of plant origin is responsible for sometimes from some varieties of the avocado tree (Persea americana);
devastatingly large episodes of poisoning of ruminants. Plants the active principle “persin” is a monoglyceride that has struc-
known to accumulate fluoroacetate in lethal quantities for tural affinities with polyether ionophore antibiotics. Animals
ruminants are Gastrolobium spp. and Acacia georginae in may die suddenly after ingesting comparatively few leaves,
Australia, Dichapetalum spp. (gibflaar) in Africa, and Pali- whereas others may show few ill effects. In those that die,
courea marcgravii in Brazil. Whether fluoroacetate has any role lesions consist of endocardial hemorrhage, especially of the
in the physiologic economy of the plants is not known, but in papillary muscles; hydropericardium; pale, flabby heart;
the case of A. georginae, there are differences in the develop- ascites; hepatic degeneration; and pale kidneys. Cardiac lesions
ment of toxicity in the species. In D. cymosum, there are are those of cardiac myocyte necrosis and congestion and hem-
seasonal differences, toxicity being greater in spring and orrhage of variable severity. Although horses can be poisoned
autumn, and especially in young leaves. Young leaves, includ- following the ingestion of avocado leaves, it is not usually fatal.
ing sucker growth, and pods and seeds are more toxic than Consumption of avocado leaves also results in depression
the mature leaves of A. georginae. of milk production in lactating goats. The affected mammary
The syndromes of intoxication vary with the species glands are edematous and reddened with clots in the large
affected but are either chiefly neurologic, as in dogs, which ducts. The Guatemalan, but not the Mexican, variety of
become extremely excited and convulsive, or chiefly cardiac, avocado induces these changes in the mammary gland.
as in ruminants. Sheep may collapse suddenly and die within
a few minutes. Those less severely affected may develop car- Taurine deficiency in cats
diorespiratory distress and weakness if driven, with death Taurine-deficiency myocardial failure (TDMF) in cats is a
supervening shortly thereafter. Some showing these signs, if primary systolic myocardial disorder associated with taurine defi-
left undisturbed, may recover to appear normal until again ciency; many cases of feline dilated cardiomyopathy are actu-
forced to exercise. The syndrome in cattle is the same as in ally examples of TDMF. Decreased systolic function results in
sheep, death occurring with cardiac failure, fibrillation, cyano- signs associated with decreased cardiac output giving rise to
sis, dyspnea, and terminal convulsions. Exercise, excitement, bilateral congestive heart failure. End-diastolic ventricular
or a large drink of water may precipitate clinical signs. volume and pressure are increased, as are atrial volume and
The postmortem findings in ruminants are referable to pressure.
myocardial injury. This may or may not be conspicuous, Taurine (2-aminoethane sulfonic acid), an essential amino
depending on the size of the dose and the opportunity for acid for cats, is abundant in fresh meat, but must be supple-
repeated episodes of poisoning. The concentration of fluoro- mented in commercial feline diets to prevent the develop-
acetate in D. cymosum is large, and histologic evidence of acute ment of TDMF, central retinal degeneration, and developmental
myocardial injury is seen. In A. georginae poisoning, both acute abnormalities in kittens. Taurine is required in myocardium
and chronic myocardial changes may be seen. There is some for the modulation of tissue calcium influx through cardiac
flabbiness of the myocardium, with prominent hemorrhages calcium channels. Taurine supplementation will restore myo-
beneath the cardiac serosa. In acute cases, there are irregular cardial function to normal in most cats with low plasma
areas of myocardial pallor and mottling sometimes associated taurine levels and echocardiographic evidence of cardiac
with older scars. There is multifocal myocytolysis or hyaline chamber dilation and myocardial failure. Cats, and other
degeneration of the myocardial fibers, with intense infiltration mammals, have an obligatory need to conjugate bile acids with
of mononuclear cells. Loss of sarcoplasm leaves an open mesh- taurine or glycine; cats not only have a limited capacity to
work of reticulum and vessels, which eventually condenses synthesize taurine, but are unable to use glycine for bile acid
and scars. conjugation.
Diseases of the Heart Myocardial Disease 39
As the syndrome is now well recognized, cats are myocardial muscle. The development of PSS is intimately
unlikely to die of TDMF. In cats that do die, gross and histo- associated with stocking density, transportation time, and
logic cardiac lesions are as described later for feline dilated other antemortem stressors. Death from PSS may occur as a
cardiomyopathy. result of peracute heart failure secondary to the metabolic and
hormonal sequelae of PSS, namely, acidosis, hyperkalemia,
Myocardial necrosis secondary to neural injury hyperthermia, and hypercatecholemia. The latter may produce
The effect of the central nervous system on the myocardium myocardial necrosis. Sudden death caused by cardiac failure
is mediated by the autonomic nervous system and, in particu- also occurs in sows, both with and without association with
lar, the sympathetic nervous system. The heart is richly inner- the PSS gene mutation.
vated with autonomic fibers, and myocytes, particularly Clinically, affected pigs exhibit muscular tremor, dyspnea,
ventricular myocytes, have high concentrations of β receptors. hyperthermia, and cutaneous blanching and erythema. Death
Both the rate and inotropic state of the heart are stimulated quickly ensues. Typical autopsy findings include the rapid
by catecholamines. In a number of species, the continuous development of rigor, pulmonary edema, hydropericardium,
administration of norepinephrine for 1-2 weeks results in focal and splanchnic congestion. In some, there is epicardial and
myocardial necrosis. Multifocal myocardial necrosis may endocardial hemorrhage with irregular areas of pallor in the
develop in dogs with paroxysmal tachycardia resulting from left ventricular myocardium. The presence or absence of myo-
functional pheochromocytomas. Also, experimentally induced cardial necrosis in PSS is a major difference between the
intracranial hemorrhage produces focal myocardial necrosis, European and North American descriptions of the disease.
which can be prevented by prior administration of either Myocardial necrosis is a common finding in European cases.
reserpine, a catecholamine-depleting drug, or propanolol, When present, the necrotic areas are prominent in the inner
which blocks β receptors. third of the wall and papillary muscles. The microscopic
Multifocal myocardial necrosis occurs in dogs, horses, cows, appearance of the necrotic fibers is characterized by loss of
sheep, pigs, goats, and wildlife in association with neurologic the normal striation pattern, the presence of contraction
disease of diverse origin (“brain-heart syndrome”), from exter- bands, and fine granulation of the sarcoplasm.
nal trauma to infectious disease. The primary lesion may A variant of PSS associated with a mutation in the dystro-
involve the head, central nervous system, or major nerve plex- phin gene, and markedly decreased expression of dystrophin in
uses. The microscopic appearance of the myocardial lesions is both cardiac and skeletal myocytes has been recently described.
dependent on the time elapsed between insult and death. It
varies from acute myocardial degeneration and necrosis to Mulberry heart disease of swine
almost complete resolution by fibrosis. There are, no doubt, a The name “mulberry heart” is vaguely suggested by the exten-
number of cases with no gross or microscopic lesions where sive hemorrhages on the surface of the heart, and its major fea-
insufficient time elapsed between the onset of clinical signs tures are depicted in eFigure 1-7. The disease occurs in pigs
and death. The findings of multifocal myocardial necrosis on only, chiefly those 2-4 months of age and in excellent condi-
autopsy in any species should alert the pathologist to examine the tion, but it has been observed in animals from 3 weeks to 4
central nervous system for abnormality. Secondary multifocal years of age. Among old pigs, the incidence is sporadic, but in
myocardial necrosis also occurs in dogs with gastric torsion, young pigs, it occurs in short, snappy outbreaks. In most cases,
and in dogs and cats with acute necrotizing pancreatitis and typically affected animals are found dead. The circumstances
septic peritonitis. of sudden death combined with the gross and microscopic
lesions strongly suggest that the affected animals die of acute
Doxorubicin (Adriamycin) cardiotoxicosis heart failure following the development of ventricular dys-
Doxorubicin, an antineoplastic agent of the anthracycline rhythmias (Figs. 1-43, 1-44). Despite the associated gross and
antibiotic group, is used in the treatment of lymphoma and microscopic findings, mulberry heart disease is generally a
other neoplasia in dogs; cardiotoxicosis is the major factor limit- diagnosis of exclusion; this is particularly the case today when
ing its use. Acute cardiotoxicosis appears to be mediated by
peroxidative injury or expression of cytokines. As well, binding
of doxorubicin to nuclear and mitochondrial DNA causes
blockage of DNA, RNA, and protein synthesis. Chronic doxo-
rubicin cardiotoxicosis, which may be due to decreased protein
synthesis as well as altered divalent cation concentration,
occurs in dogs given cumulative doses. Congestive heart
failure occurs in such dogs; microscopic myocardial changes
consist of myocytic vacuolar degeneration (“adria cells”), myo-
cytolysis, myofibril atrophy, and fibrosis. The cardiotoxicity of
doxorubicin is reduced when administered as a pegylated
liposomal form.
Histopathology
Myocardial necrosis
Widespread fibrinoid necrosis of arteriolar walls
Hyaline thrombi, disruption of endothelium
Leukoencephalomalacia
extensive arrays of molecular diagnostic tests are often in the fluid. The fibrin is not fixed to the serous surface and,
available. from where it is in contact with the epicardium, it can easily
Raising weanling piglets on a diet deficient in selenium and be lifted off to reveal a clean, glistening, serous membrane.
vitamin E can regularly reproduce the disease. Such animals may Hemorrhages, linear and ecchymotic, are present beneath the
develop disease within 2 weeks. As discussed with diseases of epicardium. They may be few, or they may be extensive and
muscle (in Vol. 1, Muscle and tendon), selenium is an integral involve the epicardium of all chambers, the myocardium, and
part of the membrane enzyme glutathione peroxidase, which beneath the endocardium of the papillary muscles and septum.
reduces toxic lipid peroxides to hydroxy acids. Vitamin E is In some, multiple pale streaks and patches of necrosis extend
an antioxidant and acts synergistically with selenium to protect from the epicardial surface into the myocardium. There may
membranes from high concentrations of lipoperoxides. Field be similar lesions visible from the endocardial surface.
studies, particularly from the Scandinavian countries, have The abdominal cavity contains a small volume of clear
shown that although dietary selenium supplementation mark- transudate and some fine unattached strands of fibrin on the
edly reduces the incidence of hepatosis dietetica and nutri- intestine. The stomach usually contains a mass of dry feed,
tional myopathy, the prevalence of mulberry heart disease and its fundic mucosa is diffusely congested. The small intes-
remains the same. It is also evident that tissue levels of sele- tine is empty and dry, with serosal vessels congested. The liver
nium, particularly those in the heart and liver, are within the is congested, sometimes markedly so, with edema of the
normal range. It is now considered that vitamin E deficiency wall of the gallbladder. In some animals that survive 24
plays a central role in the development of mulberry heart disease. hours or more, there is bilaterally symmetrical softening of the
However, there is not universal agreement on this. Although white matter forming the cores of the cerebral gyri. The soften-
some studies show lower tissue levels of vitamin E in affected ings are visible grossly as gray, translucent, depressed areas
pigs, others show no difference. Additionally, it has been sug- studded with tiny hemorrhages that are sometimes confluent
gested that the disease is the result of altered vitamin E (Fig. 1-45).
metabolism and not a consequence of inadequate dietary Microscopically in acute deaths, degeneration of myofibers
vitamin E levels. It may be that mulberry heart disease is may be minimal or absent. In these cases, there is merely
precipitated following a lack of bioavailability of vitamin E in subserosal edema, with some plugging of lymphatics by fibrin,
tissues, or possibly a greater requirement for vitamin E under and interstitial hemorrhage. In others, which are probably less
certain dietary circumstances, such as diets containing large acute cases, there are substantial areas of myocardial necrosis
amounts of unsaturated fat. (Fig. 1-46). The extent of mineralization of the necrotic fibers
Animals dying of mulberry heart disease are always in varies, but never appears to be as severe as that seen in lambs
excellent body condition. There may be slight cyanosis of the or calves with nutritional myopathy.
ears and ventral abdomen, and exophthalmos, the latter result- The second prominent lesion, which is most probably unrelated
ing from orbital and palpebral edema. The intermuscular con- to the myocardial necrosis, is observed in arterioles of many
nective tissues are usually wet, and there may be obvious organs. The change is seen in the heart, kidneys, liver, stomach,
edema, especially in the axillary and inguinal regions and near intestine, mesentery, skeletal muscle, and skin. There appears
the xiphoid process. The skeletal muscles are normal. to be gradation in the severity of change, from endothelial
The principal gross lesions occur in the thorax. Some 50 mL swelling with increased permeability, to necrosis of smooth
or more of heavy, straw-colored fluid that clots on exposure muscle cells of the media. The basic appearance includes the
to air is invariably present in the pleural cavity. The lungs are accumulation of fibrinoid in arteriolar walls, formation of hyaline
edematous and slightly or severely congested, but not severely thrombi, disruption of endothelium, and necrosis of smooth muscle
enough to account for the degree of edema. The pericardium cells. Periodic acid–Schiff (PAS) staining of affected arterioles
is edematous and opaque and is always acutely distended with emphasizes the accumulation of fibrinoid. The lungs show
fluid transudate. Either heavy strands or a lace of fibrin float congestion and edema only. There is congestion and edema of
Diseases of the Heart Myocardial Disease 41
Further reading
Barbut S, et al. Progress in reducing the pale, soft and exudative (PSE)
problem in pork and poultry meat. Meat Sci 2008;79:46-63.
Baroldi G, et al. Myocardial contraction bands. Definition, quantifica-
tion and significance in forensic pathology. Int J Legal Med
2001;115:142-151.
Burrows GW, Tyrl RL. Toxic Plants of North America. 2nd ed. Ames,
Iowa: Wiley-Blackwell; 2013.
Figure 1-46 Myocardial hemorrhage with necrosis and mineral- Caloni F, et al. Plant poisoning in domestic animals: epidemiological
ization of myocardiocytes in mulberry heart disease. H&E. data from an Italian survey (2000-2011). Vet Rec 2013;172:580-
583.
Davis TZ, et al. Toxicokinetics and pathology of plant-associated acute
the liver, associated in some cases with central necrosis in the selenium toxicosis in steers. J Vet Diagn Invest 2012;24:319-327.
lobules. Proteinaceous fluid produces focal detachments of the Galey FD, et al. Diagnosis of oleander poisoning in livestock. J Vet
retina and intercapillary edema of the glomerular tufts. Diagn Invest 1996;8:358-364.
The development of the cerebral lesions can be correlated Ganote CE. Contraction band necrosis and irreversible myocardial
roughly with the duration of the clinical illness. In the majority injury. J Mol Cell Cardiol 1983;15:67-73.
of cases, where death occurs suddenly, there is no microscopic Guardia MD, et al. Risk assessment of PSE condition due to pre-
change in the brain, or merely some slight venous congestion slaughter conditions and RYR1 gene in pigs. Meat Sci 2004;67:471-
and edema of the cortical white matter. In pigs that live for 478.
some hours, there is edematous separation of the fiber tracts Kellerman TS, et al. Plant Poisonings and Mycotoxicoses of Livestock
of the white matter of the frontal cortex, with acute swelling in Southern Africa. 2nd ed. Cape Town: Oxford University Press;
and fragmentation of oligodendroglia. The overlying gray 2005.
matter is edematous. In animals that survive for 24 hours or McKenzie RA. Australia’s Poisonous Plants, Fungi and Cyanobacteria:
more, it is usual to find severe lysis of the white matter in the A Guide to Species of Medical and Veterinary Importance.
cerebrum, which is more or less extensive but usually avoids Collingwood. Victoria, Australia: CSIRO Publishing; 2012.
the internal capsule, corpus medullare, and association fibers. Nonneman DJ, et al. A defect in dystrophin causes a novel porcine
The cores of the gyri of the frontal lobes are most consistently stress syndrome. BMC Genomics 2012;13:233.
and severely involved, but in some cases, all portions of the Panciera RJ, et al. Hairy vetch (Vicia villosa Roth) poisoning in cattle:
cerebrum are involved, and in these, there may be similar update and experimental induction of disease. J Vet Diagn Invest
lesions in the thalamus and brainstem. The vessels, venules 1992;4:318-325.
especially, in the degenerate areas are severely injured and may Reiner AC, et al. Oleander toxicosis in equids: 30 cases (1995-2010).
be totally necrotic, although more frequently, there is only J Am Vet Med Assoc 2013;242:540-549.
endothelial and adventitial swelling and proliferation. Hyaline Shen H, et al. Vitamin E and selenium levels are within normal range
thrombi are formed in many vessels, and droplets of similar in pigs diagnosed with mulberry heart disease and evidence for viral
character form in the perivascular spaces. The overlying gray involvement in the syndrome is lacking. Transbound Emerg Dis
matter is edematous. The vessels are hypertrophic and cuffed 2011;58:483-491.
by adventitial cells and a few eosinophils. In a few cases, Shen H, et al. Vitamin E and selenium levels are within normal range
degenerate foci are also present in the cerebellum; these in pigs diagnosed with mulberry heart disease and evidence for viral
involve the molecular layer with foci of softening or narrow involvement in the syndrome is lacking. Transbound Emerg Dis
sheets of hemorrhage. 2011;58:483-491.
The lesions in mulberry heart disease depend on the length Sula MJM, et al. Characterization of cardiac lesions in calves after
of time pigs survive after the initial damage occurs. Most pigs ingestion of Japanese yew (Taxus cuspidata). J Vet Diagn Invest
die from ventricular dysrhythmia, and those that die immedi- 2013;25:522-526.
ately no doubt have substantial areas of myofiber death, but Wrogemann K, Pena SDJ. Mitochondrial calcium overload: a general
there has been insufficient time for the morphologic manifes- mechanism for cell necrosis in muscle diseases. Lancet 1976;
tations of the necrosis to appear. A period of 6-12 hours must 1:672-673.
elapse before myofiber necrosis can be reliably recognized.
After that, the lesions become increasingly evident and prog-
ress through stages to replacement fibrosis of the necrotic Myocarditis
areas if the pig survives. Myocarditis, or inflammation of the myocardium, is a common
In the experimentally induced disease, serum enzyme lesion found in a wide variety of systemic diseases (Table 1-6),
levels indicative of myocardial damage may be raised for up but it is rarely primary. It occurs hematogenously in many
to 21 days before death. The extent of cardiac damage is infectious diseases, and also by direct extension from inflam-
related to the length of time the serum enzymes are raised or, matory lesions of the endocardium and pericardium. A
41.e1
Table • 1-6
Causes of myocarditis in domestic animals
Viruses Canine herpesvirus, canine parvovirus 2,
encephalomyocarditis virus, equid herpesvirus 1,
foot-and-mouth disease virus, murid herpesvirus
(murine cytomegalovirus), porcine circovirus 2
and/or porcine parvovirus (in postweaning
multisystemic wasting syndrome [PMWS]),
pseudorabies virus, West Nile virus
Bacteria Actinobacillus equuli, Actinobacillus suis,
Bartonella vinsonii, Borrelia burgdorferi (Lyme
disease), Clostridium chauvoei, Histophilus
somni, Leptospira spp., Streptococcus suis,
Neorickettsia (Ehrlichia) risticii
Protozoa Neospora caninum, Sarcocystis, Toxoplasma
gondii, Trypanosoma spp.
Helminths Trichinella spiralis A
Figure 1-48 Unusually severe parvoviral myocarditis (pale areas) but susceptible pigs kept in close contact with infected pigs
in a dog. (Courtesy D. Hayden.) did not develop disease.
Sudden death or death following a brief period of excita-
tion and collapse characterizes the clinical disease in the per-
acute form in swine. In less severe cases, there may be fever,
Myocarditis is part of a number of important and wide- anorexia, and progressive paralysis. The mortality rate is vari-
ranging clinical and pathologic syndromes in porcine fetuses, able. At autopsy, there is hydrothorax, hydropericardium,
stillborn piglets, and young piglets. These include postweaning ascites, and pulmonary congestion and edema. In severe cases,
multisystemic wasting syndrome (PMWS), porcine dermatitis there is extreme pallor of the ventricles, with yellow-to-white
and nephropathy syndrome (PDNS), and reproductive failure foci 2-10 mm in diameter throughout the myocardium. In less
caused by porcine circovirus 2; porcine reproductive and severe cases, gross lesions are minimal to absent. Microscopi-
respiratory syndrome (PRRS) caused by the PRRS arterivirus; cally, the dominant lesions are focal-to-diffuse myocardial
and porcine myocarditis syndrome (PMC) caused by the necrosis. Patchy mineralization of necrotic areas is evident,
novel Bungowannah pestivirus (see Vol. 3, Female genital accompanied by a mononuclear inflammatory reaction that
system). varies greatly in intensity. Survival allows fibrous scarring to
“Eosinophilic myocarditis” is so called because the reaction develop. There is little evidence of encephalomyelitis. EMCV
to sarcocysts is predominantly by eosinophils, which produce infection has also been associated with reproductive failure
the typical, small, green to gray-green foci observed occasion- characterized by mummified fetuses and stillbirth, as well as
ally in cattle at routine meat inspection. This syndrome is not failure of conception and early embryonic deaths. Fetuses that
to be confused with the eosinophilic myocarditis present in die toward the end of gestation have multifocal myocardial
cases of poisoning by ingestion of hairy vetch (Vicia villosa). necrosis.
Atrial myocarditis is an infrequently reported entity of Experimentally infected swine may die between 2 and 11
undetermined cause in dogs that manifests clinically as an days postinoculation. Virus is present in the feces for 7-9 days
arrhythmia (sinoatrial arrest, supraventricular tachyarrhyth- following oral administration and may be isolated from all
mias). Lesions are confined to the atria and can vary from organs, with the myocardium exhibiting the highest titer of
a lymphocyte predominant infiltration to extensive fibrosis virus. The virus titer falls rapidly and may not be found in
(Fig. 1-49). cases that have been infected for 11 days or more. Experimen-
tal inoculation of mice regularly produces both encephalitis
Encephalomyocarditis virus infection and myocarditis. Strains of EMCV may be adapted to produce
There are 3 members of the genus Cardiovirus in the family either encephalitis or myocarditis.
Picornaviridae, and the type species is Encephalomyocarditis
virus (EMCV). All species are antigenically related and by Parasitic myocarditis
most tests are indistinguishable from each other. EMCV can The parasites that tend to localize in the myocardium are the
infect humans and other mammals, principally swine and sub- same as those that have an affinity for skeletal muscle. Parasites
human primates. Rodents, in which it appears to be clinically without such affinity may also be found in the myocardium
inapparent and behaves as an enterovirus, may act as reservoir in the course of their wanderings, especially if they are migrat-
hosts, but infection in laboratory rodents commonly produces ing in an abnormal host or in unusually large numbers in the
fatal encephalitis or myocarditis. The source of infection in normal host.
outbreaks of myocarditis in swine is thought to be through Of those parasites with an affinity for cardiac and skeletal
consumption of feed or water contaminated with virus from muscle, the ubiquitous sarcocysts are the most common (see
rats or other rodents. Ingestion of diseased rodent carcasses is Vol. 1, Muscle and tendon). The finding of myocardial sarcocysts
also a likely source of infection. Experimental transmission of is very common in ruminants. This increases with the age of
disease to swine has been accomplished by feeding the virus, the animal and implies a previous acute sarcocystosis in which
44 CHAPTER 1 • Cardiovascular System Myocardial Disease
Cardiomyopathies
The term cardiomyopathy was originally coined for a group
of human myocardial diseases in that were of unknown or
obscure cause. Cardiomyopathies are now well-defined clini-
copathologic entities that have been increasingly shown to be
either genetically determined abnormalities of myocardial
contractile, cytoskeletal or mitochondrial proteins, or respon-
sive to substances such as taurine and carnitine. Initially, a
diagnosis of cardiomyopathy was arrived at by the absence of
common causes of heart failure and the presence of abnor-
malities not readily explained. In humans, where cardiomy-
opathies were first recognized, there must be absence of
significant coronary arterial disease; vascular disease or anomaly;
systemic hypertension, past or present; and vascular shunts inside
Figure 1-50 Lymphoplasmacytic myocarditis (Chagas disease) or outside the heart. Features usually present include cardio-
caused by Trypanosoma cruzi in a dog. Note the amastigote- megaly, either as dilation or hypertrophy; mural thrombosis,
containing pseudocyst in a cardiac myocyte. H&E. (Courtesy B. F. usually in the left ventricle; and, fibrosis or other lesions indicative
Porter.) of generalized myocardial involvement.
44.e1
Further reading
Agungpriyono DR, et al. Subacute massive necrotizing myocarditis by
canine parvovirus type 2 infection with diffuse leukoencephaloma-
lacia in a puppy. Vet Pathol 1999;36:77-80.
Appel MJG. Lyme disease in dogs and cats. Compend Contin Educ
Pract Vet 1990;12:617-626.
Barber JS, Trees AJ. Clinical aspects of 27 cases of neosporosis in dogs.
Vet Rec 1996;139:439-443.
Bolt DM, et al. Non-suppurative myocarditis in piglets associated with
porcine parvovirus infection. J Comp Pathol 1997;117:107-118.
Breitschwerdt EB, et al. Bartonella vinsonii subsp. berkhoffii and related
members of the alpha subdivision of the Proteobacteria in dogs
with cardiac arrhythmias, endocarditis, or myocarditis. J Clin Micro-
biol 1999;37:3618-3626.
Cassidy JP, et al. Myocarditis in sibling boxer puppies associated with
Citrobacter koseri infection. Vet Pathol 2002;39:393-395.
Deem DA, Fregin GF. Atrial fibrillation in horses: a review of 106 clini-
cal cases, and consideration of prevalence, clinical signs, and prog-
nosis. J Am Vet Med Assoc 1982;180:261-265.
Dubey JP, Lindsay DS. A review of Neospora caninum and neosporosis.
Vet Parasitol 1996;67:1-59.
Ellis J, et al. Reproduction of lesions of postweaning multisystemic
wasting syndrome in gnotobiotic piglets. J Vet Diagn Invest
1999;11:3-14.
Gajadhar AA, Marquardt WC. Ultrastructural and transmission evi-
dence of Sarcocystis cruzi associated with eosinophilic myositis in
cattle. Can J Vet Res 1992;56:41-46.
Hattel AL, et al. Neosporosis-associated bovine abortion in Pennsylva-
nia. Vet Parasitol 1998;74:307-313.
Hervas J, et al. Myocarditis associated with Theileria spp. in calves.
Zentralbl Veterinarmed B 1998;45:401-405.
Kimeto BA, et al. Haemorrhagic pancarditis in cattle infected with
Trypanosoma vivax. Vet Parasitol 1990;34:295-301.
Lange LG, Schreiner GF. Immune mechanisms of cardiac disease. N Engl
J Med 1994;330:1129-1135.
Lees W, et al. Outbreak of Cysticercus bovis (Taenia saginata) in feedlot
cattle in Alberta. Can Vet J 2002;43:227-228.
Machado EM, et al. A study of experimental reinfection by Trypano-
soma cruzi in dogs. Am J Trop Med Hyg 2001;65:958-965.
Machida N, et al. Cardio-histopathological observations on aborted
equine fetuses infected with equid herpesvirus 1 (EHV-1). J Comp
Pathol 1997;116:379-385.
Ndung’u JM, et al. Cardiac damage in dogs infected with T. brucei;
clinical and electrocardiographic features. J Small Anim Pract
1991;32:579-584.
Nho WG, et al. Detection of canine parvovirus in naturally infected
dogs with enteritis and myocarditis by in situ hybridization. J Vet
Diagn Invest 1997;9:255-260.
Reams RY, et al. Streptococcus suis infection in swine: a retrospective
study of 256 cases: II. Clinical signs, gross and microscopic lesions,
and coexisting microorganisms. J Vet Diagn Invest 1994;6:326-334.
Segales J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Thurmond MC, et al. Predictive values of fetal histopathology and
immunoperoxidase staining in diagnosing bovine abortion caused
by Neospora caninum in a dairy herd. J Vet Diagn Invest 1999;11:90-
94.
Uzal FA, et al. Outbreak of clostridial myocarditis in calves. Vet Rec
2003;152:134-136.
Van Rensburg IBJ. The differential diagnoses of myocarditis and myo-
cardial necrosis in puppies. J S Afr Vet Assoc 1988;59:107.
Young JK, et al. Naturally occurring Tyzzer’s disease in a puppy. Vet
Pathol 1995;32:63-65.
Diseases of the Heart Myocardial Disease 45
Of the features described for humans that must be teins. There is massive loss of myocytes with fatty infiltration
absent, coronary arterial disease and systemic hypertension and fibrosis. ARVC also occurs in dogs, especially Boxer dogs;
may be disregarded in domestic animals because of their com- in cats; and in Hereford cattle.
parative rarity. In domestic animals, the diagnosis of a cardio- Hypertrophic cardiomyopathy (HCM) is a diastolic rather
myopathy rests on the absence of significant congenital or than a systolic ventricular disorder. The hypertrophic ventricle
acquired valvular or vascular abnormality, the presence of dila- is abnormally stiff (less compliant), resulting in impaired ven-
tion or hypertrophy of one or both ventricles and possibly all 4 tricular filling. It is most commonly inherited as an autosomal
chambers, and accompanied in some cases by diffuse fibrosis. dominant characteristic within which there is a high preva-
An additional exclusion, at least for cats, should be that of lence of subclinical disease. Sudden unexpected death is often
hyperthyroidism. the first manifestation of HCM. There is left, and sometimes
Since the original definition, the term cardiomyopathy has right, ventricular hypertrophy, reduced size of the ventricular
been used loosely to describe any abnormality of the myocar- lumen, and dilation and often hypertrophy of the atria. The
dium for which an etiology cannot be defined. There has also pattern and extent of the ventricular hypertrophy varies from
been some attempt to classify cardiomyopathies into primary localized hypertrophy of the ventricular septum (asymmetrical
(obscure etiology) and secondary (known systemic or etiologic septal hypertrophy), to the hypertrophy being symmetrical or
abnormalities) categories. A classification of similar style cat- even apical in nature. Microscopically, the myocytes are hyper-
egorizes cardiomyopathies as either intrinsic or extrinsic in trophied, with many arranged in a whorled or disorganized
cause. Under this classification, intrinsic causes are demonstra- pattern. Although the disordered myocyte arrangement is not
bly genetic or suspected to be so, whereas extrinsic cardiomy- unique to HCM, it is more severe. Fibrosis of variable severity
opathies include those of infectious, nutritional, or toxic accompanies the hypertrophic process.
origin. At this stage, we prefer the categorization of cardiomyopa- Mutations in genes that code for proteins associated with the
thies as either primary (of genetic or suspected genetic origin) or process of cardiac contraction have been identified in cases of
secondary (of known cause other than genetic). HCM. Understanding of the molecular nature of HCM in
Great progress has been made in the understanding of people has progressed rapidly, providing insight into cardio-
primary cardiomyopathies. Mutations in a number of genes myopathies in domestic species. Genes involved in HCM
coding for proteins associated with cardiac contraction lead to include the cardiac troponin T gene (cTnT), the myosin heavy
the development of hypertrophic cardiomyopathy in people chain gene (MyHC), and the cardiac myosin-binding protein C
and gene abnormalities associated with cytoskeletal proteins or gene (MyBPC3). The mutations in each gene appear not to be
mitochondrial enzymes lead to the development of dilated car- singular in nature; for example, many mutations have been
diomyopathies. There is also evidence that one of the cardio- identified in the MyBPC3 gene alone. The inherited form of
myopathies in dogs, and a familial dilated cardiomyopathy in HCM is therefore a genetically diverse disease, which presents
people, results from a mutation in a carnitine transporter gene as a common clinical and pathologic syndrome. Interestingly,
causing an absolute or metabolic deficiency of carnitine and so mutations of the cTnT gene can cause both DCM and HCM,
can be classified as primary. If the understanding of the etiology and mutation in the same codon in the cardiac troponin I
and pathogenesis of the cardiomyopathies continues to prog- (cTnI) gene causes both HCM and RCM.
ress, then the term cardiomyopathy may become obsolete. Restrictive cardiomyopathy (RCM) is characterized by
Cardiomyopathies generally fall into 3 pathologic forms: (1) impaired ventricular filling because of reduced ventricular compli-
dilated (congestive), (2) hypertrophic, and (3) restrictive ance, with unimpaired systolic function. The ventricles are
forms. As the clinical and pathologic patterns of the cardio- usually of normal size, but both atria are usually dilated.
myopathies were first described in people, a brief discussion Reduced compliance of one or both ventricles may occur
of the essential features in this species is warranted. because of interstitial or endomyocardial fibrosis with or
Dilated (congestive) cardiomyopathy (DCM) is a without eosinophilia of the ventricles. Restrictive cardiomy-
common form in humans. The genetic basis of dilated cardio- opathy may also result from the deposition of amyloid
myopathies includes abnormalities in genes associated with or occur in association with the disease sarcoidosis. These
cytoskeletal proteins (such as desmin, lamin A and B) and mito- infiltrative cardiomyopathies are, strictly speaking, secondary
chondrial genes, the latter leading to defects in oxidative cardiomyopathies.
phosphorylation. The endomyocardial form of human RCM is subdivided
DCM is characterized by dysfunction of the systolic phase of into 2 major forms: Loeffler endomyocarditis occurs predomi-
the cardiac cycle, where there is lowered force of contraction nantly in temperate climates; endomyocardial fibrosis is most
and increased ventricular end-diastolic volume. There is common in equatorial Africa. Although the end-stage of both
enlargement and dilation of both atria and ventricles. The forms is pathologically indistinguishable, the natural history
ventricles are hypertrophied, but, because of the dilation, the and clinical patterns are quite separable. The Loeffler (hypere-
hypertrophy is not as apparent as in the hypertrophic form of osinophilic) variant principally affects males and is associated
the disease. Microscopically, there is variation in myocyte size, with hypereosinophilia, thromboembolism, and arteritis. In
myocyte degeneration and necrosis, and variably severe fibro- endomyocardial fibrosis, there is no male predominance, and
sis. These changes are however, from a pathologist’s viewpoint, it occurs in younger patients with no accompanying eosino-
disappointingly nonspecific. philia. At least for the Loeffler variant, endomyocardial fibrosis
A variant of DCM is that of arrhythmogenic right ventricular results from release of granules from infiltrating eosinophils in
cardiomyopathy (ARVC). ARVC is an inherited disease of the earlier phase of the disease.
cardiac myocytes in humans that is characterized by right The major features of the primary cardiomyopathies are
ventricular failure and severe disturbances of cardiac rhythm, depicted in eFigure 1-10. Cardiomyopathies occurring in
including ventricular tachycardia or fibrillation. The molecular domestic animals have been similarly classified and have been
basis of ARVC revolves around defects in desmosomal pro- documented in cats, dogs, cattle, and pigs.
45.e1
but especially notable for the left ventricle (Fig. 1-51A). The
Further reading
left ventricular lumen is often slit-like. Some cases have asym-
Amat di San Filippo C, et al. Cardiomyopathy and carnitine deficiency. metrical hypertrophy of the left ventricle, with the ventricular
Mol Genet Metab 2008;94:162-166. septum thicker than the left ventricular free wall. Findings of
Gomes AV, Potter JD. Molecular and cellular aspects of troponin car- lesser frequency include atrial thrombi, focal areas of ventricu-
diomyopathies. Ann N Y Acad Sci 2004;1015:214-224. lar fibrosis, and fibrosis of the endocardium in the region of
Hare JM. The dilated, restrictive and infiltrative cardiomyopathies. In: the left ventricular outflow tract.
Bonow RO, et al., editors. Braunwald’s Heart Disease: A Textbook Microscopically, myofibers are hypertrophied and contain
of Cardiovascular Medicine. 9th ed. Philadelphia: Elsevier Saunders; vesicular nuclei. Myofiber disarray, characterized by inter-
2012. p. 1561-1581. weaving of myofibers in the left ventricular free wall and
Maron BJ. Hypertrophic cardiomyopathy. In: Bonow RO, et al., editors. ventricular septum, may be observed (Fig. 1-51B). This may
Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. also be present in the right ventricle. Extensive interstitial fibro-
9th ed. Philadelphia: Elsevier Saunders; 2012. p. 1582-1594. sis is also a consistent feature (Fig. 1-51C), especially in the
Nout YS, et al. Cardiac amyloidosis in a horse. J Vet Intern Med inner 2 3 of the left ventricular free wall. Scattered focal areas
2003;17:588-592. of dense replacement fibrosis are seen in a minority of cats.
Schoen FJ, Mitchell RN. The heart. In: Kumar VK, et al., editors. Robbins As indicated by increased plasma cTnI concentrations, cats
and Cotran Pathologic Basis of Disease. 8th ed. Philadelphia: with moderate to severe HCM have ongoing myocardial
Saunders Elsevier; 2010. p. 529-587. damage, which may be the stimulus for replacement fibrosis.
Focal endocardial thickening by fibrosis also occurs commonly.
Intramyocardial arteries may have medial hypertrophy, and
Feline cardiomyopathies scattered perivascular accumulations of lymphocytes and
Feline cardiomyopathies constitute a well-recognized, but diverse, monocytes may be present.
group of morphologic and functional disorders (eFig. 1-11). Ultrastructurally, the hypertrophied myofibers have large
Echocardiography is the definitive test used clinically to dif- pleomorphic nuclei with undulating surfaces and prominent
ferentiate and classify feline cardiomyopathies. Hypertrophic nucleoli. Dense accumulations of Z-band material are also
cardiomyopathy is most commonly encountered (58%), fol- evident in myocytes, as is the presence of lipofuscin granules.
lowed by restrictive (21%), dilated (10%), unclassified (10%), Although these changes are seen in normal cat myocytes, the
and excessive left ventricular moderator band (<1%) cardio- intensity of the changes is greater in cardiomyopathic cases.
myopathies. Although feline cardiomyopathy was only recog- A concentrically hypertrophied heart also occurs in cats
nized as an entity in the relatively recent past, a common with hyperthyroidism, and this should not be confused with
consequence of cardiomyopathy, iliac thromboembolism, was hypertrophic cardiomyopathy (see Cardiac hypertrophy,
originally described >70 years ago. There is a wide range in previously).
the age of onset of clinical signs, from 7 months to 24 years Restrictive cardiomyopathy is a less common and less well-
of age. Presenting clinical signs include lethargy, anorexia, defined form of feline cardiomyopathy and is characterized by
dyspnea, tachypnea, and occasionally abdominal distension. impaired diastolic ventricular filling, which may be due to
Murmurs, most often associated with mitral or tricuspid insuf- severe endomyocardial fibrosis. Systolic function is usually
ficiency, gallop rhythms, and dysrhythmias of various types are normal. Feline RCM has also been termed “left ventricular
frequently encountered. Approximately 13 of cats with car- endocardial fibrosis” (LVEF). Endomyocarditis may be an ante-
diomyopathy develop unilateral or bilateral thromboembolic cedent to LVEF. Feline RCM occurs predominantly in older
hindlimb ischemia. The causes of feline cardiomyopathy cats with clinical signs of left-sided or bilateral heart failure.
include genetic and nutritional origins, and a possible role for Cardiac murmurs and dysrhythmias are common. Pathologic
viral infection following the detection by PCR of feline pan- features include severe endocardial thickening with mural
leukopenia virus genome in cats with idiopathic hypertrophic, thrombosis. Left atrial enlargement is marked, the result of the
dilated, and restrictive cardiomyopathies and myocarditis. restriction of ventricular filling. The left ventricle is thickened,
Hypertrophic cardiomyopathy, the most common form of and the lumen volume may be significantly diminished.
cardiomyopathy in cats, is a diastolic disorder, resulting from Microscopically, the myocardium and endocardium may be
ventricular myocardial hypertrophy in the absence of an replaced by granulation tissue of various ages; adjacent myo-
obvious cause. There is normal or near-normal systolic myo- cardium may be infiltrated by histiocytes, lymphocytes, and
cardial function, but diminished capacity to accept diastolic plasma cells. Bartonella infection has been suggested as a pos-
flow from the left atrium. Left ventricular volume is normal sible cause of feline endomyocarditis. RCM has also been
or decreased, and the papillary muscles are usually greatly reported in cats with hypereosinophilic syndrome.
enlarged in relation to the volume of the ventricle. The left Dilated cardiomyopathy has decreased markedly in pre
atrium is usually dilated. valence since the discovery of taurine-deficiency myocardial
It is inherited as an autosomal dominant trait in Maine failure in cats. On postmortem, all chambers of the heart are
Coon and Ragdoll cats, the basis of which appear to be muta- enlarged, and the ventricles are dilated and flabby with thinned
tions in the gene coding for myosin binding protein C3, a walls (Fig. 1-52). The endocardium may be pale and slightly
defect also described in hypertrophic cardiomyopathy in thickened by subendocardial fibrosis. The papillary muscles
people. Similar and additional mutations in genes coding for and trabeculae may be atrophied and appear small in relation
contractile genes are likely in other breeds, including the Sibe- to the ventricular volume. Often only minor lesions are found
rian, Sphynx, Bengal, Chartreux, and Norwegian Forest cats. on microscopy. Myocardial fibers are moderately hypertro-
The gross pathologic features of feline HCM include an phied, accompanied by mild diffuse interstitial fibrosis. There
enlarged heart, with comparatively massive symmetrical con- may also be focal areas of myofiber loss with replacement
centric hypertrophy of both ventricles in the majority of cases, fibrosis. In some cases, there may be extensive areas of
46.e1
Further reading
Anan R, et al. Patients with familial hypertrophic cardiomyopathy
caused by a Phe110Ile missense mutation in the cardiac troponin T
gene have variable cardiac morphologies and a favorable prognosis.
Circulation 1998;98:391-397.
Dai KS, et al. Intramural coronary arterial disease in swine with natu-
rally occurring hypertrophic cardiomyopathy. J Submicrosc Cytol
Pathol 1997;29:511-519.
Hughes SE. The pathology of hypertrophic cardiomyopathy. Histopa-
thology 2004;44:412-427.
Kushwaha SS, et al. Restrictive cardiomyopathy. N Engl J Med
1997;336:267-276.
Liu SK, et al. Comparison of morphologic findings in spontaneously
occurring hypertrophic cardiomyopathy in humans, cats and dogs.
Am J Cardiol 1993;72:944-951.
Marian AJ, Roberts R. Molecular genetics of hypertrophic cardiomy-
opathy. Annu Rev Med 1995;46:213-222.
Moolman-Smook JC, et al. Identification of a new missense mutation
in MyBP-C associated with hypertrophic cardiomyopathy. J Med
Genet 1998;35:253-254.
Sauramura A, et al. Taurine modulates ion influx through cardiac
calcium channels. Cell Calcium 1990;11:251-259.
Sisson DD, Thomas WP. Myocardial diseases. In: Ettinger SJ, Feldman
EC, editors. Textbook of Veterinary Internal Medicine: Diseases of
the Dog and Cat. 7th ed. Philadelphia: WB Saunders; 1995.
p. 995-1031.
Yu B, et al. Molecular pathology of familial hypertrophic cardiomyopa-
thy caused by mutations in the cardiac myosin binding protein C
gene. J Med Genet 1998;35:205-210.
46.e2
Dilated
Taurine deficiency*
Systolic Dysfunction
Depressed contractility
Ventricles flabby/dilated.
Hypertrophic
Diastolic disorder-
decreased compliance
Concentric hypertrophy Restrictive
Autosomal dominant Feline Severe endomyocardial
in some breeds Cardiomyopathies fibrosis
Mutations in myosin Impaired diastolic filling
binding protein C
Myofiber disarray,
interstitial fibrosis
Excessive moderator
bands
Moderator bands enlarged
Probably a congential
defect rather than
a true primary
cardiomyopathy
eFigure 1-11 Major features of feline cardiomyopathies. Dilation resulting from taurine deficiency
is not technically a cardiomyopathy because of the known etiology.*
Diseases of the Heart Myocardial Disease 47
Canine cardiomyopathies
The most commonly recognized is dilated cardiomyopathy
(DCM), especially in young to middle-aged giant and large-
breed dogs, such as the St. Bernard, Irish Wolfhound, Estrela
Mountain dogs, and Great Dane, but also afflicting an ever-
growing list of other breeds, including Airedale Terriers,
Boxers, Doberman Pinschers, English Cocker Spaniels,
Newfoundlands, Portuguese Water dogs, Presa Canario dogs,
Standard Poodles, and Toy Manchester Terriers. The major
features of the disease are depicted in eFigure 1-12.
Although the causes of canine DCM are still mostly unknown,
it is increasingly apparent that most have a genetic basis, but as
yet, no abnormalities in myocardial cytoskeletal genes have been
identified as they have been in human dilated cardiomyopathy. A
There is a familial tendency in the Doberman Pinscher, English
Cocker Spaniel, Boxer, Great Dane, Irish Wolfhound, and
Newfoundland; DCM may be an X-linked recessive trait in
Great Danes. Infantile dilated cardiomyopathy is inherited in
Portuguese Water dogs as an autosomal recessive trait. There
is a strong association between the presence of cardiomyopa-
thy and a particular complement C4 phenotype (C4:4) in the
English Cocker Spaniel. This is not suggested to be causal, but
to indicate a genotype that is predisposed to the development
of the disease. A singular finding is that of a deficiency in the
mitochondrial respiratory chain in affected Doberman Pin-
schers, which has its origin in a 16-bp deletion in the pyruvate
dehydrogenase kinase 4 (PDK4) gene on chromosome 14.
Carnitine deficiency may play a role in some subtypes of
cardiomyopathy, although the evidence is not strong. Low
blood taurine concentrations have also been found in dogs B
with DCM that had been fed certain lamb-rice commercial
diets. The DCM in Portuguese Water dogs can be reversed in Figure 1-53 Canine dilated cardiomyopathy. A. Dilated left ven-
some pups by oral taurine supplementation. Hypothyroidism tricular lumen accompanied by thinning of the left ventricular
has been noted as a reversible cause of myocardial failure in free wall and interventricular septum. B. Thin, wavy cardiac myo-
2 Great Danes. cytes often seen in dilated cardiomyopathies. (Courtesy E. Olson.)
48.e1
Further reading
Baty CJ, et al. Natural history of hypertrophic cardiomyopathy and
aortic thromboembolism in a family of domestic shorthair cats.
J Vet Intern Med 2001;15:595-599.
Bond BR, et al. Echocardiographic findings in 103 cats with hyperthy-
roidism. J Am Vet Med Assoc 1988;192:1546-1549.
Fox PR, et al. Echocardiographic assessment of spontaneously occur-
ring feline hypertrophic cardiomyopathy. An animal model of
human disease. Circulation 1995;92:2645-2651.
Herndon WE, et al. Cardiac troponin I in feline hypertrophic cardiomy-
opathy. J Vet Intern Med 2002;16:558-564.
Liu SK, et al. Excessive moderator bands in the left ventricle of 21 cats.
J Am Vet Med Assoc 1982;180:1215-1219.
Liu SK, et al. Hypertrophic cardiomyopathy and hyperthyroidism in the
cat. J Am Vet Med Assoc 1984;185:52-57.
Meurs KM, et al. Molecular screening by polymerase chain reaction
detects panleukopenia virus DNA in formalin-fixed hearts from cats
with idiopathic cardiomyopathy and myocarditis. Cardiovasc Pathol
2000;9:119-126.
Nakagawa K, et al. Hypertrophic cardiomyopathy in a mixed breed cat
family. J Vet Med Sci 2002;64:619-621.
Pion PD, et al. Myocardial failure in cats associated with low plasma
taurine: a reversible cardiomyopathy. Science 1987;237:764-768.
Saxon B, et al. Restrictive cardiomyopathy in a cat with hypereosino-
philic syndrome. Can Vet J 1991;32:367-369.
Stalis IH, et al. Feline endomyocarditis and left ventricular endocardial
fibrosis. Vet Pathol 1995;32:122-126.
Taugner FM. Stimulation of the renin-angiotensin system in cats with
hypertrophic cardiomyopathy. J Comp Pathol 2001;125:122-129.
Van Vleet JF, et al. Pathologic alterations in hypertrophic and conges-
tive cardiomyopathy of cats. Am J Vet Res 1980;41:2037-2048.
48.e2
Boxer cardiomyopathy
Arrhythmogenic Right Ventricular Doberman cardiomyopathy
Cardiomyopathy (AVRC) 16bp deletion in pyruvate
Autosomal dominant [incomplete Canine dilated dehydrogenase kinase
penetrance]: 8bp deletion in striatin cardiomyopathies 4[PDK4]gene on chromosome
gene on chromosome 17 14 leading to mitochondral abnormalities
Striatin colocates with 3 and lipofuscin accumulation
desmosomal proteins
distant organs. The finding, in some cases, of multifocal myo- striatin gene located on chromosome 17 in affected Boxer
cardial degeneration, necrosis, or fibrosis is expected, but dogs is encouraging. Striatin co-localizes in the region of the
unrewarding, with regard to possible causes. Ultrastructural intercalated disc with 3 desmosomal proteins. Recent evi-
examination of myocardium from cases of dilated cardiomy- dence also shows that dysfunction in the Wnt/β-catenin
opathy shows increases in intermyofibrillar spaces, lipofuscin pathway is involved where there is mislocalization of
granules, fat droplets and myelin figures, mitochondrial hyper- β-catenin and striatin and an increase in the total amount of
plasia, disruption of myofibrils, and Z-band thickening. These β-catenin in Boxer dogs with ARVC.
ultrastructural changes are not specific for cardiomyopathy, Hypertrophic cardiomyopathy is much less common than
but are more severe than seen with other causes of congestive the dilated form. Associated clinical syndromes include sudden
heart failure. death, death during anesthesia, and congestive heart failure.
There appear to be 2 histologically distinct forms of DCM: Disproportionate thickening of the ventricular septum may
(1) the “fatty infiltration–degenerative” type seen, for example, cause the ratio of the interventricular wall thickness to left
in Boxers and Doberman Pinschers, and (2) the “attenuated ventricular free wall thickness to exceed 1.2:1, and there may
wavy fiber” type seen in many giant-, large-, and medium-sized be histologic evidence of myofiber disarray in the ventricular
breeds, including some Boxers and Doberman Pinschers (Fig. septum.
1-53B). This histologic classification of canine DCM may be In canine X-linked muscular dystrophy in Golden Retriev-
superior to classification by breed-specific syndromes, because ers, an animal model for Duchenne muscular dystrophy in
both forms may affect some breeds, such as Boxers and humans, affected and carrier dogs develop Duchenne cardio-
Doberman Pinschers. This postmortem classification does not myopathy characterized by myocardial interstitial, especially
however assist antemortem etiologic diagnosis of DCM. subepicardial, fibrosis, leading to cardiac insufficiency.
A variant of DCM is arrhythmogenic right ventricular
cardiomyopathy (ARVC), a primary familial myocardial
disease in humans and in Boxer dogs that is associated with Further reading
cardiovascular morbidity and risk of sudden death. It is trans- Bélanger MC, et al. Taurine-deficient dilated cardiomyopathy in a
mitted as an autosomal dominant trait in humans and Boxers. family of golden retrievers. J Am Anim Hosp Assoc 2005;41:284-
ARVC in Boxers is characterized by various events, alone or 291.
in combination, including ventricular arrhythmias of sus- Delmar M, et al. The cardiac desmosome and arrhythmogenic
pected right ventricular (RV) origin, syncope, heart failure, cardiomyopathies: from gene to disease. Circ Res 2010;107:
and/or sudden death. Right ventricular dilation or aneurysms 700-714.
are common. Histopathologic findings include severe myocyte Everett RM, et al. Dilated cardiomyopathy of Doberman pinschers:
loss in the RV, with replacement by adipose or fibroadipose retrospective histomorphologic evaluation of heart from 32 cases.
tissue (Fig. 1-54). Focal fibroadipose lesions may also be Vet Pathol 1999;36:221-227.
present in both atria and in the left ventricle (LV). Myocarditis Legge CH, et al. Histological characterization of dilated cardiomyopa-
may be present in the RV and LV in dogs that have died sud- thy in the juvenile toy Manchester terrier. Vet Pathol 2013;50:1043-
denly and may be the source of arrhythmias. 1052.
ARVC is an ion channel defect in humans, with mutations Lobo L, et al. Histologic characterization of dilated cardiomyopathy in
in genes coding for protein constituents of the special junc- Estrela Mountain Dogs. Vet Pathol 2010;47:637-642.
tions and some nondesmosomal proteins. Mutations identified Meurs KM, et al. A splice site mutation in a gene encoding for PDK4,
include those coding for desmocollin-2, desmoplakin and pla- a mitochondrial protein, is associated with the development of
kophilin, ryanodine receptor 2, desmin, lamins A and C, titin, dilated cardiomyopathy in the Doberman pinscher. Hum Genet
and striatin. The recent discovery of an 8-bp deletion in the 2012;131:1319-1325.
Muers KM, et al. Association of dilated cardiomyopathy with striatin
mutation genotype in Boxer dogs. J Vet Intern Med 2013;27:1437-
1440.
O’Sullivan ML, et al. Evaluation of 10 genes encoding cardiac proteins
in Doberman Pinschers with dilated cardiomyopathy. Am J Vet Res
2011;72:932-939.
Oxford EM, et al. Change in β-catenin localization suggests involve-
ment of the canonical Wnt pathway in Boxer dogs with arrhyth-
mogenic right ventricular cardiomyopathy. J Vet Intern Med
2014;28:92-101.
Ricklet S, Pieperhoff S. Mutations with pathogenic potential in proteins
located in or at the composite junctions of the intercalated disk
connecting mammalian cardiomyocytes: a reference thesaurus for
arrhythmogenic cardiomyopathies and for Naxos and Carvajal dis-
eases. Cell Tissue Res 2012;348:325-333.
Vollmar A, et al. Dilated cardiomyopathy in juvenile doberman pin-
schers. J Vet Cardiol. 2003;5:23-27.
Werner P, et al. A novel locus for dilated cardiomyopathy maps to
canine chromosome 8. Genomics 2008;91:517-521.
Figure 1-54 Arrhythmogenic right ventricular cardiomyopathy Wiersma AC, et al. Evaluation of 15 candidate genes for dilated car-
in a Boxer dog. Note the extensive, cardiac myocyte replacement diomyopathy in the Newfoundland dog. J Hered 2008;99:73-80.
by adipose tissue. (Courtesy E. Olson.)
49.e1
Bovine cardiomyopathies†
Several syndromes of cardiomyopathy are recorded in cattle.
Dilated cardiomyopathy occurs in Holsteins in many countries,
including Canada, Australia, and Japan, and in Simmental-Red
Holstein crossbreds in Switzerland. Many of the cases emanate
from common sires, and an autosomal recessive mode of
inheritance has been suggested. A nonsense mutation in the
optic atrophy 3 (OPA3) gene on chromosome 18 is present
in affected Red Holstein cattle. OPA3 is located on the mito-
chondrial membrane, and mutations lead to disruption of
mitochondrial morphology, and presumably, mitochondrial
dysfunction. OPA3 mutations are also involved in the devel-
opment of optic atrophy, cataracts, and neurologic disorders.
The cardiomyopathy occurs in young adult to mature animals, A
with the clinical signs particularly referable to right-sided
heart failure, including dependent subcutaneous edema,
hydrothorax, ascites, and severe hepatic congestion. There is
no indication of the presence of electrocardiographic abnor-
malities. The heart is enlarged with dilation of both ventricles.
Microscopically, there is a mixture of atrophied and hypertro-
phied myofibers with vacuolation, and there are islands of
interstitial and replacement fibrosis, fatty replacement, and
ongoing myofiber necrosis.
Dilated cardiomyopathy in Japanese black calves is con-
sidered to be inherited as an autosomal recessive trait. Sudden
death or death after a short period of severe dyspnea occurs
in calves younger than 30 days. Lesions found at autopsy
include marked cardiac enlargement with left ventricular
dilation, hydropericardium, hydrothorax, ascites, pulmonary
edema, and hepatic and splenic congestion. Extensive myo- B
cardial degeneration and necrosis with fibrosis are present in
the left ventricle, particularly affecting the papillary muscles.
The right ventricle is similarly but less often involved. The
clinical and pathologic pattern is reminiscent of that seen in
Hereford calves with cardiomyopathy.
A cardiomyopathy associated with a tightly curled
(“woolly”) haircoat in polled and horned Herefords has also
been described. This cardiocutaneous syndrome is inherited
as an autosomal recessive trait and is now known to be caused
by a 7-bp duplication in the NF kappaB interacting protein 1
gene on chromosome 18. In contrast, similar human cardio-
cutaneous diseases, such as Naxos disease and Carvajal syn-
drome, are caused by mutations in genes encoding proteins
associated with composite intercellular junctions.
Affected animals are identifiable at birth by their distinc- C
tive haircoat and signs of cardiac dysfunction, including Figure 1-55 Cardiomyopathy and woolly haircoat syndrome in
arrhythmias. Some calves develop bilateral ocular keratitis Hereford calves. A. Extensive subepicardial fibrosis of the right
immediately after birth. Most calves are found dead at <12 ventricle in a 7-day-old calf. B. Severe myocardial necrosis, min-
weeks of age. Occasionally, calves are seen to collapse and die eralization, and fibrosis of both ventricles in a 5-day-old calf.
following exertion. Even in some calves that die at 1 week of C. Extensive subepicardial myocyte loss with replacement fibrosis
age, there are severe lesions in the ventricles consisting of in a 17-day-old calf. Masson trichrome. (Courtesy R.W. Cook.)
necrosis, mineralization, and fibrosis of the myocardium, and
are detectable at birth, an indication of their in utero onset
(Fig. 1-55A-C). heart failure, and in these, the heart is eccentrically
Hypertrophic cardiomyopathy has been reported in hypertrophied.
Holsteins.
Bovine generalized glycogenosis type II (Pompe’s disease),
although not a primary cardiomyopathy, deserves mention. Further reading
Most affected animals have generalized muscle weakness. Furuoka H, et al. Hereditary dilated cardiomyopathy in Holstein-Friesian
Occasional cases, however, exhibit clinical signs of left-sided cattle in Japan: association with hereditary myopathy of the dia-
phragmatic muscles. J Comp Pathol 2001;125:159-165.
†
Contribution to this section by Dr. R. Cook is gratefully Nart P, et al. Morphometry of bovine dilated cardiomyopathy. J Comp
acknowledged. Pathol 2004;130:235-245.
50.e1
Further reading
Bradley R, et al. Cardiomyopathy in adult Holstein Friesian cattle in
Britain. J Comp Pathol 1991;104:101-112.
Dolf G, et al. Evidence for autosomal recessive inheritance of a major
gene for bovine dilated cardiomyopathy. J Anim Sci 1998;76:1824-
1829.
Machida N, et al. Two necropsy cases of hypertrophic cardiomyopathy
in Holstein cattle. J Vet Med Sci 1996;58:929-932.
Storie GJ, et al. Cardiomyopathy and wooly haircoat syndrome of
Hereford cattle. Aust Vet J 1991;68:119.
Watanabe S, et al. Evidence for a new lethal gene causing cardiomy-
opathy in Japanese black calves. J Heredity 1979;70:255-258.
Weekes J, et al. Bovine dilated cardiomyopathy: proteomic analysis of
an animal model of human dilated cardiomyopathy. Electrophoresis
1999;20:898-906.
Diseases of the Heart Diseases of the Conduction System 51
Owczarek-Lipska M, et al. A nonsense mutation in the optic atrophy paroxysmal AV block could be related to the lesion in the
3 gene (OPA3) causes dilated cardiomyopathy in Red Holstein common bundle, but the sinus pauses are probably the result
cattle. Genomics 2011;97:51-57. of excessive parasympathetic activity. Affected dogs are abnor-
Simpson MA, et al. A mutation in NFkappaB interacting protein 1 mally sensitive to small amounts of acetylcholine.
causes cardiomyopathy and woolly haircoat syndrome of Poll Her- Deafness in the Dalmatian dog is associated with an abnor-
eford cattle. Anim Genet 2009;40:42-46. mal blotchy coat color, and such animals may die suddenly. A
proportion of affected dogs exhibit episodes of sinus pauses.
In one case, the right atrium was fibrotic and atrophied. This
DISEASES OF THE CONDUCTION SYSTEM was accompanied by marked narrowing of the coronary arter-
ies, including those of the sinus node. These clinical and patho-
The clinical and electrocardiographic features of primary con- logic findings are similar to those seen in congenital deafness
duction system disturbances are well documented, but com- in humans.
paratively rare. The clinical signs are primarily intermittent The presence of an atrophic and fibrotic atrium in the
collapse, and sometimes sudden death. Electrocardiography previous case is the outstanding feature of the syndrome of
may show a variety of abnormalities, such as sinoatrial persistent atrial standstill, which occurs in dogs (most com-
arrest, second- or third-degree atrioventricular (AV) block, monly in English Springer Spaniels) and has been described in
AV dissociation, left or right bundle branch block, Wolff- Siamese cats. The atrium is grossly dilated, and the walls are
Parkinson-White syndrome (rarely), and ventricular tachycar- thin, transparent, and pink. Microscopically, there is myocyte
dia. It should not be forgotten that many if not most atrophy and fibrosis, with a variable mononuclear cell pres-
dysrhythmias are secondary to more or less extensive myocardial ence. In some cases, atrophy of skeletal musculature is also
degeneration, necrosis, inflammation, or neoplasia, particularly evident. Given the nature of the end-stage lesions, the ante-
when in close proximity to the conduction system. cedent may be an active myocarditis (see Fig. 1-49). The
In contrast, reports on the gross and microscopic examination syndrome is similar in many respects to a form of muscular
of cases of primary conduction system disturbances are remark- dystrophy in people termed Emery-Dreifuss disease.
ably sparse. This may be due in part to negative pathologic Sick sinus syndrome occurs in Miniature Schnauzers, West
findings in some cases, or to time and effort required to ade- Highland White Terriers, and Dachshunds, and it is familial in
quately examine the conduction system. When an abnormal- Miniature Schnauzers. Prolonged sinus pauses cause syncope.
ity of the conduction system is suspected, tissue samples from Defects of the conduction system of Alaskan sled dogs
the appropriate regions should be collected as part of the that died suddenly during the Iditarod race included marked
postmortem (see Examination of the heart, previously). The fibrosis or fatty infiltration of the sinus node, AV node, AV
use of special stains such as Masson trichrome and phospho- bundle, and bundle branches, and focal scarring of the left
tungstic acid hematoxylin (PTAH) assist in highlighting the ventricle. These pathologic changes may have led to fatal
presence of excessive fibrosis and the relative paucity of con- dysrhythmias.
tractile elements in the cells of the conduction system, respec- Equine grass sickness (equine dysautonomia) is suspected
tively. For purposes of comparison, it is advisable to have a to be a clinical form of botulism. The neurodegenerative
reference set of blocks of the conduction system from normal changes noted in terminal parasympathetic ganglionic neurons
animals. in the heart, which include chromatolysis and vacuolation,
Sudden unexpected death, sudden episodes of viciousness may account for the tachycardia noted in this disease.
or seizures have been associated with AV nodal, or common Ventricular pre-excitation, a rare cause of weakness,
bundle degeneration, particularly in the Doberman Pinscher. syncope, or congestive heart failure in dogs and cats, can result
Note that the presence of mineralized cartilage or osseous when sinus node impulses bypass the normal conduction
metaplasia in the central fibrous body in close proximity to system via accessory pathways (bundle of Kent, James fibers,
conduction tissue is a normal finding in large-breed dogs at all Mahaim fibers, or intranodal tract) to cause premature ven-
ages. The common bundle is fibrotic, degenerate, and in some tricular activation.
cases replaced by fat. In most cases, there is myointimal
proliferation in arterioles in this region, possibly leading to Further reading
ischemia of the common bundle. A similar phenomenon Fonfara S, et al. English Springer Spaniels with significant
has been observed in other breeds, including the German bradyarrhythmias-presentation, troponin I and follow up after pace-
Shepherd dog. maker implantation. J Small Anim Pract 2010;51:155-161.
There is also a syndrome of sudden death in outwardly Kaneshige T, et al. Complete atrioventricular block associated with
healthy, nonsyncopal young German Shepherd dogs that is sus- lymphocytic myocarditis of the atrioventricular node in two young
pected to be hereditary in nature. Affected animals die unex- adult dogs. J Comp Pathol 2007;137:146-150.
pectedly during sleep or during rest following exercise. Park DS, Fishman GI. The cardiac conduction system. Circulation
Ventricular tachycardia is the most common arrhythmia, the 2011;123:904-915.
frequency of which increases during rest when the heart rate Perkins JD, et al. Functional and histopathological evidence of cardiac
is slowest, and ends in ventricular fibrillation. The underlying parasympathetic dysautonomia in equine grass sickness. Vet Rec
defect is suggested to be regional paucity of sympathetic 2000;146:246-250.
nerves in ventricular myocardium. Sosunov EA, et al. Mechanisms of alpha-adrenergic potentiation of
Hereditary stenosis of the common bundle has been ventricular arrhythmias in dogs with inherited arrhythmic sudden
observed in cases of syncope and sudden death in Pug dogs. death. Cardiovasc Res 2004;61:715-723.
Electrocardiographically, such dogs have intermittent sinus Woolley R, et al. Atrial myocarditis as a cause of sinus arrest in a dog.
arrest and paroxysmal second-degree AV block. The sinus J Small Anim Pract 2007;48:455-457.
node, the AV node, and the bundle branches are normal. The
51.e1
Further reading
Beckett SD, et al. Syncopal attacks and sudden death in dogs: mecha-
nisms and etiologies. J Am Anim Hosp Assoc 1978;14:378-386.
Bharati S, et al. The conduction system in sudden death in Alaskan sled
dogs during the Iditarod race and/or during training. Pacing Clin
Electrophysiol 1997;20(3 Pt 1):654-663.
Brain CM, et al. Sudden and unexpected death in horses and ponies:
an analysis of 200 cases. Equine Vet J 1988;20:99-103.
Gavaghan BJ, et al. Persistent atrial standstill in a cat. Aust Vet J
1999;77:574-579.
Hill BL, Tilley LP. Ventricular preexcitation in seven dogs and nine cats.
J Am Vet Med Assoc 1985;187:1026-1031.
James TN. Congenital deafness and cardiac arrhythmias. Am J Cardiol
1967;19:627-643.
James TN, et al. Hereditary stenosis of the His bundle in pug dogs.
Circulation 1975;52:1152-1160.
James TN, Drake EH. Sudden death in Doberman pinschers. Ann Intern
Med 1968;68:821-829.
Kiryu K, et al. Pathologic and electrocardiographic findings in sudden
cardiac death in racehorses. J Vet Med Sci 1999;61:921-928.
Liu SK, et al. Lesions of the conduction system in the cat with cardio-
myopathy. Recent Adv Cardiac Struct Metab 1975;10:681-693.
Meierhenry EF, Liu SK. Atrioventricular bundle degeneration associated
with sudden death in the dog. J Am Vet Med Assoc 1978;172:1418-
1422.
Moise NS. Inherited arrhythmias in the dog: potential experimental
models of cardiac disease. Cardiovasc Res 1999;44:37-46.
Robinson WF, et al. Sinoatrial arrest associated with primary atrial
myocarditis in a dog. J Small Anim Pract 1981;22:99-107.
Sandusky GE Jr, et al. Morphologic variations and aging in the atrio-
ventricular conduction system of large breed dogs. Anat Rec
1979;193:883-902.
52 CHAPTER 1 • Cardiovascular System Neoplasms of the Heart
A
a variety of organs, including the lung, brain, meninges, and
tongue. The tumor has a distinctive light and electron micro-
scopic appearance consisting of spindle-shaped to large polyg-
onal cells containing prominent cytoplasmic granules within
lysosomes. The cells are considered to be of neural origin as
nerve-specific S100 protein is present within the cytoplasmic
granules.
Neurofibromas (schwannomas) are either isolated or mul-
tiple benign neoplasms of peripheral nerves (Fig. 1-58, eFig.
1-13). Cattle are most frequently affected, with the most
common sites being peripheral nerves, brachial plexus, auto-
nomic ganglia, intercostal nerves, and cardiac nerves. The
disease is usually detected only at slaughter. When the heart
is involved, the tumors are single or multiple, round or nodular
masses, either on the epicardial surface or within the myocar-
dium. The microscopic appearance is of interwoven bundles
or whorls of elongated cells. There may be palisading of nuclei B
and variable amounts of collagen present. The principal cell is
Figure 1-59 Metastatic lymphoma in a dog. A. Lymphoma in all
probably of Schwann or perineural origin.
chambers of the heart. B. Opened atria showing lymphoma pro-
Lymphoma (lymphosarcoma) is the most common meta-
truding into atrioventricular lumen. (Courtesy A. G. Armien.)
static neoplasm involving the heart (Fig. 1-59A, B), and occurs
most commonly in the cow and the dog. It may be nodular
or diffuse, although the distinction is arbitrary because there
is overlap of the 2 forms. In the nodular form, there are foci,
primarily in the atria (particularly the right atrium), which
may be up to 5 cm or more in diameter. The nodules are Further reading
covered by endothelium and are therefore smooth. When Akkoc A, et al. Cardiac metastasing rhabdomyosarcoma in a great
beneath the epicardium, they may be difficult to distinguish dane. Vet Rec 2006;158:803-804.
from epicardial fat. They are prone to central necrosis, and this Aupperle H, et al. Primary and secondary heart tumours in dogs and
resembles necrotic adipose tissue. On section, the wall of the cats. J Comp Pathol 2007;136:18-26.
atrium is more diffusely thickened, is moderately soft to cut, Castleman WL, et al. Rhabdomyosarcoma in 8 horses. Vet Pathol
and has a pale appearance. If squeezed, milky fluid exudes 2011;48:1144-1150.
from the cut surface. Globular masses like those beneath the Jacobsen B, et al. Proposing the term purkinjeoma: protein gene
epicardium are also found under the endocardium projecting product 9.5 expression in 2 porcine cardiac rhabdomyomas indi-
into the cardiac cavities. In the diffuse or infiltrating form, the cates possible purkinje fiber cell origin. Vet Pathol 2010;47:738-
myocardium appears irregularly thickened and gray-white, 740.
with the ventricular walls being especially involved. These foci Misdorp W. Congenital and hereditary tumours in domestic animals:
or areas of infiltration blend with normal myocardium and 2. Pigs. A review. Vet Q 2003;25:17-30.
hence are difficult to distinguish from foci of myocardial Pavarini SP, et al. Malignant peripheral nerve sheath tumor as a cause
degeneration or myocarditis. If they cause some thickening of of chronic cardiac insufficiency in cattle. Acta Vet Scand 2013;55:
the myocardium, such lesions are to be first regarded as lym- 7-13.
phoma and indicate the need for careful search for primary Soilleux EJ, Davies DR. Epithelial cyst of the cardiac papillary muscle:
lesions elsewhere in the body. Lymphoid neoplasms are con- case report and review of the literature. J Clin Pathol 2006;59:1203-
sidered in detail in Vol. 3, Hematopoietic system. 1205.
53.e1
Further reading
Albers TM, et al. Histochemical and ultrastructural characterization of
primary cardiac chondrosarcoma. Vet Pathol 1997;34:150-151.
Balli A, et al. Cardiac tamponade due to pericardial mesothelioma in
an 11-year-old dog: diagnosis, medical and interventional treat-
ments. Schweiz Arch Tierheilkd 2003;145:82-87.
Bradley R, et al. Ovine and porcine so-called cardiac rhabdomyoma
(hamartoma). J Comp Pathol 1980;90:551-558.
Campbell MD, Gelberg HB. Endocardial ossifying myxoma of the right
atrium in a cat. Vet Pathol 2000;37:460-462.
Colbourne CM, et al. Mesothelioma in horses. Aust Vet J 1992;69:275-
278.
Foale RD, et al. Left ventricular myxosarcoma in a dog. J Small Anim
Pract 2003;44:503-507.
Girard C, et al. Intrapericardial neoplasia in dogs. J Vet Diagn Invest
1999;11:73-78.
Machida N, et al. Cardiac myxoma of the tricuspid valve in a dog.
J Comp Pathol 2003;129:320-324.
Machida N, et al. Primary malignant mixed mesenchymal tumour of
the heart in a dog. J Comp Pathol 2003;128:71-74.
Machida N, et al. Myocardial hamartoma of the right atrium in a dog.
J Comp Pathol 2002;127:297-300.
Merlo M, et al. Primary right atrium haemangiosarcoma in a cat.
J Feline Med Surg 2002;4:61-64.
Omi K, et al. An immunohistochemical study of peripheral neuro
blastoma, ganglioneuroblastoma, anaplastic ganglioglioma,
schwannoma and neurofibroma in cattle. J Comp Pathol 1994;111:
1-14.
Perez J, et al. Right-sided heart failure in a dog with primary cardiac
rhabdomyosarcoma. J Am Anim Hosp Assoc 1998;34:208-211.
Sanford SE, et al. Primary cardiac granular cell tumor in a dog. Vet
Pathol 1984;21:489-494.
Swartant MS, et al. Intracardiac tumors in two dogs. J Am Anim Hosp
Assoc 1987;23:533-538.
Tanimoto T, Ohtsuki Y. The pathogenesis of so-called cardiac rhabdo-
myoma in swine: a histological, immunohistochemical and ultra-
structural study. Virchows Arch 1995;427(2):213-221. Erratum in:
Virchows Arch 1996;428:69.
Taylor DP, et al. Primary cardiac rhabdomyosarcoma in a steer. Aust Vet
J 2002;80:571-572.
Uno K, et al. Extraskeletal mesenchymal chondrosarcoma in a cow.
J Comp Pathol 1989;101:31-38.
Venco L, et al. Primary cardiac rhabdomyosarcoma in a cat. J Am Anim
Hosp Assoc 2001;37:159-163.
Ware WA, Hopper DL. Cardiac tumors in dogs: 1982-1995. J Vet Intern
Med 1999;13:95-103.
54 CHAPTER 1 • Cardiovascular System General Considerations
Tursi M, et al. Myocardial adenomatoid tumor in eight cattle: evidence expansion of the elastic arteries. Elastic fibers decrease in the
for mesothelial origin of bovine myocardial epithelial inclusions. Vet adventitia with decreasing vessel size. Vasa vasorum and nervi
Pathol 2009;46:897-903. vasorum supply the adventitia and the outer half of the media.
Une Y, et al. Cardiac angioleiomyoma in 44 cattle in Japan (1982- The intima and inner half of the media are avascular and depen-
2009). Vet Pathol 2010;47:923-930. dent upon diffusion from the vascular lumen, and are thus
more subject to degenerative changes than the outer media.
The microcirculation is the exchange system in which gases,
nutrients, and waste products are transferred between the blood
DISEASES OF THE VASCULAR SYSTEM
and the extravascular tissues. The microcirculation consists of
GENERAL CONSIDERATIONS vessels of <100 µm in diameter: namely, arterioles, terminal
arterioles (metarterioles, precapillary sphincter areas), capillaries,
The vascular system may be arbitrarily divided into a delivery postcapillary venules, and venules. This classification overlaps
system (the arterial system), an exchange network (the microcir- microcirculation and macrocirculation (arteries and veins),
culation), and a removal system (the venous and lymphatic but is useful conceptually as will be seen in disorders such as
systems). Impaired function of the vascular system can be disseminated intravascular coagulation, which affect primarily
generalized, as occurs in shock, or may be localized when the the microcirculation. Arterioles open through precapillary
supply of oxygenated arterial blood to tissue is decreased, sphincters or through metarterioles into capillaries in most
causing ischemia. Impaired venous drainage causes congestion, tissues, or into sinusoids in the liver. Capillaries are low-
and decreased lymphatic drainage of tissue fluids causes pressure tubules, of ~8 µm in diameter, composed of endo-
lymphedema. thelial cells surrounded by a basal lamina; the endothelial cells
The arterial system is subdivided into large elastic arteries, are connected by tight junctions that allow rapid passage of
medium and small muscular arteries, and arterioles, with gradual small molecules such as glucose. The basal lamina is a molecu-
transitions between these divisions. Arterial vessels are char- lar sieve that prevents passage of larger protein molecules.
acterized histologically by walls composed of 3 layers: the Capillary endothelial cells possess few endoplasmic organelles,
internal, middle, and external tunics; or tunica interna (intima), but often contain pinocytotic vesicles. Capillaries may be con-
tunica media (media), and tunica externa (adventitia). tinuous, the most common type; fenestrated (60-80 µm fenes-
The intima consists of endothelium; subendothelial con- trae closed by thin diaphragms), as in the gastrointestinal tract
nective tissue, which contains collagen, elastin, proteoglycan and endocrine glands; or porous (without diaphragms closing
(ground substance), fibroblasts and smooth muscle cells; and the pores), as in renal glomeruli. Fenestration of the endothe-
the internal elastic membrane, which is the outer limit of the lial cells allows increased permeability. During tissue healing,
intima. The thickness of the intima decreases as the vessel size cords of endothelial cells grow into the tissues by mitosis,
decreases, until the subendothelial layer eventually disappears. develop lumina, and become functional capillaries. Undiffer-
The internal elastic membrane is not readily distinguishable entiated perivascular cells, or pericytes, are ensheathed by gly-
in elastic arteries because of its continuity with medial elastic cocalyx that is continuous with the capillary basal lamina.
tissue, but is very prominent in muscular arteries, and disap- Mitosis of pericytes is easily stimulated, and they may be
pears at the level of the smaller arterioles. transformed into fibroblasts or smooth muscle cells. Sinusoids
The media consists of concentric layers of smooth muscle are less uniform than capillaries and more permeable because
cells and elastic fibers, and the external elastic membrane. there are large openings between the endothelial cells and a
In elastic arteries, the media consists of fenestrated elastic discontinuous basal lamina.
laminae, with smooth muscle cells lying between laminae. Veins are termed small, medium, or large or, alternatively,
Intercellular ground substance is especially prominent in the venules, collecting veins, and great veins; all have large lumina
tunica media of elastic arteries in the horse. The elastic laminae in relation to their wall thickness. Classification of veins by
diminish and smooth muscle predominates as vessels become wall characteristics is difficult because the layers in their walls
more distant from the heart. The media of muscular arteries is may be absent or difficult to distinguish. Venules of >30 µm
up to 40 muscle cells thick, whereas the media of arterioles in diameter have an incomplete muscular media and thin
is 1-3 cells thick. Definitions of the upper limit of arteriolar adventitia. Venular endothelium is normally more permeable
diameter range from 300 µm if tissues are fixed by perfusion than that of capillaries and is also more sensitive to vasoactive
to 100 µm if allowed to contract, but there are no sharp dis- amines, the action of which can cause leakage. In the lymph
tinctions between small arteries and large arterioles. The thick- node paracortex, postcapillary venules, which are nonmuscular
ness of the media as seen in routine material is greatest in venules with prominent endothelium, are important sites of
relation to the luminal diameter in small arteries and arteri- lymphocytic traffic. The media is of increasing thickness in
oles, and it is these vessels, particularly arterioles, which par- medium and large veins, and the internal elastic lamina
ticipate actively in blood pressure regulation and also bear the becomes more prominent. However, the adventitia is the thick-
consequences of hypertension. Contraction of muscular arter- est layer in veins, whereas the media predominates in arteries.
ies and arterioles upon an animal’s death forces blood from Backflow of blood in veins is prevented by the presence of
the lumina, and causes longitudinal folding that appears as semilunar valves, which are invaginations of the intima into
scalloping of the internal elastic membrane when seen in the venous lumen. Venous valves are not present in venae
cross-section. The external elastic membrane is best defined cavae or hepatic portal vein. Paucity of valves in veins of the
in the large elastic arteries, and becomes indistinct in muscular head and face may contribute to incidental venous congestion
arteries. in these areas.
The adventitia consists of a feltwork of elastic and collagen Lymphatic capillaries originate in loose connective tissue,
fibers continuous with the surrounding connective tissue. The and consist of very permeable walls and endothelial cells that
interlacing network of collagen fibers in the adventitia limits may lack, or have a discontinuous, basal lamina. In larger
Diseases of the Vascular System General Considerations 55
lymphatics, valves are present, the basal lamina is continuous, Endothelial cells aid in the regulation of inflammation and
and walls consist of 3 ill-defined layers; an internal elastic immunity through production of IL-1 and various adhesion
lamina is usually absent. The thin-walled veins and lymphatics molecules, which moderate adhesion and hence emigration of
are more susceptible to compression and occlusion, are more leukocytes. The most important adhesion molecule pairs are
often involved by inflammation in adjacent tissue, and are the selectins, the immunoglobulins intercellular adhesion
more liable to neoplastic invasion than are the thicker-walled molecule 1 (ICAM-1) and vascular cell adhesion molecule 1
arteries. (VCAM-1), and the β2 and β1 integrins. Endothelial cells also
Endothelium and smooth muscle, the main components of aid in regulation of cell growth by production of growth stimula-
vessel walls, play important roles in all types of vascular disease. tors (platelet-derived growth factor, colony-stimulating factor,
A wealth of information is accumulating about the important and fibroblast growth factor), and production of growth inhib-
properties and reactive capabilities of these seemingly simple itors (heparin, transforming growth factor-β). Endothelial cells
cells. For example, in addition to maintaining a permeability produce basement membrane, and are capable of contraction.
barrier between blood and tissues, the endothelium is recognized The endothelium is a semipermeable membrane that can
as the largest paracrine organ in the body. It produces antico- also transport metabolites, including proteins through the
agulants, procoagulants, fibrinolytic agents, prostanoids, con- cytoplasm via pinocytotic vesicles. Weibel-Palade bodies,
nective tissue components, adenosine, and a host of other rod-shaped cytoplasmic organelles that store von Willebrand
substances. Vascular homeostasis is maintained by complex factor, serve as ultrastructural markers of endothelial cells.
interactions among endothelial cells, leukocytes, and platelets, Subendothelial connective tissues consist of various types of
each of which produce vasodilators and vasoconstrictors and collagen, elastin, proteoglycans, fibronectin, laminin, and
can interact to inhibit or promote thrombosis. thrombospondin. Of these, fibrillar collagen is the most potent
Vascular endothelial cells, as well as forming the throm stimulus for platelet adhesion and activation; collagen also
boresistant monolayer lining of the vascular system, activates the intrinsic pathway of coagulation. Fibronectin, or
mechanically insulate the circulating blood from the highly “molecular glue,” normally functions to stabilize cell-to-cell
thrombogenic subendothelial materials. The thromboresis- and cell-to-substrate attachments, but also becomes cross-
tance of the endothelium is normally maintained by a balance linked to fibrin and helps to anchor hemostatic plugs.
between antithrombotic and thrombotic factors; stimulation Mild endothelial injury, as occurs in the course of inflam-
of excessive prothrombosis can lead to clotting and thrombo- mation, may be apparent histologically as hypertrophy of
sis, whereas excessive antithrombosis can lead to ineffective endothelial cells (“reactive” cells). As well, increased vascular
hemostasis and bleeding (eFig. 1-14). permeability may lead to insudation of plasma proteins,
Antithrombosis is normally accomplished through including fibrinogen, into the subendothelial area, and hence
• Binding and inhibition of thrombin via activation by contribute to vascular hyalinosis. Because the intima and inner
thrombomodulin of protein C and protein S, via accentua- media depend upon diffusion of metabolites from the vascular
tion of antithrombin activity by heparin-like molecules, lumen for their nutrition, such subendothelial deposits may
and via the presence of α2-macroglobulin impair the viability of smooth muscle cells and contribute to
• Inhibition of platelet aggregation through elaboration of degeneration, or fibrinoid necrosis, of vessel walls. Thus the
prostacyclin (PGI2), a potent inhibitor of platelet aggrega- endothelial barrier must be preserved to maintain a normal envi-
tion and a vasodilator, and by adenosine diphosphatase ronment for medial smooth muscle cells. Necrosis of endothe-
(ADPase)-mediated conversion of pro-aggregating ADP to lium, which may be caused by a wide variety of agents, leads
adenine nucleotide platelet inhibitors to exposure of subendothelial collagen, a potent inducer of
• Promotion of fibrinolysis by synthesis of tissue plasminogen coagulation and platelet aggregation, and hence thrombosis.
activators Endothelial cells at the edges of denuded areas will proliferate
Procoagulant activities include: and migrate to repair the endothelial defect or to form an
• The presence of minute amounts of tissue factor (tissue endothelial covering over (endothelialize) a mural thrombus.
thromboplastin) in endothelial cells, further production of Severe microvascular damage, as occurs because of lipoperoxi-
which can be stimulated by endotoxin and by cytokines dation of endothelial membranes in vitamin E/selenium defi-
such as interleukin-1 (IL-1) and tumor necrosis factor ciency in pigs, can result in hemorrhage and organ failure.
• Synthesis and secretion of von Willebrand factor, needed Vascular smooth muscle cells are important both as effec-
for adherence of platelets to subendothelial components, tors of vasoconstriction and dilation, and as cells capable of
and secretion of platelet activating factor, an activator and synthesizing basement membrane, collagen, elastin, and pro-
aggregator of platelets teoglycans of the extracellular space. In response to growth
• Inhibition of fibrinolysis through release of plasminogen factors derived from platelets and monocyte/macrophages,
activator inhibitors smooth muscle cells of the media migrate through fenestrae
In addition to their role in hemostasis, endothelial cells of the internal elastic lamina to the subendothelial area where,
participate in modulation of blood flow and vascular reactivity as “myointimal” cells, they proliferate and are responsible for
by production of endothelium-derived relaxing factor (nitric organization or collagenization of deposits, including thrombi.
oxide); endothelin, a vasoconstrictor; angiotensin converting Examples of endoarterial organization and arterio-occlusive
enzyme, which converts angiotensin I to angiotensin II; and disease are discussed later in this chapter. In common with
prostacyclin. Endothelial cells modulate the actions of various other muscle cells, medial smooth muscle cells respond to an
vasoconstrictors (catecholamines, serotonin, arginine, vaso- increased workload by hypertrophy. Medial hypertrophy is a
pressin) and vasodilators (histamine, leukotrienes, adenine prominent consequence, as well as a cause, of pulmonary
nucleotides), and in concert with the endothelium-derived hypertension. Sustained vasoconstriction, as is induced by
factors can thereby allow blood vessels to rapidly adapt to ergot (Claviceps purpurea) or fescue grass (Festuca arundina-
changes in hemodynamic conditions. cea, Festuca eliator) poisoning, can lead to gangrene of the
55.e1
Thrombosis Antithrombosis
Release of tissue factor Binding and inhibition of thrombin
from subendothelium after via thrombomodulin activation
endothelial cell injury. of protein C & S
Heparin-like molecules
-2 macroglobulin
eFigure 1-14 Balance between thrombotic and antithrombotic factors. ADP, adenosine
diphosphate.
56 CHAPTER 1 • Cardiovascular System Arteries
extremities; fescue toxicosis in cattle (summer syndrome) is capillaries. They may also connect with coronary arterioles to
caused by infestation of the grass by the endophyte Neotypho- form direct connections between the coronary arterioles and
dium (Acremonium) coenophialum, which produces the ergo- the cardiac chambers. Areas of myocardium in which the
peptide alkaloids, ergovaline, ergosine, and ergonine. Along Thebesian vein system is richly persistent are randomly dis-
with the other components of the vessel wall, smooth muscle tributed, and the true nature of the defect may be overlooked
cells may be involved in degenerative and inflammatory because of the tortuous aneurysmal dilation of the affected
changes, as described later, and contribute to fibrinoid necrosis coronary artery. Injection studies are necessary to demonstrate
of the wall. the extent of the anastomosis.
Normal aging changes of vessels include intimal thickening
resulting from proliferation of myointimal cells and accumula-
tion of their products, deterioration of medial elastic fibers, Further reading
medial fibrosis and loss of medial smooth muscle, and accu- Hosgood G. Arteriovenous fistulas: pathophysiology, diagnosis, and
mulation of ground substance in the media. These slowly treatment. Compend Contin Educ Pract Vet 1989;11:625-636.
progressive changes are usually of little consequence given the Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
large functional reserve of the vascular system, but do lead to patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
loss of resilience of the vessel walls and may cause vessel wall Sci 2004;66:299-302.
thinning, stretching, and hence increased tortuosity. Nakata TM, et al. Transarterial coil embolization of an abdominal aor-
tocaval fistula in a dog. J Vet Intern Med 2014;28:656-660.
Further reading
Bajema IM, Bruijn JA. What stuff is this! A historical perspective on Degeneration of arteries
fibrinoid necrosis. J Pathol 2000;191:235-238. Arteriosclerosis
Botha CJ, et al. Gangrenous ergotism in cattle grazing fescue (Festuca Arteriosclerosis literally means “hardening of the arteries,” and
elatior L.) in South Africa. J S Afr Vet Assoc 2004;75:45-48. is more fully defined as chronic arterial change consisting of
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth hardening, loss of elasticity, and luminal narrowing resulting
2004;93:105-113. usually from proliferative and degenerative, rather than inflam-
Miller LM, et al. Cardiovascular system and lymphatic vessels. In: matory, changes of the media and intima. The term athero
Zachary JF, McGavin MD, editors. Pathologoc Basis of Veterinary sclerosis is applied to lesions of arteriosclerosis in which
Disease. 5th ed. St Louis: Elsevier; 2012. p. 539-588. degenerative fatty changes also occur. Atherosclerosis is the most
Mitchell RN, Schoen FJ. Blood vessels. In: Kumar V, et al., editors. common and important type of arteriosclerosis in humans, and
Robbins and Cotran Pathologic Basis of Disease. 8th ed. the terms can thus be used interchangeably with little loss of
Philadelphia: Saunders-Elsevier; 2010. p. 487-528. meaning when discussing this species. In domestic animals,
Plendl J. Cardiovascular system. In: Eurell JO, Frappier BL, editors. Dell- arteriosclerosis is common, but of little clinical importance, and
man’s Textbook of Veterinary Histology. 6th ed. Ames, Iowa: Wiley atherosclerosis is rare.
Blackwell; 2007. p. 117-133. Arteriosclerosis develops slowly in animals, its extent and
incidence being greater in older animals. The disease may
become so widespread in individual animals that microscopi-
ARTERIES cally normal vessels may be difficult to find. The sclerotic
Congenital anomalies vessels are usually not accompanied by significant distur-
Minor variations occur in the course and distribution of arter- bances of blood flow, although ischemic change, especially of
ies among individuals of a species, but these are of little sig- brain and heart, may be seen. Well-developed lesions may be
nificance except possibly in surgical procedures. good sites for thrombus formation in animals when thrombo-
Arteriovenous fistula, the communication of an artery and genic circumstances prevail.
vein that bypasses the capillary system, is a defect that may Arteriosclerosis uncomplicated by focal degeneration in the
arise developmentally or be acquired subsequent to physical sclerotic plaques and with no or minimal lipid deposition is the
trauma, inflammatory necrosis involving adjacent vessels, neo- lesion usually found in older horses, ruminants, and carnivores.
plastic infiltration, or rupture of an arterial aneurysm into a There is a predilection for the abdominal aorta and points of
vein. Fistulas occur in dogs, cats, horses, and cattle, but are arterial branching, but it is also seen in peripheral and pulmo-
uncommon. Clinically, fistulas most commonly occur in the nary arteries and in the thoracic aorta. The extensiveness of
extremities and appear as a pulsating, fluctuant swelling in the lesions is very variable, so that there is no clear differentia-
which there is a palpable thrill and a machinery-like bruit on tion between a permissible aging change and a pathologic
auscultation. In general, arteriovenous fistulas cause decreased process. The nature of the insult (or insults) to the vessel walls
peripheral resistance and increased venous return to the right that result in sclerosis is not known, although there are numer-
heart. When 20-50% of the cardiac output is shunted through ous possibilities. Hemodynamic factors probably contribute,
the fistula, high-output cardiac failure can occur. The veins especially to development of plaques about the orifices of
involved are usually thick-walled (“arterialized”), may be arterial branches.
dilated and extremely tortuous, and may have intimal sclero- Arteriosclerotic plaques produce a slight thickening and
sis. Hepatic arteriovenous fistula (congenital hamartoma) wrinkling of the intima and are white, well delineated, and
occurs in dogs and cats, and can cause portal hypertension, oval to linear in shape. They can be found microscopically in
portocaval shunts, and ascites (see Vol. 3, Liver and biliary many animals in which they are not visible to the naked eye.
system). Their presence in peripheral, including coronary and cerebral
Thebesian veins connect the cardiac chambers, between vessels, can be correlated with arteriosclerosis of the abdomi-
the trabeculae carneae, with the myocardial sinusoids and nal aorta.
56.e1
Further reading
Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol
2004;36:961-968.
Bassenge E. Endothelial function in different organs. Prog Cardiovasc
Dis 1996;39:209-228.
Blodgett DJ. Fescue toxicosis. Vet Clin North Am Equine Pract
2001;17:567-577.
Carvalho D, Savage C. Cytokines, adhesion molecules, antiendothelial
cell autoantibodies and vascular disease. Cardiovasc Pathol
1997;6:61-78.
Cotran RS, Mayadas-Norton T. Endothelial adhesion molecules in
health and disease. Pathol Biol (Paris) 1998;46:164-170.
Fagrell B, Intaglietta M. Microcirculation: its significance in clinical and
molecular medicine. J Intern Med 1997;241:349-362.
Gwathmey JK, Paige JA. Endothelin and vasoactive peptides: new
cardiovascular mediators. J Vet Pharmacol Ther 1994;17:420-425.
Hirschi KK, D’Amore PA. Pericytes in the microvasculature. Cardiovasc
Res 1996;32:687-698.
Ju H, Dixon IM. Extracellular matrix and cardiovascular diseases. Can J
Cardiol 1996;12:1259-1267.
Michel CC. Capillaries, caveolae, calcium and cyclic nucleotides: a new
look at microvascular permeability. J Mol Cell Cardiol 1998;30:2541-
2546.
Schiffrin EL, Touyz RM. Vascular biology of endothelin. J Cardiovasc
Pharmacol 1998;32(Suppl. 3):S2-S13.
Turk JR. Physiologic and pathophysiologic effects of endothelin: impli-
cations in cardiopulmonary disease. J Am Vet Med Assoc
1998;212:265-270.
56.e2
Further reading
Bouayad H, et al. Peripheral acquired arteriovenous fistula: a report of
four cases and literature review. J Am Anim Hosp Assoc
1987;23:205-211.
Lamb CR, Naylor JM. Arteriovenous fistula in the orbit of a calf. Can
Vet J 1985;26:105-107.
Parks AH, et al. Lameness in a mare with signs of arteriovenous fistula.
J Am Vet Med Assoc 1989;194:379-380.
Diseases of the Vascular System Arteries 57
The initiating lesion(s) and the evolution of plaque forma- intimal lesion, are common in the aorta and large arteries of
tion are not fully elucidated. Microthrombi composed chiefly domestic animals, especially ruminants and swine, and humans.
of platelets are deposited at natural sites of turbulence or of The streaks, which are soft, smooth, nonelevated lesions
endothelial denudation, and may initiate the lesion. Platelets ranging from pinpoint size up to several square centimeters,
secrete platelet-derived growth factor (PDGF), epidermal are rarely visible grossly unless the aorta is stained with a fat
growth factor, transforming growth factor-β, and other mito- stain such as Sudan IV, which stains the lesions bright orange.
gens; PDGF stimulates migration and proliferation of smooth Streaks and plaques may coexist in the same area, but fatty
muscle cells. Alternatively, the initial change in the vessel wall streaks also occur in areas in which plaques do not occur; thus,
may occur as the result of a nondenuding insult to the endo- the role of fatty streaks in the genesis of atherosclerosis is
thelium; endothelial cells themselves produce several mito- unresolved. The major features of atherosclerosis are shown
gens, including PDGF. in eFig. 1-15.
Histologically, the internal elastic lamina shows an early Multiple pathogenetic influences can contribute to the develop-
distinctive change, becoming irregular in outline, partially ment of plaques. The various events and theories of develop-
duplicated, and fragmented or discontinuous. Smooth muscle ment of atherosclerosis have been unified in the “response to
cells migrate into the intima from the media to function as do injury” hypothesis. Endothelial injury or dysfunction can occur
fibroblasts outside of arteries; these intimal smooth muscle as the result of hyperlipidemia, with the cholesterol present
cells produce most of the connective tissue matrix of the in low-density (LDL) and very-low-density lipoproteins
intimal plaque, including collagen, elastic tissue, and proteo- (VLDL) seen as a primary culprit. Additional risk factors in
glycans. In young plaques, or the deeper portions of older ones, humans are genetics, hypertension, smoking, obesity, inactiv-
the smooth muscle cells (“myointimal cells”) are numerous and ity, and diabetes mellitus. Immunologic mechanisms, toxins,
intimately mixed with collagen, elastic fibrils, basement mem- and viruses may also damage endothelium. Infectious agents,
brane, and proteoglycans as the so-called musculoelastic layer. such as Chlamydia pneumoniae, have been proposed as con-
In large and older plaques, a more superficial elastic hyper- tributing to the pathogenesis of atherosclerosis in humans, but
plastic layer may be recognized by a more compact arrange- there is no evidence to date of a similar link in dogs or cats.
ment of collagen and elastica with relatively few cells. This Endothelial injury leads to platelet adhesion, monocyte
lamination of plaques is not always clearly evident, and its adhesion and infiltration, and smooth muscle migration and
development may depend on the age of the lesion as well as proliferation, as discussed above under Arteriosclerosis. The
on the segment of vessel involved, whether chiefly muscular involvement of various proinflammatory cytokines and che-
or chiefly elastic. mokines are also considered to influence the development of
the atheromatous plaque. The feature added in atherosclerosis
is insudation of lipid, which is seen as extracellular lipid, often
Further reading with acicular clefts or as intracellular lipid in “foam cells.” The
Falk T, et al. Arteriosclerotic changes in the myocardium, lung, and lipid-laden foam cells that are characteristic of both fatty
kidney in dogs with chronic congestive heart failure and myxoma- streaks and atheromatous plaques may be either activated
tous mitral valve disease. Cardiovasc Pathol 2006;15:185-193. macrophages or smooth muscle cells; macrophages predomi-
Fishbein GA, Fishbein MC. Arteriosclerosis: rethinking the current clas- nate in streaks, whereas smooth muscle cells predominate in
sification. Arch Pathol Lab Med 2009;133:1309-1316. the fibrous cap of plaques. Endothelial cell dysfunction is
Williams KJ. Coronary arteriosclerosis with myocardial atrophy in a emerging as an endocrinopathy that may contribute to the
13-year-old dog. Vet Pathol 2003;40:695-697. effects of atherosclerosis through impaired ability of endothe-
lial cells to produce endothelial-derived relaxing factor and
through increased production of endothelin.
Atherosclerosis Atherosclerosis develops commonly only in the pig among
Atherosclerosis is of little practical importance in domestic domestic species. Fatty streaks and atheromatous plaques
animals, but is primarily of interest for the development of develop in the aorta, extramural coronary arteries, cerebral
animal models of the human disease. The atherosclerotic and iliac arteries, as in man, and the plaques may cause con-
susceptibility of animals varies; rabbits, chickens, and pigs are siderable stenosis of vessels in swine 8-12 years of age. The
atherosensitive, whereas dogs, cats, cattle, goats, and rats are extent of lipid deposition can be influenced by feeding
atheroresistant. Swine and nonhuman primates are usually extraordinary diets containing much lipid, including choles-
considered to be the best large-animal models of human ath- terol, but the atheromas rarely reach the degree of develop-
erosclerosis, and genetically modified mice are proving to be ment seen in humans, and they do not lead to occlusive
valuable in the elucidation of the contribution of single factors thrombus formation, which usually requires softening and
to the pathogenesis of the disease. ulceration of the atheromatous plaque. The initial deposition
In humans, atherosclerosis and its complications of myocar- of lipid occurs in the proliferated smooth muscle cells, which
dial infarction, stroke, and peripheral vascular disease are major show signs of degeneration and which may become foam cells.
causes of morbidity and mortality in the developed world. Ath- Macrophages also appear, containing lipid. Fat may be demon-
erosclerosis affects the large elastic arteries (aorta, iliac) and strable extracellularly, presumably released by degenerate
the large and medium caliber muscular arteries (carotid, coro- cells. Deposits of cholesterol and mineral, not extensive, may
nary, femoral). The essential lesion is the atheroma or fibrofatty be associated with softening of larger atheromatous plaques.
plaque, which is a focal, raised, intimal plaque with a core of However, except in pigs fed high-fat diets, lipid is usually a
lipid (predominantly cholesterol and its esters) covered by a minor component of the predominantly fibromuscular
fibrous cap. Complications of plaques include mineralization, plaques.
ulceration, superimposed thrombosis, intraplaque hemorrhage, Of the domestic animals, the deposition of cholesterol and
and aneurysmal dilation. Fatty streaks, another type of fatty other lipids in the arteries in more than trace amounts occurs
57.e1
Further reading
Fankhauser R, et al. Cerebrovascular disease in various animal species.
Ann N Y Acad Sci 1965;127:817-859.
Luginbuhl H. Vascular diseases in animals: comparative aspects of
cerebrovascular anatomy and pathology in different species. In:
Millikan CH, Siekert RG, et al., editors. Cerebral Vascular Diseases.
New York: Grune and Stratton; 1966. p. 3-27.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Marcus LC, Ross JR. Microscopic lesions in the hearts of aged horses
and mules. Pathol Vet 1967;4:162-185.
Nanda BS, Getty R. Age related histomorphological changes in the
cerebral arteries of domestic pig. Exp Gerontol 1971;6:453-460.
Prasad MC, et al. Caprine arterial diseases: I. Spontaneous aortic
lesions. Exp Mol Pathol 1972;17:14-28.
Schaub RG, et al. Platelet adhesion and myointimal proliferation in
canine pulmonary arteries. Am J Pathol 1981;104:13-22.
Whitney JC. Some aspects of the pathogenesis of canine arteriosclero-
sis. J Small Anim Pract 1976;17:87-97.
57.e2
Location
Large elastic arteries
and large/medium
muscular arteries
Atherosclerosis Complications
Essential lesion
Common in Mineralization/
Sub-intimal humans ulceration/
atheroma-fibrofatty
Uncommon in thrombosis of
plaque
domestic animals the plaque
Plaque
composition
Lipids especially
cholesterol both
intra and
extracellular
Further reading
Armstrong ML, Heistad DD. Animal models of atherosclerosis. Athero-
sclerosis 1990;85:15-23.
Chastain CB, Graham CL. Xanthomatosis secondary to diabetes mel-
litus in a dog. J Am Vet Med Assoc 1978;172:1209-1211.
DeBowes LJ. Lipid metabolism and hyperlipoproteinemia in dogs.
Compend Contin Educ Pract Vet 1987;9:727-734.
Johnstone AC, et al. The pathology of an inherited hyperlipoprotein-
aemia of cats. J Comp Pathol 1990;102:125-137.
Maher ER Jr, Rush JE. Cardiovascular changes in the geriatric dog.
Compend Contin Educ Pract Vet 1990;12:921-931.
Ross R. Atherosclerosis-an inflammatory disease. N Eng J Med
1999;340:115-126.
Vanhoutte PM. Endothelial dysfunction: the first step toward coronary
arteriosclerosis. Circ J 2009;73:595-601.
Diseases of the Vascular System Arteries 59
Arteriolosclerosis
Arteriolosclerosis describes a heterogeneous group of arteriolar
lesions that may be predominantly hyaline or predominantly
hyperplastic. The major cause of these changes in vessels in
humans is hypertension, but the pathogenesis of the lesions
in domestic animals is often not determined. Endothelial
damage is likely the primary event in these conditions. Hyaline
degeneration—the microscopic appearance of amorphous,
brightly eosinophilic material in vessel walls—can occur as the
result of increased vascular permeability that allows insuda-
tion of various plasma components; it includes the amyloid
deposits of renal glomeruli and elsewhere, and the fibrin and
necrotic smooth muscle of “fibrinoid necrosis.” Fibrinoid necro-
sis may predate and initiate inflammatory cellular infiltration,
after which the reaction would be termed arteritis. Thickening
of the arteriolar wall may cause luminal narrowing and hence
ischemia of the region supplied.
Systemic hypertension, or persistently elevated systemic
A blood pressure, is an important disease of humans, and occurs
as either primary (essential) hypertension or secondary hyperten-
sion. Both forms of hypertension are typically prolonged in
their clinical course, but accelerated or malignant hypertension
develops in about 5% of affected individuals. Both primary
and secondary hypertensions have been reported in dogs and
cats; the primary form is rare, and the secondary form is more
common. Hypertension may often go unrecognized as the
routine measurement of blood pressure in domestic animals
is problematic and as such is not part of the routine physical
examination. The diagnosis of hypertension could well become
more frequent as noninvasive techniques for measurement of
blood pressure come into common use.
Renal disease, likely the most common cause of hypertension
in dogs and cats, may be either a cause or an effect of hyper-
tension, thus determining whether a hypertensive vascular
B lesion is a primary or a secondary event is difficult. Primary
hypertensive lesions can lead to decreased renal perfusion,
Figure 1-63 Atherosclerosis. A. Extensive subintimal and medial activation of the renin-angiotensin-aldosterone system, and
infiltration with lipid macrophages (“foam cells”) accompanied by hence more hypertension. On the other hand, primary chronic
perivascular lymphocytic infiltration in a dog. B. Large complex renal disease can lead to inadequate excretion of sodium and
fibrofatty plaque within the subintima of a coronary artery of a water, blood volume expansion, and hence secondary hyper-
human. Note the severe vascular luminal compromise. (Courtesy tension. In either case, hypertension is self-perpetuating as
S. Mackey-Bojack.) medial hypertrophy and hyalinization of renal arteries
lead to more nephrosclerosis, further hypertension, and more
pressure-induced vascular damage.
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hemorrhage. Left ventricular hypertrophy commonly occurs
60 CHAPTER 1 • Cardiovascular System Arteries
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Diseases of the Vascular System Arteries 61
Further reading
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Drazner FH. Hypercalcemia in the dog and cat. J Am Vet Med Assoc
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62 CHAPTER 1 • Cardiovascular System Arteries
Further reading
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Diseases of the Vascular System Arteries 63
Further reading
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64 CHAPTER 1 • Cardiovascular System Arteries
Further reading
Oyamada T, et al. Pathology of aortic-iliac thrombosis in two horses.
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a b c d
e f g
Further reading
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459-462.
Diseases of the Vascular System Arteries 65
to demonstrate. Red cells that impinge on fibrin strands in the cardiorespiratory system to adjust to the hypoxia of higher
microcirculation may fragment; these red cell fragments altitudes. There are species differences in the hypertensive
(schistocytes) may be detected within blood vessels in histo- response to hypoxia; sheep and dogs are hyporesponders,
logic sections as well as blood smears, thus serving as indica- humans are intermediate, whereas cattle and pigs are hyper-
tors of DIC. responders and are prone to develop hypertensive heart failure
at altitudes of ~2,500 meters and above. There are also varia-
tions within species, and some cattle react dramatically to
Further reading degrees of hypoxia that only mildly inconvenience others.
Bensaude E, et al. Classical swine fever virus induces proinflammatory Young cattle are more susceptible than adults, and the mor-
cytokines and tissue factor expression and inhibits apoptosis and bidity rate is highest in animals exposed to high altitudes for
interferon synthesis during the establishment of long-term infection the first time. In animals imported from low altitudes to about
of porcine vascular endothelial cells. J Gen Virol 2004;85:1029- 3,500 meters, the incidence of severe pulmonary hypertension
1037. approaches 50%, whereas in herds maintained at such alti-
Chantrey J, et al. Haemolytic-uraemic syndrome in a dog. J Vet Med A tudes for many generations, high-altitude disease may not
Physiol Pathol Clin Med 2002;49:470-472. affect >2%. The different morbidity rates are probably attrib-
Dallap BL. Coagulopathy in the equine critical care patient. Vet Clin utable to natural selection in the resident population.
North Am Equine Pract 2004;20:231-251. Cattle exposed to critical altitudes, or experimentally to
De Laforcade AM, et al. Serial evaluation of protein C and antithrom- comparable degrees of hypoxic stimulation, develop a several-
bin in dogs with sepsis. J Vet Int Med 2008;22:26-30. fold increase in pulmonary arterial pressure and pulmonary
Dolente BA, et al. Clinicopathologic evidence of disseminated intravas- vascular resistance that may gradually be reduced to near-
cular coagulation in horses with acute colitis. J Am Vet Med Assoc normotensive levels when the animals are returned to low
2002;220:1034-1038. altitudes. A distinctive feature of the pulmonary vasculature
Gao H, et al. Bench-to-bedside review: sepsis, severe sepsis and septic in cattle is the inherently well-developed muscular media of
shock—does the nature of the infecting organism matter. Critical the arteries and veins with diameters as small as 20 µm, which
Care 2008;12:212-217. implies an unusual potential for vasomotor activity. Hypoxia-
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec- induced vasoconstriction leads to work-induced hypertrophy of
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48. the muscular media of pulmonary arteries and arterioles, and
Hardaway RM. A review of septic shock. Am Surg 2000;66:22-29. hence hypertension, and may be compounded by reaction
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Putsche JC, Kohn B. Primary immune-mediated thrombocytopenia in uniformly prominent hypertrophy of the muscular media of
30 dogs (1997-2003). J Am Anim Hosp Assoc 2008;44:250-257. pulmonary arteries and arterioles, and usually adventitial pro-
Vallee I, et al. African swine fever virus infection of porcine aortic liferation around pulmonary arteries of all sizes. The activation
endothelial cells leads to inhibition of inflammatory responses, of platelet-derived growth factor-β receptor-JNK1 signaling
activation of the thrombotic state, and apoptosis. J Virol may initiate this proliferation. The hypertension may also
2001;75:10372-10382. cause endothelial damage, thrombosis, intimal proliferation,
and medial mineralization, especially in elastic pulmonary
arteries.
Arterial hypertrophy
Hypertrophy of arteries may affect one or all components of
the arterial wall. High-altitude disease of cattle, described later, Further reading
is a result of hypoxia-induced pulmonary arterial constriction Newman JH, et al. High altitude pulmonary hypertension in cattle
and subsequent hypertrophy that lead to pulmonary hyper- (brisket disease): candidate genes and gene expression profiling of
tension and eventual right heart failure (cor pulmonale). peripheral blood mononuclear cells. Pulm Circ 2011;1:462-469.
Various cardiac anomalies cause pulmonary arterial hyperten- Panzhinskiy E, et al. Hypoxia induces a unique proliferative response in
sion and hyperperfusion, which result in pulmonary arterial adventitial fibroblasts by activating PDGF( receptor-JNK1 signalling.
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hypertrophy occurs in collateral vessels in response to the extra
load they carry after occlusion of the artery that usually sup-
plies an area. A specific form of hypertrophy occurs in the Congenital and acquired cardiac disease and
pulmonary arteries of cats and is described later. Systemic arte- pulmonary arterial hypertension
rial involvement in the hypertension associated with chronic Congenital heart diseases that feature increased pulmonary
renal disease is described previously. arterial pressure (hypertension) and increased blood flow
(hyperperfusion) often occur with left-to-right shunting of
“High-altitude disease” of cattle blood, such as a large ventricular septal defect or patent
This disease is caused by pulmonary hypertension that results in ductus arteriosus. Pulmonary arterial hypertension, which
dilation and hypertrophy of the right ventricle with the ultimate may even lead to reversal of the shunt and cyanosis (Eisen-
development of cardiac decompensation and right-sided congestive menger’s syndrome), produces pulmonary arterial constriction
cardiac failure. Edematous swelling of the venter, as is typical and hypertrophy, increased pulmonary vascular resistance, and
of congestive heart failure in cattle, is responsible for the sustained pulmonary hypertension by means of a number of
synonym “brisket disease.” The syndrome in cattle resembles, arterial responses. These responses range from persistence of
in many respects, the chronic mountain sickness of humans the normal thick muscular wall configuration of fetal life, to
residing at high altitude, and represents failure of the acquired lesions that are the response to hypertension. These
66.e1
Further reading
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septicemia of Haemophilus parasuis infection. J Vet Med Sci
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dicator of disseminated intravascular coagulation in cats with
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Hargis AM, Feldman BF. Evaluation of hemostatic defects secondary to
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Hoffmann R. Adrenal lesions in calves dying from endotoxin shock,
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Kraje AC, et al. Unusual metastatic behavior and clinicopathologic
findings in eight cats with cutaneous or visceral hemangiosarcoma.
J Am Vet Med Assoc 1999;214:670-672.
Long PH, Payne JW. Red maple-associated pulmonary thrombosis in a
horse. J Am Vet Med Assoc 1984;184:977-978.
Machida N, et al. Myocardial infarction secondary to a disseminated
coagulopathy in a cow. Cornell Vet 1991;81:129-135.
Maxie MG, et al. A comparative study of the disease in cattle caused
by Theileria parva or T. lawrencei: II. Hematology, clinical chemistry,
coagulation studies and complement. Vet Parasitol 1982;10:1-19.
Millis DL, et al. Abnormal hemostatic profiles and gastric necrosis in
canine gastric dilatation-volvulus. Vet Surg 1993;22:93-97.
Momotani E, et al. Histopathological evaluation of disseminated intra-
vascular coagulation in Haemophilus somnus infection in cattle.
J Comp Pathol 1985;95:15-23.
Morris CF, et al. Hemolytic uremic-like syndrome in two horses. J Am
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Norris CR, et al. Pulmonary thromboembolism in cats: 29 cases (1987-
1997). J Am Vet Med Assoc 1999;215:1650-1654.
Semeraro N, Colucci M. Changes in the coagulation-fibrinolysis balance
of endothelial cells and mononuclear phagocytes: role in dissemi-
nated intravascular coagulation associated with infectious diseases.
Int J Clin Lab Res 1992;21:214-220.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
Teige J Jr, Gamlem H. The generalized Shwartzman reaction in asso-
ciation with E. coli enterotoxemia in a pig. Acta Vet Scand
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Valladares JE, et al. Study of haemostatic disorders in experimentally
induced leishmaniasis in beagle dogs. Res Vet Sci 1998;64:195-198.
Wellde BT, et al. Trypanosoma vivax: disseminated intravascular coagu-
lation in cattle. Ann Trop Med Parasitol 1989;83(Suppl. 1):177-183.
Yeruham I, et al. Clinical, clinico-pathological and serological studies
of Babesia ovis in experimentally infected sheep. Zentralbl Veteri-
narmed B 1998;45:385-394.
66.e2
Further reading
Bisgard GE. Pulmonary hypertension in cattle. Adv Vet Sci Comp Med
1977;21:151-172.
Tucker A, Rhodes J. Role of vascular smooth muscle in the development
of high altitude pulmonary hypertension: an interspecies evalua-
tion. High Alt Med Biol 2001;2:173-189.
Diseases of the Vascular System Arteries 67
Further reading
Connolly DJ, et al. Right-to-left shunting patent ductus arteriosus with
pulmonary hypertension in a cat. J Small Anim Pract 2003;44:184-
188. erratum in J Small Anim Pract 2003;44:226.
Glaus TM, et al. Clinical and pathological characterisation of primary
Figure 1-73 Medial hyperplasia/hypertrophy with mild periar-
pulmonary hypertension in a dog. Vet Rec 2004;154:786-789.
teritis in dirofilariasis in a cat. H&E. (Courtesy A. Allen, coordina-
Kellihan HB, Stephien RL. Pulmonary hypertension in dogs: diagnosis
tor, Western Conference of Veterinary Diagnostic Pathologists.)
and therapy. Vet Clin North Am Small Anim Pract 2010;40:623-
641.
Matsui K, et al. Immunohistochemical study of endothelin-1 and matrix Thrombosis has not been observed, but adhesion of endothe-
metalloproteinases in plexogenic pulmonary arteriopathy. Pathol lial surfaces across the lumen occurs, providing sinuous
Res Pract 2002;198:403-412. channels and an appearance similar to that of an organized,
recanalized thrombus. Frequently, the arterial hypertrophy is
accompanied by fibromuscular hyperplasia in the pulmonary
Medial hypertrophy of the pulmonary parenchyma and around alveolar ducts.
arteries of cats Similar pulmonary arterial lesions have been described in
Pulmonary medial hypertrophy and hyperplasia commonly occur cats infected with the parasites Aelurostrongylus abstrusus and
in cats, but are of no clinical significance even when very severe Dirofilaria immitis (Fig. 1-73).
and generalized. The change is seen with equal frequency in
specific-pathogen-free and conventional cats; displays no age,
sex, or breed predilection; and appears to be normal anatomic Further reading
variation in cats. Pulmonary hypertension does not result from Browne LE, et al. Pulmonary arterial disease in cats seropositive to
the vascular change, right ventricular pressure does not Dirofilaria immitis but lacking adult heartworms in the heart and
increase, nor does the right ventricle hypertrophy. The most lungs. Am J Vet Res 2005;66:1544-1549.
severely affected vessels may be grossly visible on the cut
surface of the lung and through the pleura when the lungs are
collapsed, and are even palpable in some cases. The histologic Vasculitis
spectrum of arterial changes ranges from mild sporadic (Fig. Vasculitis, or inflammation of a vessel, is characterized by the
1-72) or generalized hypertrophy of the tunica media, to presence of inflammatory cells within and around the blood vessel
marked medial hypertrophy and hyperplasia with concomi- wall with concomitant vessel wall damage as indicated by fibrin
tant intimal proliferation and severe luminal encroachment. deposition, collagen degeneration, and necrosis of endothelial and
67.e1
Further reading
Dorfmuller P, et al. Pathology and aspects of pathogenesis in pulmo-
nary arterial hypertension. Sarcoidosis Vasc Diffuse Lung Dis
2003;20:9-19.
Fishman AP. Changing concepts of the pulmonary plexiform lesion.
Physiol Res 2000;49:485-492.
Kolm US, et al. Plexogenic pulmonary arteriopathy in a Pembroke
Welsh corgi. J Small Anim Pract 2004;45:461-466.
Turk JR, et al. Plexogenic pulmonary arteriopathy in a dog with ven-
tricular septal defect and pulmonary hypertension. J Am Anim Hosp
Assoc 1982;18:608-612.
67.e2
Further reading
Lister AL, Atwell RB. Feline heartworm disease: a clinical review. J Feline
Surg Med 2008;10:137-144.
Rawlings CA, et al. Response of the feline heart to Aelurostrongylus
abstrusus. J Am Anim Hosp Assoc 1980;16:573-578.
Rogers WA, et al. Pulmonary artery medial hypertrophy and hyperplasia
in conventional and specific-pathogen-free cats. Am J Vet Res
1971;32:767-774.
68 CHAPTER 1 • Cardiovascular System Arteries
smooth muscle cells. The fibrillary, homogeneous, or granular 1-2), although its origin remains undetermined in many cases.
eosinophilic material observed by light microscopy and Vascular degeneration that lacks a significant inflammatory cell
referred to as “fibrinoid” consists of fibrin, immunoglobulins, component occurs in a number of toxic and metabolic conditions,
complement, and platelets. Degenerate collagen and smooth such as mercury poisoning and mulberry heart disease, and
muscle also contribute to increased eosinophilia of the vascu- has been excluded from this classification. The terms vasculitis
lar wall. Thrombosis may occur because of endothelial injury and angiitis are used interchangeably and may be used in
and initiation of coagulation. The above changes in the blood preference to the more specific term arteritis, because arteries,
vessel wall distinguish vasculitis from perivascular infiltration capillaries, and veins may be involved simultaneously in some
with inflammatory cells. Neutrophils, lymphocytes, or macro- conditions. Also, the wall of the vessel may be obscured or
phages may predominate in vasculitis, and the predominant obliterated by inflammatory changes, precluding definitive
cell type may be used to classify the vasculitis. Neutrophilic classification. The consequences of vasculitis depend upon the
vasculitis may be further subdivided into leukocytoclastic, in size, numbers, and types of vessels affected, and upon the
which fragmented neutrophil nuclei or “nuclear dust” are degree of obstruction caused, as noted under Arterial throm-
present, and nonleukocytoclastic, in which there is little bosis and embolism. Vasculitis in general and specific forms of
nuclear dust. The predominant cell type may vary over the arteritis will be discussed in this section; phlebitis and lymphan-
course of the vasculitis, as the condition becomes chronic or gitis are discussed in the sections Veins and Lymphatics,
resolves (eFig. 1-19). respectively.
Vasculitis is an important component of a wide variety of Vasculitides may be classified according to the size of the
inflammatory diseases, both infectious and noninfectious (Box blood vessels involved (large, medium, small), the histologic
BOX • 1-2
Causes of vasculitis in domestic animals
Primary area
affected
(Endotheluim,
media, adventitia)
Morphology
Etiologies
Fibrinoid change
in wall of vessel Infectious [bacteria,
viruses], immune-
Cell type present
mediated [type III
[neutrophils,
and Type IV],
lymphocytes,
toxins, drugs
macrophages] Vasculitis
(Angiitis)
eFigure 1-19 Common types of vasculitis and their major features. DIC, disseminated intravas-
cular coagulation.
Diseases of the Vascular System Arteries 69
characteristics of the lesion, or clinical effects. However, many encountered most often in bacterial pneumonias, adjacent to
cases overlap in their morphologic and clinical manifestations, abscesses, in purulent meningitis, in local lesions of aspergil-
and are simply termed “systemic necrotizing vasculitis.” losis and mucormycosis, and in acute metritis, especially if
Improvement in the classification of necrotizing vasculitides complicated by necrobacillosis. Fungi of the family Mucorales
will require further characterization of causes and of the spec- have a distinct affinity for arteries and produce necrotizing,
trum of immune-mediated changes in vessels. Until such time, thrombotic arteritis.
the use of accurate morphologic descriptions of vascular Vasculitis may also develop from within the vessel as a result
lesions is preferable to placing vasculitides, especially those of of endothelial injury by infectious agents and/or immune reac-
known cause, in such ill-defined categories as “polyarteritis tions. Endothelial damage and exposure of subendothelial
nodosa.” The wide range of lesions observed probably reflects collagen leads to activation of Hageman factor, and hence
the variety of antigens or other agents involved, the intensity activation of complement, kinin, and plasmin systems, and to
and chronicity of antigenic exposure, the relative contribu- increased vascular permeability and inflammation. Infectious
tions of immune-complex versus delayed-hypersensitivity agents may cause endothelial damage either directly or
reactions, the genetic variation among individuals, and the through the actions of various toxic products, such as endo-
stage of development at which the lesion is observed. toxins of gram-negative bacteria, or exotoxins of bacteria such
Vasculitis may be of considerable significance in the pathogen- as Corynebacterium pseudotuberculosis. Mannheimia haemolyt-
esis of a condition, usually because of the occurrence of thrombo- ica endotoxin (lipopolysaccharide [LPS]) can directly damage
sis, ischemia, and infarction (Fig. 1-74). As well as having local endothelial cells; such damage may be reduced or increased
effects resulting from thrombosis and infarction, arteritis may by the activity of neutrophils, depending on the concentration
affect distant organs, as occurs when obliterative pulmonary of LPS present. The mechanism of LPS-mediated damage may
endoarteritis leads to congestive heart failure in dogs infected involve prostaglandins or production of oxygen radicals by
with Dirofilaria immitis. (The term endoarteritis is used in endothelial cells. In the absence of LPS, M. haemolytica leu-
preference to endarteritis to avoid implying that end arteries kotoxin may contribute to endothelial damage. In the case of
are primarily affected.) Actinobacillus pleuropneumoniae, rather than endotoxin causing
Arteritis of hematogenous origin occurs in the course of endothelial damage, cytotoxicity is apparently caused by a
conditions such as septicemias and bacterial endocarditis. The 104 kDa hemolysin. Histophilus somni lipo-oligosaccharide
primary injury may be to the endothelium and intima or it has been shown to cause cytotoxicity and apoptosis of bovine
may, when the organisms localize in the vasa vasorum, affect endothelial cells through the generation of reactive oxygen
first the adventitia and outer lamellae. The arteritis in pigs and nitrogen intermediates. Many viruses are endotheliotro-
with septicemic salmonellosis, erysipelas, or classical swine pic, for example, the viruses of equine arteritis, infectious
fever is conspicuously expressed cutaneously as erythematous canine hepatitis, canine distemper, Hendra virus, African swine
areas of purple discoloration on the ears, perineum, snout, and fever, and classical swine fever (see Box 1-2).
venter, which, if the animal survives, may become necrotic and Immune reactions are primary causes of vasculitis
slough. Lesions with this basis may also occur in other organs, in domestic animals, but appear to be less important than
and indeed are often seen as infarcts in the spleen in erysipelas in man.
and classical swine fever. In affected portions of vessels, the Type III hypersensitivity reactions, or Arthus reactions, cause
endothelium swells and proliferates, and vessel walls undergo necrotizing vasculitis by the deposition of immune complexes
acute fibrinoid necrosis. The formation of thrombi in these in vessel walls, usually in association with the endothelial
areas in turn gives rise to infarcts and necrosis. basement membrane. The complexes fix complement, and
Vasculitis arising by extension of inflammation and infection complement fragments attract neutrophils that release lyso-
from adjacent tissues may occur, especially if the original somal enzymes and oxygen radicals (superoxide anion, hydro-
inflammatory process is suppurative or necrotizing. It is gen peroxide, hydroxyl radical, hypochlorous acid) in the
process of phagocytosing immune complexes, and hence cause
necrosis. As the Arthus reaction matures, neutrophils diminish
and mononuclear cells, including plasma cells, predominate.
The morphology of immune-complex–mediated vasculitis can
be modified by the relative concentrations of immune reac-
tants or secondary mediators; increases in antibody or comple-
ment concentrations can change an Arthus-like reaction to a
Shwartzman-like reaction. Immune complexes can be found
in vessel walls in a variety of immune-mediated conditions,
including systemic lupus erythematosus, Aleutian disease of
mink, feline infectious peritonitis, and systemic coronavirus-
associated disease in ferrets. However, even though immuno-
globulins or immune complexes are found in the walls of
affected vessels, this is not definitive proof that the immune
reaction caused the vasculitis. Conversely, the absence of
immune complexes from a vessel wall lesion does not rule out
immune-complex vasculitis, because immune reactants can
disappear rapidly. The underlying lesion in porcine dermatitis
and nephropathy syndrome (PDNS) is necrotizing systemic
Figure 1-74 Necrotizing vasculitis of arteriole in malignant
vasculitis, which has a predilection for skin and kidney, and
catarrhal fever in an ox. H&E. (Courtesy J. Schefers.)
is thought to have an immune-complex origin; porcine
70 CHAPTER 1 • Cardiovascular System Arteries
circovirus 2 antibody titers were excessively high in PDNS antineutrophil cytoplasmic antibodies (ANCA) and other
pigs in a case-control study. immunologic irregularities similar to Kawasaki disease in
Cell-mediated type IV, or delayed hypersensitivity, reactions humans.
may be involved in some types of vasculitis in which there is An idiopathic vasculopathy occurs in kenneled and racing
lymphocytic predominance, such as the arteritis of malignant Greyhound dogs (Alabama rot), involving skin and occasionally
catarrhal fever and of Border disease. In malignant catarrhal kidneys. Deep, slowly healing cutaneous ulcers occur as the
fever, the vasculitis is characterized by accumulations of prin- result of fibrinoid arteritis, thrombosis, and hemorrhagic
cipally lymphocytes and fewer macrophages in the adventitia infarction. Renal lesions include acute necrosis of glomeruli
and intima of affected small and medium arteries and veins and of afferent arterioles, glomerular capillary thrombosis, and
of the alimentary tract, eye, kidney, liver, lung, and brain; acute tubular necrosis. The pathogenesis of the condition is
neutrophils and plasma cells are rare. Lymphocytes may later thought to be the result of the effects of Shiga toxin from E.
invade the media, although adventitial infiltration continues coli O157:H7 producing a variant of the hemolytic-uremic
to predominate, and there may be medial myocyte necrosis syndrome.
with variable amounts of fibrinoid degeneration and endothe-
lial hyperplasia; thrombosis may be seen in advanced cases.
There is a possibility of, but little direct evidence for, direct Further reading
viral cytolysis in malignant catarrhal fever. Buxton D, et al. Ovine chlamydial abortion: characterization of the
Vasculitis in humans has been associated with a variety inflammatory immune response in placental tissues. J Comp Pathol
of drugs (see Hypersensitivity vasculitis). Examples of 2002;127:133-141.
hypersensitivities in dogs include itraconazole, ivermectin, Caswell JL, Nykamp SG. Intradural vasculitis and hemorrhage in full
allergy immunotherapy (hyposensitization) injections, and sibling Welsh springer spaniels. Can Vet J 2003;44:137-139.
ibuprofen. Eaton BT, Broder CC. Hendra and Nipah viruses: different and danger-
Genetic predisposition to vasculitis occurs in a number of ous. Nat Rev Microbiol 2006;4:23-35.
dog breeds, for instance, Beagle (“Beagle pain syndrome”), Font A, et al. Acute paraplegia associated with vasculitis in a dog with
Greyhound, Chinese Shar-Pei (“Shar-Pei fever”), German leishmaniasis. J Small Anim Pract 2004;45:199-201.
Shepherd dog, Bernese Mountain dog. Vasculitis may be pre- Garner MM. Clinicopathologic features of a systemic coronavirus-
cipitated by vaccination or infection, but is more often of associated disease resembling feline infectious peritonitis in the
obscure cause. Arteritis may be found as an incidental “back- domestic ferret (Mustela putorius). Vet Pathol 2008;45:236-246.
ground” lesion in clinically normal animals. For example, mild Hansen S, et al. Coxiella burnetii associated placental lesions and infec-
idiopathic arteritis and intimal thickening occurs in extramu- tion level in parturient cows. Vet J 2011;190:e135-e139.
ral coronary arteries in 5-10% of young Beagle and mixed- Hooper P, et al. Comparative pathology of the diseases caused by
breed dogs, which can complicate the interpretation of lesions Hendra and Nipah viruses. Microbes Infect 2001;3:315-322.
in dogs used in arterial toxicity studies. Innerå M. Cutaneous vasculitis in small animals. Vet Clin North Amer
A more severe, febrile syndrome, variously named Beagle Sm Anim Pract 2013;43:113-134.
pain syndrome, canine juvenile polyarteritis syndrome, or idio- Kipar A, et al. Morphologic features and development of granuloma-
pathic canine polyarteritis, occurs in Beagles and other breeds. tous vasculitis in feline infectious peritonitis. Vet Pathol 2005;42:321-
In this syndrome, necrotizing arteritis affects the coronary, 330.
mediastinal and cervical spinal arteries, resulting in thrombo- Maratea KA, et al. Vascular lesions in nine Gottingen minipigs with
sis, infarction, and hemorrhage as well as progressive atrophy thrombocytopenic purpura syndrome. Vet Pathol 2006;43:447-
of temporal and cervical muscles; amyloidosis occurs in 454.
some chronically affected dogs (Fig. 1-75). The syndrome McClenahan D, et al. Effects of lipopolysaccharide and Mannheimia
appears to be immune mediated; some affected dogs have haemolytica leukotoxin on bovine lung microvascular endothelial
cells and alveolar epithelial cells. Clin Vaccine Immunol 2008;15:338-
347.
Opriessnig T, Langolir I. Current state of knowledge of porcine circovi-
rus type 2-associated lesions. Vet Pathol 2013;50:23-38.
Paessler S, Walker DH. Pathogenesis of viral hemorrhagic fevers. Ann
Rev Pathol 2013;8:411-440.
Richards A, Kavanagh D. Pathogenesis of thrombotic microangiopathy:
insights from animal models. Nephron Exp Nephrol 2009;113:97-
103.
Russell GC, et al. Malignant catarrhal fever: a review. Vet J 2009;
179:324-335.
Snyder PW, et al. Pathologic features of naturally occurring juvenile
polyarteritis in Beagle dogs. Vet Pathol 1995;32:337-345.
Wellenberg GJ, et al. Excessive porcine circovirus type 2 antibody titres
may trigger the development of porcine dermatitis and nephropa-
thy syndrome: a case-control study. Vet Microbiol 2004;99:203-
214.
Wong KT, Tan CT. Clinical and pathological manifestations of human
henipavirus infection. Curr Top Microbiol Immunol 2012;359:
Figure 1-75 Lymphoplasmacytic vasculitis in the leptomeninges 95-104.
in Beagle pain syndrome. H&E.
70.e1
Polyarteritis nodosa (panarteritis, to describe a stage in the vascular reaction in which mono-
or periarteritis nodosa) nuclear cells surround the vessel, but the term is now
The term “polyarteritis nodosa” has been applied to a hetero- little used.
geneous group of arteritides, which occur sporadically in all Microscopic polyangiitis (hypersensitivity vasculitis, micro-
species of domestic animals, on the basis of similarities with scopic polyarteritis, leukocytoclastic vasculitis) affects smaller
classic polyarteritis nodosa in humans, in which small and vessels in humans, namely, arterioles, capillaries, and venules in
medium-sized arteries undergo severe necrotizing inflammation, skin, mucous membranes, lungs, brain, heart, gastrointestinal
often in a sharply segmental (nodose) pattern, and with a predi- tract, kidneys, and muscle. Suspected causes include many
lection for branching points. As all layers of the arterial wall common drugs such as penicillin, microbes such as strepto-
are involved, the lesion is also referred to as “panarteritis.” cocci, heterologous proteins, and tumor antigens. The reaction
Arterioles, capillaries, and venules are not involved, and glo- often occurs 7-10 days after exposure to the stimulus; remis-
merulonephritis is not present. sion usually follows removal of the agent. Lesions typical of
The only agent thus far associated with the condition in leukocytoclastic vasculitis are seen. Because larger arteries are
man is hepatitis B antigen, which is found in 25-40% of indi- spared, macroscopic infarcts are uncommon. Hypersensitivity
viduals with necrotizing vasculitis. High mortality occurred in vasculitis appears to be the basis of some cases of hemorrhagic
the human disease before the advent of corticosteroid and purpura in horses; other causes of subcutaneous edema and
cyclophosphamide therapy. Polyarteritis nodosa has been mucosal hemorrhages, such as equine viral arteritis, equine
reported in dogs having rheumatoid arthritis and systemic infectious anemia, and equine ehrlichiosis, must also be
lupus erythematosus; separation of the vasculitis component considered. Trimethoprim-sulfadiazine and trimethoprim-
from disease syndromes is of problematic value. Also, as noted sulfamethoxazole have caused hypersensitivity vasculitis
previously in the section Vasculitis, a more appropriate term in dogs.
for idiopathic vasculitides is probably systemic necrotizing
vasculitis rather than polyarteritis nodosa, which has tended
to become a catchall term. Further reading
A wide variety of clinical and pathologic manifestations Clemo FA, et al. Differentiating spontaneous from drug-induced vas-
occur in polyarteritis nodosa as described in man and domestic cular injury in the dog. Toxicol Pathol 2003;31(Suppl.):25-31.
animals. Although occasionally associated with the death of Eleftheriou D, et al. Systemic polyarteritis nodosa in the young: a single
an animal, lesions are also noted in otherwise normal animals centre experience over 32 years. Arthritis Rheum 2013;65:2476-
at slaughter. Renal, coronary, hepatic, and gastrointestinal 2485.
vessels are perhaps most commonly involved (Fig. 1-76). Arte- Ferreras MC, et al. Pathologic features of systemic necrotizing vasculi-
rial lesions at all stages of development, namely, acute, healing, tis (polyarteritis nodosa) in sheep. J Comp Pathol 2013;149:74-81.
and healed, may occur simultaneously in one individual and even Hughes LB, Bridges SL Jr. Polyarteritis nodosa and microscopic polyan-
within the same vessel. giitis: etiologic and diagnostic considerations. Curr Rheumatol Rep
The acute lesions are often typical of immune-complex– 2002;4:75-82.
induced arteritis, and inflammation and necrosis of the arte- Son WC. Idiopathic canine polyarteritis in control beagle dogs from
rial wall may be segmental or circumferential. Thrombosis toxicity studies. J Vet Sci 2004;5:147-150.
may occur and lead to infarction and hemorrhage. As the
reaction progresses, neutrophils are replaced in the media by
mononuclear cells, and fibroplasia may result in grossly visible Viral vasculitides
fibrous thickening of the wall. The vascular lumen may be Equine viral arteritis. This disease is caused by species
obliterated by organization of a thrombus plus intimal prolif- Equine arteritis virus (EAV), an RNA virus of the family
eration. The term “periarteritis” has been used in the past Arteriviridae, genus Arterivirus, which is pathogenic only for
horses and is cytopathic in equine kidney culture. Although
serologic surveys indicate that infection with EAV is common
in North America and Europe, clinical disease is uncommon.
Most strains of EAV are avirulent, and mortality is rare in
natural outbreaks. Long-lasting immunity follows recovery.
Transmission of virus occurs primarily by respiratory and vene-
real routes during the acute phase of infection; venereally
infected mares can infect nonimmune mares by aerosol trans-
mission. Long-term carrier stallions play an important role in
perpetuation and dissemination of the virus; a carrier state has
not been demonstrated in mares or foals. There is some evi-
dence for resistance/susceptibility to the severity of the disease
based on the host’s permissiveness of infection of CD3+ lym-
phocytes. The major features of the disease are shown in
eFigure 1-20.
The clinical disease is characterized by fever; variable
anorexia and depression; leukopenia; edema of the ventral
body wall and limbs, especially the hindlimbs; skin rash, most
commonly on the neck; serous, later mucopurulent, oculona-
Figure 1-76 Chronic fibrosing vasculitis in renal artery (polyar- sal discharge with rhinitis and conjunctivitis; and periorbital/
teritis nodosa) in a goat. H&E. (Courtesy E. Olson.) supraorbital edema. Dyspnea, coughing, ataxia, and diarrhea
71.e1
Further reading
Carpenter JL, et al. Polyarteritis nodosa and rheumatic heart disease in
a dog. J Am Vet Med Assoc 1988;192:929-932.
Curtis R, et al. Polyarteritis in a cat. Vet Rec 1979;105:354.
Elling F. Nutritionally induced necrotizing glomerulonephritis and poly-
arteritis nodosa in pigs. Acta Path Microbiol Scand A 1979;87A:387-
392.
Gardiner AC, et al. Periarteritis in experimental border disease of
sheep: III. Immunopathological observations. J Comp Pathol
1980;90:469-474.
Jansen JH, Nordstoga K. Renal lesions in Norwegian slaughter pigs.
Macroscopic and light microscopic studies. Zentralbl Veterinarmed
A 1992;39:582-592.
Rae CA. Lymphocytic enteritis and systemic vasculitis in sheep. Can Vet
J 1994;35:622-625.
Werner LL, et al. Acute necrotizing vasculitis and thrombocytopenia in
a horse. J Am Vet Med Assoc 1984;185:87-90.
71.e2
Arterivirus
[RNA virus]
Virulence varies
Most strains avirulent
Transmission aerosol
and venereal
are less frequent. Pregnant mares often abort during or shortly intestine and lungs. The arterial lesions occur in many organs
after the febrile period, probably resulting from myometritis but are perhaps most consistently present in the gut and adrenals.
and decreased progesterone production by a hypoxic pla- Infarction is most common in the intestines, particularly in
centa. Specific lesions are present occasionally in aborted the cecum and colon. Massive necrosis of lymph nodes also
fetuses, and include necrotizing vasculitis, and inflammatory occurs. Extensive necrosis of the adrenals may result from
foci in various organs. Newborn foals may succumb to inter- direct viral injury and infarction.
stitial pneumonia. There is also a necrotizing vasculitis in the Diagnosis is made through detection of seroconversion or
placenta. more commonly, identification of the virus in the presence of
The virus is pathogenic to endothelial cells and causes pan- compatible lesions. Differential diagnoses for EVA include dis-
vasculitis, that is, inflammation of veins, lymphatics, and arteries. eases caused by other viruses (equid herpesvirus 1, equine
Following initial replication of the virus in macrophages, endo- adenovirus, influenza A virus, equine infectious anemia virus,
thelial cells are invaded beginning 3 days after experimental African horse sickness virus, Hendra virus, Getah virus), plus
aerosol infection. As inflammation progresses and neutrophils purpura hemorrhagica, septic shock, and poisoning by the
damage the internal elastic lamina, medial cells are invaded. toxic plant hoary alyssum (Berteroa incana).
The most severe edema occurs at days 6 and 7 when phlebitis,
lymphangitis, and capillary damage are most pronounced.
Arterial necrosis peaks at day 10, when edema has largely Further reading
disappeared. The vascular lesions will resolve if the horse
Del Piero F. Equine viral arteritis. Vet Pathol 2000;37:287-296.
survives. Antibody appears to play little role in the pathogen-
Go YY, et al. Assessment of correlation between in vitro CD3+ T cell
esis of the disease, in contrast to the immune-complex com-
susceptibility to EAV infection and clinical outcome following exper-
ponent of some other viral vasculitides.
imental infection. Vet Microbiol 2012;157:220-225.
The gross lesions of the disease, in addition to the changes
Miszczak F, et al. Emergence of novel equine arteritis virus (EAV)
observed clinically, consist principally of hemorrhages and
variants during persistent infection in the stallion: origin of the
edema. Petechial hemorrhages are found on all serous mem-
2007 French EAV outbreak was linked to an EAV strain present
branes, in the substance of the lungs, and in the gastric mucosa.
in the semen of a persistently infected carrier stallion. Virol
Larger hemorrhages may be present in the adrenals. There is
2012;423:165-174.
excessive fluid that contains much protein and some strands
of fibrin in all serous cavities. As much as 10 L may be present
in the pleural and peritoneal cavities. The connective tissues
and mesenteries of the body cavities are saturated with edema African horse sickness. African horse sickness (AHS) is a
fluid, and the wall of the gut may be thickened by edema. vector-borne disease of solipeds, and occasionally of dogs
Enteritis, hemorrhagic, or diphtheritic in character, usually and camels, caused by species African horse sickness virus
more severe in the large than in the small intestine, is regularly (AHSV), family Reoviridae, genus Orbivirus, that is closely
present. The lungs are more-or-less severely edematous. related to bluetongue virus. The disease is endemic in sub-
Characteristic microscopic lesions occur focally or segmen- Saharan Africa, from where it spreads to southern Africa and
tally in the media of small muscular arteries (Fig. 1-77). The occasionally northern Africa. It has also extended on occasion
smooth muscle cells undergo necrosis and are replaced by through the Middle East as far as India, and apparently with
hyaline or fibrinoid material. There is edema of the wall and climate change, the vector has become established in southern
adventitia and infiltration of leukocytes, chiefly lymphocytes, Europe. Its importance lies in the extreme lethal potential of the
the nuclei of which undergo fragmentation with necrosis. The infection in susceptible horses and the very wide distribution of
endothelium and intima may have been repaired so that the competent insect vectors.
thrombosis is unusual; thrombosis may, however, occur in the The vectors of AHSV are primarily Culicoides biting
midges, particularly Culicoides imicola. Transmission by mos-
quitoes or ticks is of minor importance. AHSV requires an
ambient temperature of ≥15° C to replicate and be transmit-
ted by Culicoides. Historically, in enzootic areas south of the
Sahara, outbreaks of disease occurred in seasons when noctur-
nal biting insects were active, outbreaks subsiding shortly after
the first frosts. It is possible that, in climatically suitable areas,
transmission might occur throughout the year. Annual recru-
descence poses the question of reservoirs for over-winter per-
sistence; the natural reservoir remains unknown, although the
zebra is most likely. Even in districts where AHS occurs annu-
ally, the distribution tends to be limited to low-lying areas
such as valleys, swamps, and areas of summer rain.
African horse sickness is primarily a disease of the horse and
its close relatives, but a wide range of species is susceptible to
the virus experimentally, including goats, guinea pigs, mice,
ferrets, and rats. The major features of the disease are shown
in eFig. 1-21. The horse is the most susceptible to infection
Figure 1-77 Multifocal vasculitis with fibrosing perivascular and and to illness; the mortality rate in susceptible populations of
perineural inflammation in equine viral arteritis. (From an Armed horses may be as high as 95%. The mortality rate in mules
Force Institute of Pathology Wednesday Slide Conference, 2000.) (~80%) is less than that in horses, but greater than that in the
72.e1
Further reading
Cho HJ, et al. Detection of antibodies to equine arteritis virus by a
monoclonal antibody-based blocking ELISA. Can J Vet Res
2000;64:38-43.
Del Piero F. Diagnosis of equine arteritis virus infection in two horses
by using monoclonal antibody immunoperoxidase histochemistry
on skin biopsies. Vet Pathol 2000;37:486-487.
Hullinger PJ, et al. Seroprevalence of antibodies against equine arteritis
virus in horses residing in the United States and imported horses.
J Am Vet Med Assoc 2001;219:946-949.
Szeredi L, et al. Equine viral arteritis in a newborn foal: parallel detec-
tion of the virus by immunohistochemistry, polymerase chain reac-
tion and virus isolation. J Vet Med B Infect Dis Vet Public Health
2003;50:270-274.
72.e2
Orbivirus
Closely related to bluetongue
virus
Nine major antigenic types
Infects solipeds; sometimes
camels and dogs
insect tramsmitted
Clinical signs
Four clinical syndromes:
Peracute/pulmonary form [fever,
respiratory distress]; Pathogenesis not well
understood
Subacute/cardiac form [fever, severe
subcutaneous edema, petechial Virus in many tissues
hemorrhages] No obvious endothelial invasion
Mixture of pulmonary /cardiac form
Mild form - AHS fever
[remittent fever] African
horse sickness
Gross features
Depends on clinical form Histopathology
Hydrothrax; Pulmonary edema; Diffuse severe
petechial /ecchymotic hemorrhages;
Alveolar edema; Widespread
swollen and edematous lymph nodes'
hemorrhage;
subcutaneous edema;
hydropericardium
Egyptian donkey. The South African donkey and the zebra are and in resistant species such as donkey and zebra. The mortal-
resistant. The role of dogs, and other scavenging carnivores, in ity rate is ~70%.
the disease cycle is not known. The disease is not contagious The pathogenesis of the signs and lesions is related to sites
by contact, but dogs may acquire it from eating infected of viral replication. Virus is found early and develops to
horseflesh. Infection, detected by viral isolation/detection or highest titer in spleen, lymph nodes, lung, and the large
serologically, can be common in dogs in some circumstances, intestine; the titer in myocardium is low. Viral infection
but vector transmission from dogs is unlikely. causes degeneration and loss of endothelium in myocardial
In many parts of Africa, the use of the horse, mule, and and pulmonary capillaries, with resulting increased vascular
donkey is dependent on the control of AHS, but this control permeability, edema, hemorrhage, and microthrombosis.
has been difficult to attain. The primary obstacle has been the Vascular permeability of pulmonary capillaries may be
multiplicity of antigenic types of AHSV of which there are at increased through the action of inflammatory mediators
present 9 major antigenic types. These types have a basic anti- released by activated intravascular macrophages.
genic relationship that may be demonstrated in the horse, but Gross lesions observed at autopsy depend largely on the
the relationship is not sufficiently close to provide solid immu- clinical form of disease. In the pulmonary form, the most char-
nity amongst types. Indeed, although all strains investigated acteristic changes are edema of the lungs and hydrothorax
can be fitted into one of the major types, the antigenic diver- (Fig. 1-78A). In very acute cases, edema and mottled hyper-
sity of strains within a single type is such that very few strains emia of the lungs are seen, whereas in cases with a somewhat
are identical. This is certainly the situation in enzootic areas more protracted course extensive interstitial and subpleural
where a large number of different strains may be isolated edema are also present, but hyperemia is less evident. Other
during an outbreak. On the other hand, there has been close lesions commonly observed are periaortic and peritracheal
antigenic relationship between the viruses recovered during edematous infiltration, diffuse or patchy hyperemia of the
the epizootic outbreaks that occurred outside the reservoir- glandular fundus of the stomach, hyperemia and petechial
host range where the transmission was from horse to horse. hemorrhages in the mucosa and serosa of the small and large
This suggests that, although the AHSV is extremely mutable, intestines, subcapsular hemorrhages in the spleen, and conges-
mutations do not readily occur when the disease is transmitted tion of the renal cortex. All the lymph nodes are enlarged and
from horse to horse. Recovered horses are immune to homolo- edematous, especially those in the thoracic and abdominal
gous challenge, and possess some immunity to heterologous cavities. The pericardial sac may contain variable amounts of
challenge. Vaccines are currently available to either prevent or fluid, and numerous petechial hemorrhages occur in the peri-
to lower the severity of the disease. cardium. Cardiac lesions are usually not conspicuous, but
Four clinical forms of AHS are described: pulmonary (per- epicardial and endocardial petechial hemorrhages may some-
acute), mixed (acute), cardiac (subacute), and AHS fever (mild) times be evident.
forms, from most to least severe. Most cases are of the mixed In the cardiac form, the most characteristic lesions are the
form, perhaps reflecting variations in the susceptibility of the edematous infiltration of the subcutaneous, subfascial, subse-
host, the virulence of the virus, or the tropism of virus for rous, and intermuscular tissues. Only the head and neck may
different parts of the vascular system. be involved, but in more severe cases, the edema also involves
The peracute or pulmonary form of the disease, the most lower parts of the neck, brisket, and shoulders (Fig. 1-78B).
common form in epizootics, has an incubation period of 3-5 Hydropericardium is a constant finding, the pericardial sac
days. Fever occurs suddenly and is of short duration, followed often containing 2 L or more of fluid (Fig. 1-78C). The epi-
by the acute onset of respiratory distress. Death may occur in cardium and endocardium show numerous, almost confluent
a few hours from pulmonary edema, and frothy fluid fills the ecchymotic hemorrhages. The lungs are usually normal or only
respiratory tract and may flow from the nostrils. slightly engorged, and the thoracic cavity rarely contains an
The subacute or cardiac form is usually associated with excess of fluid. The lesions in the gastrointestinal tract are
infections that are not fully virulent or are encountered in generally similar to those found in the pulmonary form,
animals in which infection by heterologous strains has stimu- except that submucosal edema tends to be far more pro-
lated some immunity. The incubation period is 7-14 days with nounced. Ascites is unusual.
clinical signs of fever lasting 3-6 days. As the fever subsides, In the mixed form, the lesions are a combination of those
edematous swellings appear in the temporal or supraorbital observed in the pulmonary and cardiac forms. In fact, most of
fossae and the eyelids. The swellings extend to the lips, cheeks, the fatal cases of AHS can be considered to be of the mixed form,
tongue, intermandibular space, and throat. Swelling from sub- with lesions typical of either the pulmonary or the cardiac
cutaneous fluid may affect the upper neck and sometimes the form predominating.
chest and shoulders. Terminally, petechial hemorrhages usually The infective dose of AHS virus for dogs is large, and high
occur on the conjunctiva and ventral surface of the tongue. infective titers are not known to be gained except by ingestion
The mortality rate may be as high as 50%, and is attributed of infected horseflesh. The course of the disease in dogs is
to cardiac failure and pulmonary edema. similar to the pulmonary form in horses with fever and severe
As observed above, many cases are mixtures of the pulmo- respiratory distress. The mortality in dogs showing respiratory
nary and cardiac form. Initial pulmonary signs of relatively signs is very high. At autopsy, the lungs are edematous and
mild degree may be followed by characteristic swelling of the may have some superimposed bronchopneumonia. There is
head and death from cardiac failure, or the cardiac form may much froth in the airways, copious hydrothorax in which the
be followed by sudden onset of dyspnea and pulmonary edema. fluid gels on exposure, and saturation of mediastinal tissues.
The mild clinical form of the disease, AHS fever, may not Histologic changes are not helpful in diagnosis or understand-
be noticed in outbreaks. It is characterized by remittent fever ing of pathogenesis.
lasting for a week or so. This is the form of the disease to be The clinical signs of AHS are usually characteristic,
expected in animals with immunity to heterologous strains although AHS might be confused with equine encephalosis,
74 CHAPTER 1 • Cardiovascular System Arteries
B
A
C
Figure 1-78 African horse sickness in a horse. A. Severe, acute pulmonary edema. B. Subcutane-
ous edema of a hindlimb. C. Excess blood-tinged fluid in the pericardial sac. (Courtesy Foreign
Animal Diseases Diagnostic Laboratory, National Veterinary Services Laboratories.)
anthrax, equine infectious anemia, equine babesiosis, purpura the virus is a constant and major threat to domestic pigs.
hemorrhagica, equine viral arteritis, equine viral rhinopneu- Originally limited to sub-Saharan Africa, the disease has
monitis, or trypanosomiasis. appeared in southern and western Europe, most recently in
Diagnosis requires virus isolation, virus identification, or Georgia in the Caucasus, the Caribbean, Brazil, Madagascar,
serology. and Mauritius. International spread of ASF is primarily through
infected pork products in garbage fed to pigs. Once a focus of
infection is established, spread is most likely to occur by direct
Further reading or indirect contact. In Africa, the transmission of the virus
Carrasco L, et al. The role of pulmonary intravascular macrophages in from wild Suidae to domestic pigs is primarily by the argasid
the pathogenesis of African horse sickness. J Comp Pathol tick Ornithodoros moubata, a true biological vector and a
1999;121:25-38. reservoir of the virus in nature. Additional arthropod vectors
Gomez-Villamandos JC, et al. Pathogenesis of African horse sickness: exist.
ultrastructural study of the capillaries in experimental infection. The causative agent, ASFV, is an enveloped DNA virus,
J Comp Pathol 1999;121:101-116. family Asfarviridae, genus Asfivirus. It is a relatively resistant
Stern AW. African horse sickness. Compend Contin Educ Vet virus that may survive in the environment or in uncooked
2011;33:E1-E5. pork products for prolonged periods. There are several anti-
genically different strains of ASFV. Viral virulence is classified
as high, moderate, and mild. In an area free of the disease, ASF
African swine fever. African swine fever (ASF) is an acute- is typically seen as a peracute or acute disease with high mor-
to-chronic, febrile, viral disease of swine, characterized by high bidity and mortality, but as virulence diminishes with time,
fever, cutaneous hyperemia, abortions, edema, and hemorrhage in subacute, chronic, and inapparent forms become increasingly
internal organs, particularly lymph nodes. Species African swine evident. Survivors remain persistently infected.
fever virus (ASFV) infects only members of the Suidae family The immunologic response of swine to strains of ASFV is
and is a harmless companion of the warthog (Phacochoerus unusual and is incompletely understood. Susceptible animals
aethiopicus) and the bush pig (Potamochoerus porcus). However, infected with African field strains develop precipitating and
74.e1
Further reading
Brown CC, et al. Presence of African horse sickness virus in equine
tissues, as determined by in situ hybridization. Vet Pathol
1994;31:689-694.
Mellor PS, Hamblin C. African horse sickness. Vet Res 2004;35:
445-466.
Diseases of the Vascular System Arteries 75
complement-fixing, but rarely neutralizing or protective, anti- contains ingesta, but the mucosa is apt to be inflamed and
bodies. The animals remain viremic and usually die within eroded. Changes in the small intestine may be absent or
7-10 days. Pigs that recover are resistant to infection with the consist of segmental areas of congestion and mucosal pete-
homologous virus. In the case of infection with highly virulent chiation. More severe intestinal changes may be found in the
ASFV, even though 10 days may have elapsed since infection, large intestine; these may include large areas of hemorrhage,
pigs typically die before development of anti-ASF immuno- severe congestion, and ulceration. Lesions suggesting “button
globulin, probably because of the demise of antigen-presenting ulcer” are very rare in this disease, presumably because few
cells in lymph nodes, spleen, and liver. animals survive long enough for their development.
There is no cross-protection conferred by infections by The postmortem appearance of subacute and chronic cases
classical swine fever virus (CSFV) and ASFV. of ASF varies considerably. In the subacute cases that die after
The ASFV replicates in and activates monocytes and mac- 3-4 weeks of illness, there may be lymph node and renal
rophages of various lymphoid tissues and organs, resulting in hemorrhage, an enlarged but not congested spleen, lobular
release of cytokines, such as interleukin-1 and tumor necrosis consolidation of cranial lung lobes, and intestinal mucosal
factor-α, and hence causes widespread cell death through hemorrhage (Fig. 1-79A, B). Prominent features of the chronic
apoptosis of T and B lymphocytes in lymphoid tissue and of form include fibrinous pericarditis and pleuritis; splenic and
endothelial cells in arterioles and capillaries, accounting for lymph node enlargement; lobular consolidation of the lungs,
the lesions of the acute disease. Activation of pulmonary intra- which may progress to necrosis and mineralization of an entire
vascular macrophages and release of cytokines incites pulmo- lobe; skin lesions ranging from raised hyperemic plaques to
nary edema, neutrophil sequestration, and formation of necrotic areas; swollen joints; and arthritis. The meningoen-
microthrombi in septal capillaries. It also appears that the cephalomyelitis and periportal hepatitis observed in the acute
virus modulates signaling pathways in macrophages, hence disease persist in the chronic disease. Lesions in aborted fetuses
interfering with the expression of host immunomodulatory are inconsistent but include petechiation of placentas, skin,
genes; this evasion of host defenses allows infections to be and myocardium, mottled lungs and liver, and anasarca.
persistent. The major features of the disease are shown in
eFig. 1-22.
The peracute form of ASF is a severe acute viral hemorrhagic
fever characterized by a 1-3 day course of pyrexia, hyperpnea,
and cutaneous hyperemia, with morbidity and mortality
approaching 100%. However, the usual clinical course of ASF
is acute. Following an incubation period of 4-10 days, there is
a reduction in appetite, pyrexia, marked cutaneous reddening,
dyspnea, and severe leukopenia. Pregnant sows may abort. The
clinical signs in the less severe forms of the disease are variable.
The signs may be a mild expression of those seen in the acute
disease and may be confused easily with other diseases. There
are recurring periods of pyrexia, dyspnea, growth retardation,
and emaciation. Death may occur during one of the periods
of pyrexia. It is important to realize that the clinical signs of
chronic ASF may be indistinguishable from those seen in classical
swine fever (CSF).
The ASFV tends to affect the same organs and tissues as A
does the CSFV. The anatomic differences tend to be quantita-
tive and dependent on the more fulminating nature of ASF;
only splenomegaly and hematoma-like visceral lymph nodes are
particularly characteristic of ASF. The vascular lesions that can
develop rapidly, namely, hemorrhage and edema, are apt to be
more severe in ASF than in CSF, whereas the lesions that
develop more slowly, such as infarction, tend to be absent.
The pig dead from acute ASF shows few or no signs of
recent wasting. Gastrosplenic and renal lymph nodes are
usually intensely hemorrhagic, and ecchymotic hemorrhages
may be present on the serous membranes. The spleen is
usually enlarged and may be markedly enlarged and friable;
infarction cannot usually be recognized grossly. Pulmonary
edema, not common in CSF, is present frequently in pigs with
ASF. The pulmonary septa are thickened by a yellow gelati-
nous infiltrate. Pulmonary hemorrhage is also common. The B
gallbladder is often edematous, and the vessels of the wall are
engorged and conspicuous. Both petechiae and ecchymoses Figure 1-79 African swine fever. A. Enlarged hemorrhagic renal
are present on the serosal and mucosal surfaces. In some out- and sublumbar lymph nodes. B. Incised, enlarged and hemor-
breaks of the disease, there are extensive pancreatic hemor- rhagic, presternal lymph nodes. (Courtesy Foreign Animal Dis-
rhages and necrosis. The renal changes are similar to those of eases Diagnostic Laboratory, National Veterinary Services
CSF and consist of subcapsular petechiae. The stomach often Laboratories.)
75.e1
Pathogenesis
ASFV replicates in cells of monocyte/
macrophage lineage and lymphoid tissues.
HISTOPATHOLOGY Subacute and chronic Leads to a massive release of cytokines
Extensive apoptosis/necrosis cases of ASF have from activated, dying and dead cells
of cells of the monocyte/ lymph node, renal
macrophage system hemorrhage, fibrinous
pericarditis and pleuritis
Extensive lymphoid
apoptosis/necrosis
Degeneration of
vascular endothelium,
fibrinoid change
and thrombosis
eFigure 1-22 Major features of African swine fever (ASF). ASFV, African swine fever virus.
76 CHAPTER 1 • Cardiovascular System Arteries
A B
C D
Figure 1-80 African swine fever in a pig. A. Extensive hemorrhage and necrosis in lymph node.
B. Necrosis/apoptosis, especially of lymphocytes in tonsil. C. Extensive thrombosis in renal vessels.
D. Necrotizing vasculitis in renal arterioles. H&E. (Courtesy Armed Forces Institute of Pathology
[archive].)
Histologically, infection by a highly virulent strain of ASFV by direct immunofluorescence, detection of ASF antibody by
causes extensive necrosis of cells of the mononuclear phago- indirect immunofluorescence or ELISA, detection of virus
cyte system, whereas infection with a moderately virulent genome by PCR, and virus isolation. Differential diagnoses
strain causes little necrosis (Fig. 1-80A, B). The histologic find- include classical swine fever (from which ASF cannot be dif-
ings in acute ASF are very similar to those of CSF, but there are ferentiated by clinical or postmortem examination), erysipe-
important differences. A major difference is that ASFV does not las, salmonellosis, pasteurellosis, and other septicemias.
infect epithelium. Necrosis with karyorrhexis in lymphoid
tissue everywhere is often very obvious in ASF; frank necrosis
is quite rare in CSF, although mature lymphocytes are apt to Further reading
be absent in lymphoid tissue. Renal tubular degeneration with Blome S, et al. Pathogenesis of African swine fever in domestic pigs
amorphous casts in the medulla is frequent in ASF, but rare and European wild boar. Virus Res 2013;173:122-130.
in CSF. In ASF, necrosis of periportal hepatocytes and infiltrat- Costard S, et al. African swine fever: how can global spread be pre-
ing lymphocytes is common, whereas microscopic hepatic vented? Philos Trans R Soc Lond B Biol Sci 2009;364:2683-2696.
lesions are usually absent in CSF. The vascular cuffs in the Gomez-Villamandos JC, et al. African swine fever and classical swine
brain in ASF contain much more necrotic debris than do the fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
lesions in CSF. The degeneration of vascular endothelium and 2003;110:165-169.
the fibrinoid arterial changes are identical (Fig. 1-80C, D). Vas- Mozos E, et al. Cutaneous lesions in experimental acute and subacute
cular endothelial damage in the lung may cause thrombosis African swine fever: an immunohistopathological and ultrastruc-
of vessels and thickening of alveolar walls. Pigs dead of acute tural study. Dtsch Tierarztl Wochenschr 2003;110:150-154.
ASF may have glomerular capillary thrombosis; surviving pigs Penrith ML. African swine fever. Onderstepoort J Vet Res 2009;76:
may develop focal segmental glomerulonephritis. 91-95.
Because there is no treatment or effective vaccine against Sanchez-Vizcaino JM, Mur L. African swine fever diagnosis update. Dev
ASF, rapid diagnosis is critical to disease control. A diagnosis Biol (Basel) 2013;135:159-165.
of ASF is confirmed by detection of ASFV antigen in tissues
76.e1
Further reading
Angulo A, et al. Virus-host interactions in African swine fever: the
attachment to cellular receptors. Arch Virol Suppl 1993;7:169-183.
Carrasco L, et al. African swine fever: expression of interleukin-1 alpha
and tumour necrosis factor-alpha by pulmonary intravascular mac-
rophages. J Comp Pathol 2002;126:194-201.
Dixon LK, et al. African swine fever virus proteins involved in evading
host defence systems. Vet Immunol Immunopathol 2004;100:117-
134.
Edwards JF, et al. Mechanism of thrombocytopenia in African swine
fever. Am J Vet Res 1985;46:2058-2063.
Gomez-Villamandos JC, et al. African swine fever virus infection of
bone marrow: lesions and pathogenesis. Vet Pathol 1997;34:97-
107.
Hervas J, et al. The lesional changes and pathogenesis in the kidney in
African swine fever. Vet Res Commun 1996;20:285-299.
Kleiboeker SB, Scoles GA. Pathogenesis of African swine fever virus in
Ornithodoros ticks. Anim Health Res Rev 2001;2:121-128.
Vallee I, et al. African swine fever virus infection of porcine aortic
endothelial cells leads to inhibition of inflammatory responses, acti-
vation of the thrombotic state, and apoptosis. J Virol 2001;75:
10372-10382.
Diseases of the Vascular System Arteries 77
Classical swine fever (hog cholera). Classical swine fever specific antibody formation, but later by immune exhaustion
(CSF) is a highly contagious viral disease of swine; it may occur and chronic disease in which the pig is viremic and more
as acute, subacute, chronic, or inapparent syndromes. Acute CSF susceptible to secondary bacterial infection. Late-onset CSF
is a disease of high morbidity and mortality caused by a viru- occurs in pigs that are persistently viremic and immunotoler-
lent strain of the virus; low-virulence virus may cause inap- ant to CSFV as a result of fetal infection by CSFV of low viru-
parent disease. Classical swine fever is said to have developed lence. The latest date for the development of a persistent
de novo in Ohio, United States, in the early 1800s. It subse- infection of the fetus appears to be about day 70 of gestation;
quently spread to almost all countries and is also known as by day 85 viral antigen may be detected in a few fetuses, but
swine fever, Schweinepest, peste du porc, and peste svina. Species virus cannot be isolated. Signs that develop in viremic, but
Classical swine fever virus (CSFV) produces disease only in previously asymptomatic, pigs include anorexia, depression,
swine. The disease has been eradicated from Australia, Canada, leukopenia, conjunctivitis, dermatitis, diarrhea, runting, and
the United Kingdom, and the United States, but it remains a paraparesis. The late-onset form of CSF is the porcine equivalent
problem in Central and South America and several European of mucosal disease in cattle, in which BVDV infection of fetal
countries. calves results in persistently viremic, immunotolerant animals.
CSF is caused by a Pestivirus, a member of the family Fla- The major clinical features of CSF are shown in eFig. 1-23.
viviridae. Other members of the genus include bovine viral The pathogenesis of CSF is not fully understood, but
diarrhea virus (BVDV), Bungowannah virus and border involves the effects of the virus on the immune system (lym-
disease virus (BDV). CSFV and BVDV are closely related phoreticular cells and macrophages), the vascular endothelium,
antigenically, and although pestiviruses other than CSFV are and epithelial cells. The effect of the monocytotropic CSFV on
thought to be harmless to pigs, natural BVDV infection can the immune system varies with the stage of differentiation;
cause clinical signs and postmortem lesions indistinguishable from mature cells degenerate, whereas undifferentiated cells
those of chronic CSF. Under appropriate circumstances, CSFV, respond by proliferation. CSFV replicates in macrophages in
BVDV, Bungowannah virus, and BDV may produce transpla- lymph nodes and lymphoid tissues and can cause depletion of
cental infection, and hence persistent infections and congeni- lymphocytes indirectly through expression of apoptotic cyto-
tal anomalies. The CSFV is an enveloped, single-stranded kines, such as tumor necrosis factor-α. Similarly, intestinal
RNA virus that replicates intracytoplasmically. Most strains do epithelial cell necrosis appears be the product of release of
not produce a cytopathic effect in porcine cell cultures. The chemical mediators from activated macrophages, rather than
enveloped nature of the virus makes it sensitive to lipid sol- direct viral infection. Endothelial changes are primarily degen-
vents and to desiccation. However, the virus may persist for erative but some proliferative changes occur. Damage to endo-
prolonged periods in uncooked pork products. thelial and other cells leads to thrombocytopenia, consumption
Antigenic variation exists among strains of CSFV, and field coagulopathy, and in turn disseminated intravascular coagula-
strains vary widely in virulence. The interaction of a particular tion and hemorrhage.
strain of virus and the host provides a range of disease syn- The classic or acute form of the disease, which affects pigs
dromes. Strains of CSFV are usually classified as being of high, of all ages, commences by entry of the virus through the
moderate, or low virulence, or as being avirulent. Highly virulent mucous membranes with initial replication in the tonsillar
strains produce the features of the classic acute disease in pigs epithelium. This is followed by spread to the cervical lymph
of all ages; the morbidity may reach 100%, with a mortality nodes with viremia within 16 hours of infection. The virus has
rate of up to 90%. Strains of moderate virulence induce sub- a propensity to replicate in cells of the immune system, par-
acute or chronic disease, and pigs may subsequently die or ticularly in lymph nodes, bone marrow, and other lymphoid
recover. In pigs infected postnatally, strains of low virulence aggregates, such as the spleen and Peyer’s patches. After 3-4
produce few or no signs of disease and induce immunity, but days, the virus invades endothelial cells and epithelial cells,
may cause fetal abnormalities. Artificially attenuated strains including those of the pharyngeal mucosa, gastrointestinal
used as vaccines are avirulent, even for fetuses. Virulence of tract, gallbladder, pancreas, salivary gland, uterus, adrenal, and
CSFV may be unstable; virulence can increase by one passage thyroid. The clinical signs are not specific and do not provide
through pigs. good correlation with pathologic changes, although, in the
Transmission of the disease is usually by direct contact of acute disease, they may be sufficient for presumptive diagnosis
infected pigs or wild boar with susceptible pigs; CSF is where the disease is endemic.
endemic in wild boar in parts of Europe. The virus is present Superficially, the eyelids are frequently adherent and sticky,
in urine, feces, and lacrimal and oronasal secretions of infected and the carcass is dehydrated and soiled by terminal diarrhea.
pigs, as well as semen of infected boars. Even with the less The irregular erythema that can be seen in the animal when
virulent strains, the virus may be excreted in the urine for alive is less obvious, but hemorrhages, particularly in unpig-
periods up to 3 months. The major mechanism of spread of mented areas of skin, may be seen. If present, they are most
virus of low virulence occurs from continuous virus shedding numerous on the abdomen and the inner aspects of the thighs.
by chronic or persistently infected asymptomatic pigs. Minor Diagnostic lesions may be sparse in CSF, especially if per-
modes of transmission include fomites and arthropods. acute, and it may be impossible to establish the diagnosis on
Clinically, classical swine fever is characteristically an acute the basis of the gross lesions in a single animal. The lesions most
disease of high morbidity and mortality, most animals surviving commonly present are hemorrhages in the periphery of the lymph
only to 14 days after showing the first signs of illness, namely, nodes and renal petechiae (Fig. 1-81A). The renal hemorrhages
anorexia, depression, fever, and leukopenia. Persistent infec- may be very few, and in all cases the kidney capsule should
tion (i.e., survival of >30 days) is caused by CSFV strains of be removed and the surface examined in good light. Hemor-
moderate or low virulence and may arbitrarily be divided into rhages in the lymph nodes are more obvious; characteristically,
chronic and late-onset types. In chronic CSF, typical acute only the periphery of the node is involved. In acute cases, this
disease is followed by clinical improvement, the result of produces a distinctive bright red halo; if the case is more
77.e1
eFigure 1-23 Major clinical syndromes of classical swine fever. CNS, central nervous system.
78 CHAPTER 1 • Cardiovascular System Arteries
Vascular lesions usually are most severe in lymphoid tissue porcine reproductive and respiratory syndrome (PRRS), post-
but may occur anywhere. The lesions vary from slight thickening weaning multisystemic wasting syndrome (PMWS), porcine
of the capillary wall to fibrinoid necrosis of arterioles. As these dermatitis and nephropathy syndrome (PDNS), salmonellosis,
changes develop, there is a tendency for extravasations to erysipelas, acute pasteurellosis, other viral encephalomyeliti-
occur and for microthrombi to form. des, streptococcosis, leptospirosis, and coumarin poisoning.
Microscopic areas of infarction are common in the lymph
nodes and skin, but only in the spleen, tonsil, gallbladder, and
large intestine are these areas usually large enough to be Further reading
grossly visible. In some cases, swelling and paleness of the
Calderon NL, et al. Ultrastructural glomerular changes in experimental
capillary wall is obvious. The nuclei of endothelia in these
infection with the classical swine fever virus. Vet Res 2000;31:447-
vessels are enlarged and the nuclear chromatin is dispersed as
453.
fine dust. Less often, the endothelial proliferation is so marked
Elbers AR, et al. Assessment of the use of gross lesions at post-mortem
as to be the most conspicuous change. In general, in acute
to detect outbreaks of classical swine fever. Vet Microbiol
cases the degenerative changes are most prominent, whereas
2003;96:345-356.
in chronic ones proliferative changes are more obvious.
Gogin A, et al. African swine fever in the North Caucasus region and
In the periphery of lymph nodes (the equivalent of the
the Russian Federation in years 2007-2012. Virus Res 2013;173:198-
medulla in other species), lesions vary from slight edema and
203.
proliferation of the reticuloendothelial elements to extensive
Gomez-Villamandos JC, et al. African swine fever and classical swine
hemorrhage. It is the intermediate stages that are the most
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
common and in which the nature of the lesion is best visual-
2003;110:165-169.
ized; in these, there is necrosis of the small vessels and second-
Paton DJ, Greiser-Wilke I. Classical swine fever: an update. Res Vet Sci
ary hemorrhages and parenchymal necrosis.
2003;75:169-178.
In the spleen, the most pronounced lesions are in the fol-
Sanchez-Cordon PJ, et al. A histopathologic, immunohistochemical,
licular arteries, particularly those at the apex of the pyramidal
and ultrastructural study of the intestine in pigs inoculated with
infarcts. The swelling and hyalinization of these vessels may
classical swine fever virus. Vet Pathol 2003;40:254-262.
be so severe as to occlude the lumen. Survival of tissue within
Tao J, et al. Bovine viral diarrhea virus (BVDV) infections in pigs. Vet
the infarcted area will depend on how long the infarction
Microbiol 2013;165:185-189.
preceded death. Even if the spleen is free of gross and microscopic
infarction, vascular changes of the type seen elsewhere can usually
be found. They are often associated with perivascular hemor-
rhage. In addition, there is reticuloendothelial hyperplasia and Bovine ephemeral fever. Bovine ephemeral fever (BEF), a
absence of mature lymphocytes. noncontagious vector-borne viral disease of cattle and water
The kidney tubules often show nonspecific degenerative buffalo, is characterized by sudden onset of fever, stiffness, and
changes. The subcapsular hemorrhages seen grossly are the lameness, usually with high morbidity and low mortality, and
result of increased vascular permeability and erythrodiapede- with rapid recovery within 3-4 days of the onset of clinical signs.
sis. Immune-complex–mediated mesangioproliferative glo- The cause is species Bovine ephemeral fever virus (BEFV),
merulonephritis occurs with deposition of IgM, IgG, and C1q genus Ephemerovirus, family Rhabdoviridae. The disease is
in mesangial, subepithelial, and subendothelial sites; infiltra- endemic in tropical regions of Africa and Asia and occurs as
tion of the mesangium by macrophages and later neutrophils; epidemics in subtropical and temperate regions of Africa, the
and ultrastructurally, the fusion of foot processes and the Middle East, Asia, and Australia. In temperate climates, BEF
presence of viral particles in glomerular endothelial cells is a disease of summer and autumn, and ceases abruptly at the
and podocytes. The major histologic features are shown in first frost; the host/reservoir for overwintering or between
eFigure 1-27. epizootics is probably in wild ruminants. Infection usually
In utero infections can result in a variety of effects, includ- confers lifelong immunity. The likely vectors are various
ing abortion, mummified fetuses, and stillborn piglets. Fetal species of Culicoides and mosquitoes.
abnormalities, such as ascites, petechiation of skin and other Clinical disease ranges from almost imperceptible clinical
organs, hepatic nodularity, pulmonary hypoplasia, microceph- signs to death, with considerable individual variation in an
alus, hydrocephalus, cerebellar hypoplasia, and hypomyelino- outbreak. Mild disease may be exacerbated by environmental
genesis, may also be observed. Persistently infected pigs that stress, for instance, exposure causing dehydration. Disease is
survive may be runts and die 2-11 months after birth. These milder in young than in mature animals, in lean than in fat
piglets have severe thymic atrophy and pale swollen lymph animals, in light steers and cows than in bulls, and in dry cows
nodes; some may have focal colonic mucosal necrosis. than in those in heavy lactation. The incubation period is
Serologic diagnosis of CSF is difficult. Antibodies to CSFV usually 2-4 days. The fever may be biphasic, triphasic, or
and BVDV cross-react in many assays; they may be differenti- multiphasic; clinical signs are milder in early than in later
ated by specific virus neutralization tests. The prescribed tests phases of fever. Mildly affected animals may have fever, be
in the World Organization for Animal Health (OIE) Manual lame, or be stiff for 1-2 days, and then recover completely.
are the neutralization peroxidase-linked assay, fluorescent Neutrophilia with a left shift and concurrent lymphopenia,
antibody virus neutralization, and ELISA. CSFV antigen can hyperfibrinogenemia, and hypocalcemia occur early in the
be detected in live pigs by real-time (RT)-PCR, and in course of disease. More severely affected animals are anorectic,
formalin-fixed tissue by semi-nested RT-PCR or by in situ have oculonasal discharge, and may have muscle tremors, stiff-
hybridization. ness, lameness, and patchy edema of the face or jaw. Rumen
Differential diagnoses for CSF include African swine fever motility ceases, and the animal may be constipated. Animals
(clinicopathologically indistinguishable), BVDV infection, in lateral recumbency are usually still able to rise. Lactation
79.e1
eFigure 1-27 Major histopathologic findings in classical swine fever. DIC, disseminated intravas-
cular coagulation.
79.e2
Further reading
Carrasco CP, et al. Interaction of classical swine fever virus with den-
dritic cells. J Gen Virol 2004;85:1633-1641.
Choi C, et al. Classical swine fever virus induces tumor necrosis factor-
alpha and lymphocyte apoptosis. Arch Virol 2004;149:875-889.
Floegel-Niesmann G, et al. Virulence of recent and former classical
swine fever virus isolates evaluated by their clinical and pathologi-
cal signs. J Vet Med B Infect Dis Vet Public Health 2003;50:214-220.
Ha SK, et al. Development of an optimized protocol for the detection
of classical swine fever virus in formalin-fixed, paraffin-embedded
tissues by semi-nested reverse transcription-polymerase chain reac-
tion and comparison with in situ hybridization. Res Vet Sci
2004;77:163-169.
Handel K, et al. Comparison of reverse transcriptase-polymerase chain
reaction, virus isolation, and immunoperoxidase assays for detect-
ing pigs infected with low, moderate, and high virulent strains of
classical swine fever virus. J Vet Diagn Invest 2004;16:132-138.
Kleiboeker SB. Swine fever: classical swine fever and African swine
fever. Vet Clin North Am Food Anim Pract 2002;18:431-451.
Moennig V, et al. Clinical signs and epidemiology of classical swine
fever: a review of new knowledge. Vet J 2003;165:11-20.
Ruiz-Villamor E, et al. Classical swine fever: pathogenesis of glomeru-
lar damage and immunocharacterization of immunocomplex
deposits. J Comp Pathol 2001;124:246-254.
Terpstra C, Wensvoort G. Natural infections of pigs with bovine viral
diarrhoea virus associated with signs resembling swine fever. Res
Vet Sci 1988;45:137-142.
80 CHAPTER 1 • Cardiovascular System Arteries
falls by an average of 50%, and does not usually recover to Rickettsial vasculitides
normal during that lactation. Cows in late pregnancy may Heartwater (cowdriosis). Heartwater is a tick-borne rickett-
abort. In very severe cases, there may be temporary or perma- siosis of ruminants that is endemic in sub-Saharan Africa and
nent paralysis of all limbs, inability to swallow, and drooling; has been identified in several Caribbean islands. The common
in 1-4 days, loss of reflexes, coma, and death follow. name, heartwater, is derived from the pericardial effusion that
Whether the disease is mild or severe, recovery commences is typically present in small ruminants, but sometimes absent
quite suddenly and is complete in 95-97% of uncomplicated cases, in infected cattle. Heartwater is a major vector-borne disease
giving rise to the name “ephemeral fever.” Although mortality is of ruminants in Africa, third in importance only to East Coast
usually <1%, the most productive mature animals are often fever and trypanosomiasis, but has a wider distribution than
lost, plus there are losses of milk production, abortion losses, either of these. Mortalities caused by heartwater are estimated
and temporary infertility in bulls. Other sequelae include fatal to be 3 times greater than those caused by babesiosis and
pulmonary emphysema, pneumonia, mastitis, and locomotor anaplasmosis. The causative agent is Ehrlichia (Cowdria)
disturbances. The total economic loss in an outbreak can be ruminantium, order Rickettsiales. Isolates of E. ruminantium
severe. cross-react strongly with Ehrlichia equi and to a lesser extent
The essential gross feature of BEF is serofibrinous polyserosi- with E. canis, in indirect fluorescent antibody tests. The vectors
tis, which variously affects the synovial, pericardial, thoracic, are 3 host ticks of the Amblyomma genus, principally A. var-
and peritoneal cavities, and is the result of increased vascular iegatum, A. hebraeum, and A. pomposum. Amblyomma macu-
permeability. The serosal membranes themselves are often latum and A. cajennense are suitable vectors present on the
edematous and may be hemorrhagic; the edema fluid in cavi- American mainland. Trans-stadial transmission occurs in
ties often contains fibrin clots. Severely affected joints may be vector ticks; transovarian transmission is infrequent. When a
surrounded by brown or yellow gelatinous periarticular fluid tick feeds on an infected host, organisms apparently first infect
that also extends along tendon sheaths and fascial planes. and develop within gut cells. Subsequent stages of the organ-
There may be patchy pulmonary edema, visceral and parietal ism continue their development in hemolymph and salivary
pleuritis, epicarditis at the base of the heart, edematous lymph gland, and are transferred to the vertebrate host during tick
nodes in the febrile stages, and necrosis in some skeletal feeding.
muscles; myonecrosis is likely the result of recumbency. The various strains of Ehrlichia ruminantium are antigeni-
Histologically, affected tissues are edematous and infil- cally similar, but differ considerably in their virulence. The
trated by neutrophils, and may also be hyperemic and hemor- various domestic hosts also differ in their susceptibility.
rhagic. Vascular changes include endothelial swelling and Imported breeds of cattle, sheep, and goats are as a rule much
hyperplasia, hyperplasia of pericytes, fibrinoid necrosis of arte- more susceptible than indigenous breeds. There is also an
rioles, perivascular fibroplasia, and thrombosis of occasional important age difference in susceptibility. Calves and lambs
vessels in muscles. Wallerian degeneration has been reported <3 weeks of age are highly resistant to heartwater. This is a
in the upper cervical spinal cord in cases with chronic paraly- true age resistance, and it is independent of maternal immu-
sis, but may be secondary to trauma. nity. Ruminants are most susceptible at about the stage of
The pathogenesis of BEF is poorly understood, but is likely early maturity, and in the absence of treatment, mortality is
mediated through cytokines. BEFV α1 protein is expressed in expected to be ~60% in cattle and close to 100% in European
infected cells and has the properties of a viroporin, which may breeds of sheep, although this will depend on the virulence of
facilitate virus replication. Neutrophils appear to play a the infecting strain.
central, but undefined, role in pathogenesis; cattle in which There also appear to be differences in susceptibility among
neutrophils are experimentally depleted develop viremia but the African antelopes. The blesbok and black wildebeest are
not clinical disease. Interferon-α, interleukin 1, and tissue known to be susceptible to infection without showing signs
necrosis factor circulate in high titer during the acute phase of illness. Wildlife may act as reservoirs of infection, although
of BEF. this is not necessary as the tick itself is a reservoir; infection
The clinical signs observed in an epizootic are usually diag- survives in adult ticks for >15 months. Domestic ruminants
nostic. The diagnosis can be confirmed by virus detection/ that have recovered from the disease seldom remain as carriers
isolation. Serologic diagnosis may be complicated by cross- of the circulating organism for >3 weeks after recovery, but it
reaction with antibody to Kimberley virus, an arbovirus that is not clear whether the agent remains in a masked form in
induces production of low levels of serum neutralizing anti- tissues. Immunity of variable duration follows recovery, often as
body to BEFV but does not protect against BEFV. premunity; sterile immunity may persist for a year or more
after disappearance of the organism. Immunity in natural
Further reading infections is expected to be reinforced by reinfections.
The early development of the parasite is not completely
Aziz-Boaron O, et al. Circulation of bovine ephemeral fever in the
understood, but probably takes place in reticulum cells and
Middle East—strong evidence for transmission by winds and animal
macrophages of lymph nodes and spleen in which initial bodies
transport. Vet Microbiol 2012;158:300-307.
are demonstrable at about the fourth day of infection. Organ-
Blasdell KR, et al. A reverse-transcription PCR method for detecting all
isms are then released into the blood and parasitize vascular
known ephemeroviruses in clinical samples. J Virol Methods
endothelial cells. The organism is demonstrable in capillary
2013;191:128-135.
endothelium of brain 1-3 days after it is demonstrable in
Joubert DA, et al. Bovine ephemeral fever rhabdovirus α1 protein has
lymph nodes. Ehrlichia ruminantium parasitizes endothelial
viroporin-like properties and binds importin β1 and importin 7. J
cells but is also present in the blood; the infection is readily
Virol 2014;88:1591-1603.
transmissible by inoculation of blood collected during the
Kirkland PD. Akabane and bovine ephemeral fever virus infections. Vet
febrile stage or shortly thereafter. The colonies (groups,
Clin North Am Food Anim Pract 2002;18:501-514.
clusters, morulae) of microorganisms in endothelial cells lie
80.e1
Further reading
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific and Technical.; 1986. p. 452-477.
St George TD. Bovine ephemeral fever: a review. Trop Anim Health
Prod 1988;20:194-202.
Uren MF, et al. Studies on the pathogenesis of bovine ephemeral fever
in experimental cattle: III. Virological and biochemical data. Vet
Microbiol 1992;30:297-307.
Wang FI, et al. Bovine ephemeral fever in Taiwan. J Vet Diagn Invest
2001;13:462-467.
Young PL, Spradbrow PB. Demonstration of vascular permeability
changes in cattle infected with bovine ephemeral fever virus.
J Comp Pathol 1990;102:55-62.
Diseases of the Vascular System Arteries 81
Further reading
Du Plessis JL. Electron microscopy of Cowdria-infected macrophages
suggests that in the absence of binary fission a mosaic of organisms
develops from an amorphous electron dense matrix. Onderstepoort
J Vet Res 1999;66:39-46.
Mwangi DM, et al. Cellular immune responses of cattle to Cowdria
ruminantium. Dev Biol Stand 1998;92:309-315.
Simbi BH, et al. Comparing the detection of exposure to Ehrlichia
ruminantium infection on a heartwater-endemic farm by the pCS20
polymerase chain reaction assay and an indirect MAP1-B enzyme
linked immunosorbent assay. Onderstepoort J Vet Res 2003;70:231-
235.
van Halderen A, et al. Abortion in a heifer associated with the intra-
uterine transmission of Cowdria ruminantium-like organisms fol-
lowing heartwater vaccination. J S Afr Vet Assoc 1996;67:158-160.
Van Heerden H, et al. Characterization of the pCS20 region of different
Ehrlichia ruminantium isolates. Vet Microbiol 2004;101:279-291.
Diseases of the Vascular System Arteries 83
The prominent histologic lesion of RMSF is necrotizing vas- America and southern temperate zones in Australia. As with
culitis of small veins, capillaries, and arterioles, with perivascular most, if not all filarid worms, D. immitis contains the bacterial
accumulations predominantly of lymphocytes and macro- endosymbiont, Wolbachia, which is essential for the normal
phages. This lesion is seen most commonly in skin, testes, development of the parasite, and also contributes to the
alimentary tract, pancreas, kidneys, urinary bladder, myocar- pathogenesis of the disease.
dium, meninges, retina, and skeletal muscle. Acute meningo- There are 40 recognized species of Dirofilaria, 6 of which
encephalitis may be present. There may also be acute splenitis, have been shown to infect humans as accidental dead-end
acute interstitial pneumonia, and multifocal necrosis of myo- hosts. Diagnostic tests based on genomics are being increas-
cardium, adrenals, and liver. A moderate degree of glomerulo- ingly used to differentiate among the Dirofilaria species infect-
nephritis may be present. ing the host. Adults of D. repens occur in subcutaneous
The most reliable serologic test for RMSF is the species- connective tissues of dogs and other carnivores (and rarely
specific microimmunofluorescent method. High antibody humans). Similarly, D. tenuis is found in the subcutaneous
titers develop to R. rickettsii, but usually decline after 3-5 connective tissue of the raccoon in the southern United States.
months. Direct fluorescent antibody staining of a skin biopsy None of these 3 filarids usually develops to maturity in
is positive in up to 80% of infected dogs; coccobacillary organ- humans, but they may be found in cysts in various parts of
isms are present in endothelial cells and vessel walls. Infection the body, especially in the lungs. D. striata, a parasite of
may also be confirmed by PCR detection of the agent in bobcats (Lynx rufus), has been reported in dogs in Florida. A
peripheral blood. species of Dirofilaria found in both dogs and humans in Hong
Kong with a 94-95% homology with D. immitis and D. repens
has been tentatively named D. hongkongensis.
Further reading Adult D. immitis worms live in the pulmonary arteries and
Elchos BN, Goddard J. Implications of presumptive fatal Rocky Moun- right heart, but they can develop in various other arteries and
tain spotted fever in two dogs and their owner. J Am Vet Med Assoc veins, and have been reported from a variety of unusual sites,
2003;223:1450-1452, 1433. including the eye and brain. Adult males are 12-20 cm long
Gasser AM, et al. Canine Rocky Mountain spotted fever: a retrospec- by 0.7-0.9 mm in diameter; females are 25-31 cm by
tive study of 30 cases. J Am Anim Hosp Assoc 2001;37:41-48. 1.0-1.3 mm. The adult female worms are viviparous, and
Labruna MB, et al. Rocky Mountain spotted fever in dogs, Brazil. Emerg release microfilariae into the bloodstream; mosquitoes obtain
Infect Dis 2009;15:458-460. microfilariae in blood meals. The first, second, and early third
Piranda EM, et al. Experimental infection of dogs with a Brazilian strain larval stages of D. immitis are obligate parasites of mosquitoes,
of Rickettsia rickettsii: clinical and laboratory findings. Mem Inst predominantly of the genera Aedes, Culex, or Anopheles.
Oswaldo Cruz 2008;103:696-701. Larvae develop to the infective stage in about 13 days in the
malpighian tubules. They then migrate to the cephalic spaces
of the head or to the proboscis of the mosquito and escape
Verminous arteritis into a new host when the mosquito feeds. The infective larvae
Here we are concerned with those parasites whose natural are about 1.2 mm long when they enter the host, and are
habitat is the lumen or the wall of arteries. Parasites that, about 5 cm long when they reach the right ventricle 3-4
accidentally or as part of their life cycle, migrate in tissues months later. In the meantime, the parasites have wandered
may, depending on the route they take, cause vasculitis in and grown in the connective tissue, chiefly those of the sub-
various organs. The chief offenders in this regard are the larvae cutis and muscles, finally leaving these to migrate to the heart
of the genera Strongylus and Ascaris; the vascular lesions of via the veins. They mature in a further 3 months. Thus the
Ascaris infestations are described under diseases of the intes- prepatent period is 6-8 months. Adults may live for several
tine (see Vol. 2, Alimentary system and peritoneum). Angio- years and microfilariae can survive in a dog for as long as 2.5
strongylus vasorum, which inhabits the pulmonary arteries of years. Adult heartworms may be found in cutaneous nodules
dogs, is described with the lungworms. Spirocerca lupi, which occasionally in dogs, and rarely in cats.
passes part of its history in the adventitia of the thoracic aorta, The clinical diagnosis of dirofilariasis in dogs depends upon
is described in its final habitat, the esophagus. the detection of microfilariae in the blood, preferably by the
Dirofilariasis (heartworm disease). The dog is the only microscopic examination of centrifuged sediment of lysed
mammal commonly infected by Dirofilaria immitis (heart- blood (modified Knott’s test), or by a filter technique. Microfi-
worm), and is the only significant reservoir of infection. In areas lariae of D. immitis (290-315 µm long, straight body and tail,
where heartworm infection is enzootic in dogs, a number of tapered head) must be differentiated from those of Dipetalo-
other mammals may become infected, including domestic cats nema reconditum (270-290 µm, curved body, blunt head,
and wild felids, wild canids (coyotes, foxes, wolves), ferrets, most have a buttonhook tail), the adults of which are non-
sea lions, muskrats, horses, and rarely humans. If D. immitis pathogenic and are commonly found in the subcutaneous
develops to maturity in hosts other than the dog, microfilare- connective tissue of dogs; these microfilariae can also be dif-
mia is usually low or absent, and heart failure is rare. Pulmo- ferentiated by PCR or histochemical means. The average
nary dirofilariasis is of considerable importance in humans number of circulating microfilariae per adult female D. immitis
because the spherical, subpleural granulomas produced may decreases as the number of adult worms increases. Hence the
be mistaken radiographically for primary or metastatic lung numbers of circulating microfilariae indicate neither the numbers
tumors, leading to thoracotomy and excisional biopsy for diag- of adult worms present nor the severity of heartworm disease in
nosis. Dirofilaria immitis is genetically heterogeneous and has a an individual dog. Although microfilariae are present in the
tropical and subtropical distribution in southern Europe, Asia, blood more or less continuously, there is a tendency to peri-
Australia, and North and South America, although its range odicity, with maximum numbers occurring in the evening
has extended into more northern temperate zones in North and in the summer, coincident with maximal activity of
83.e1
Further reading
Davidson MG, et al. Vascular permeability and coagulation during Rick-
ettsia rickettsii infection in dogs. Am J Vet Res 1990;51:165-170.
Grindem CB, et al. Platelet-associated immunoglobulin (antiplatelet
antibody) in canine Rocky Mountain spotted fever and ehrlichiosis.
J Am Anim Hosp Assoc 1999;35:56-61.
Paddock CD, et al. Short report: concurrent Rocky Mountain spotted
fever in a dog and its owner. Am J Trop Med Hyg 2002;66:197-199.
Procop GW, et al. Immunoperoxidase and immunofluorescent staining
of Rickettsia rickettsii in skin biopsies. A comparative study. Arch
Pathol Lab Med 1997;121:894-899.
84 CHAPTER 1 • Cardiovascular System Arteries
mosquitoes. Microfilariae are pooled in internal organs, espe- worms with cardiac blood flow and valve function. Pulmonary
cially the lungs, in the daytime. Fetal pups may be infected by sclerosis and hypertension slowly regress following removal of
microfilariae from the bitch and have microfilaremia, but the the adult worms.
pups do not harbor adult worms. Cats infected with D. immitis Heartworm disease is primarily a pulmonary vascular disease,
are typically amicrofilaremic, given low numbers of adult and is characterized by myointimal proliferations in small
female worms or male-only infections, hence antigen- or peripheral arteries initially, and later in the large lobar arteries,
antibody-detection tests are required for diagnosis. especially the right caudal lobar artery (Fig. 1-87A, B). The
Occult dirofilariasis, that is, heartworm infection without fibromuscular intimal proliferations in the larger vessels produce
microfilaremia, occurs in 10-67% of infected dogs, primarily as a grossly visible shaggy or roughened appearance, a change
a result of destruction of microfilariae by immune mecha- pathognomonic of heartworm disease. The vascular reaction is
nisms (“immune-mediated occult disease”), but also as the to both the immature and mature adult worms, and begins as
result of prepatent infections, single-sex infections, and drug- an endoarteritis with infiltration of leukocytes, primarily
induced sterility of adult heartworms. Clinical diagnosis of eosinophils. Neutrophils are also present in the arterial wall,
occult dirofilariasis then rests on the findings of the indirect partly in response to the intracellular bacteria Wolbachia har-
fluorescent antibody test, antigen detection tests, and cardio- bored by D. immitis. The leukocytic response subsides and is
pulmonary imaging. Circulating antibodies are usually detect- replaced by myointimal proliferation that produces irregular
able only in dogs without microfilaremia. rugose to villus projections enmeshing the worms; the myo-
The clinical signs of canine dirofilariasis are usually those intimal proliferation occurs at sites of direct contact with
of cardiovascular dysfunction, such as cough and tiring on worms, is likely due to mechanical irritation and endothelial
exercise, which may progress to congestive heart failure. damage, and is possibly mediated by platelet-derived growth
Heartworm disease is usually seen in dogs that are older than factor.
5 years and have had continuous or multiple infections. There Thrombosis may be associated with either live or dead
is a rough correlation between the numbers of worms present worms, and thromboembolism, especially following adulti-
and the severity of the disturbance, but there are exceptional cide therapy, may further exacerbate pulmonary hyperten-
cases, and severe signs may appear in dogs with only a few sion; the presence of dead parasites initiates a granulomatous
worms. Clinically normal dogs may harbor up to about 30
worms, and clinically affected dogs 50 or more. Dirofilariasis
in cats usually causes cough and dyspnea, but may as well
cause vomiting, neurologic signs, and malaise; sudden death is
another possible outcome.
Adult heartworms are normally found in the pulmonary arter-
ies and right ventricle (Fig. 1-86), but may be found in the right
atrium and venae cavae in heavy infestations. Young adult
worms usually develop first in small pulmonary arteries, and
progressively involve more proximal arteries as they grow.
Adult worms may be found in the right ventricle if more than
about 25 are present, and in the right atrium and venae cavae
if there are 50 or more worms. The caudal lobar pulmonary
arteries are usually the most heavily infested vessels. Right
heart failure develops as a consequence of pulmonary hyperten-
sion, which in turn is the result of pulmonary vascular sclerosis.
Of secondary importance is mechanical interference of the A
B
Figure 1-87 Heartworm infection in a dog. A. Pulmonary artery
with severe extensive vasculitis and heartworms in lumen. H&E.
B. Higher power of (A) showing subintimal myofibrosis and
Figure 1-86 Dirofilaria immitis (heartworm) in pulmonary villous projections into the pulmonary arterial lumen. H&E.
artery and right ventricle of a dog. (Courtesy R. Kovi.)
Diseases of the Vascular System Arteries 85
reaction in the vessel wall, which may extend into the cava and hepatic veins are similar to the reactions usually seen
pulmonary parenchyma. Thrombi may be organized and in the pulmonary arteries. Vena caval syndrome also occurs in
recanalized. Pulmonary infarction is an uncommon sequel to cats, and untreated has a poor prognosis and high mortality
thromboembolism. rate in both dogs and cats; the treatment of choice is surgical
Pulmonary parenchymal changes that accompany the above removal of the heartworms.
vascular changes include periarterial granulomatous inflam- The major features of dirofilariasis are shown in eFig. 1-28.
mation, hemosiderosis, diffuse interalveolar fibrosis, prolifera-
tion of alveolar epithelium, and fibrous pleural thickenings.
Dead worms commonly incite pulmonary granuloma forma- Further reading
tion. Adulticide therapy causes embolization of worms and Atkins CE, et al. Heartworm infection in cats: 50 cases (1985-1997).
resulting thrombosis and granulomatous inflammation; resolu- J Am Vet Med Assoc 2000;217:355-358.
tion of these lesions is underway by 6 weeks post-treatment. Bourguinat C, et al. Genetic polymorphism in Dirofilaria immitis. Vet
Proliferative intimal lesions will progressively resolve after Parasitol 2011;176:368-373.
surgical removal of adult worms; resolution of advanced, González-Miguel J, et al. Surface associated antigens of Dirofilaria
fibrotic, obstructive arterial lesions is unlikely. Severe pulmo- immitis adult worms activate the host fibrinolytic system. Vet Para-
nary arterial disease often results in chronic or low-grade DIC, sitol 2013;235-240.
and hence thrombocytopenia and hemoglobinuria. Microfi- McCall JW, et al. Heartworm disease in animals and humans. Adv
lariae entrapped in the lung in a state of antibody excess are Parasitol 2008;66:193-285.
surrounded by neutrophils and eosinophils, producing eosino- McHaffie J. Dirofilaria immitis and Wolbachia pipientis: a thorough
philic pneumonitis. This allergic pneumonitis may be the investigation of the symbiosis responsible for canine heartworm
precursor of pulmonary eosinophilic granulomatosis, which is disease. Parasitol Res 2012;110:499-502.
characterized by 1-8 cm diameter nodules composed of eosin- Paes-de-Almeida EC, et al. Kidney ultrastructural lesions in dogs exper-
ophils, lymphocytes, plasma cells, and macrophages, and imentally infected with Dirofilaria immitis (Leidy, 1856). Vet Parasi-
devoid of microfilariae, plus peripheral blood eosinophilia. tol 2003;113:157-168.
Additional lesions of heartworm disease include those of Reddy MV. Human dirofilariasis: an emerging zoonosis. Trop Parasitol
right heart failure, such as chronic passive congestion of the 2013;3:2-3.
liver, and occasionally ascites. Membranoproliferative glomeru- Simón F, et al. Immunopathology of Dirofilaria immitis infection. Vet
lonephritis occurs primarily because of glomerular deposition Res Commun 2007;31:161-171.
of immune complexes, either formed in circulating blood in Simón F, et al. Human and animal dirofilariasis: the emergence of a
a state of antigen excess, or formed in situ in the glomeruli. zoonotic mosaic. Clin Microbiol Rev 2012;25:507-544.
The intensity of the immune-complex deposition varies To KKW, et al. A novel dirofilaria species causing human and canine
directly with the intensity and duration of infection and the infections in Hong Kong. Clin Microbiol 2012;50:3534-3541.
antibody response; the immune response may be toward
immature heartworms, microfilariae, or adult heartworms.
Physical damage to glomerular endothelium has been attrib- Strongylus vulgaris in horses. Horses are commonly
uted to microfilariae. The result of glomerular disease in diro- infected with both large and small strongyles (see Vol. 2, Ali-
filariasis is proteinuria, which is usually mild to moderate in mentary system and peritoneum), but by far the most damaging
severity. Renal failure and uremia are uncommon. Microfi- to the host is the large strongyle Strongylus vulgaris. Although
lariae are usually of little consequence to the dog, but when the adults of S. vulgaris share their large intestinal habitat with
they die, they may incite formation of microgranulomas in many other strongylids, S. vulgaris is the only strongylid to
various organs, such as the lung, liver, and kidney. undergo development in the horse’s arterial system.
Aberrant migration of adult heartworms into the systemic The usual route of migration of S. vulgaris is as follows.
arterial circulation, a rare event, results in thromboembolism Infective third-stage larvae are ingested; exsheath in the small
and hence signs such as hindlimb lameness and interdigital intestine; penetrate the mucosa and submucosa of the small
ischemic necrosis. intestine, cecum, and colon within 3 days of infection; and
The vena caval syndrome (venae cavae syndrome, liver molt to fourth-stage larvae by day 7. The larval penetration of
failure syndrome) is a variant of heartworm disease seen the gut can cause the formation of large subserosal hemor-
usually in young dogs in which large numbers of adult worms rhages, called hemomelasma ilei. The fourth-stage larvae, which
(100+) fill the right atrium and venae cavae, likely as the result are about 1 mm long, penetrate submucosal arterioles, migrate
of retrograde migration from the pulmonary arteries. The in or on the intima of arterioles and arteries, being constrained
syndrome is characterized by sudden onset of weakness, anor by the internal elastic lamina from penetrating to the media,
exia, bilirubinuria, hemoglobinuria, and anemia. Shock occurs and reach the cranial mesenteric artery, the predilection site
because of obstruction and decreased venous return. The mass for further development, between day 11 and 21. After 3-4
of worms may also interfere with valve function, causing tri- months, the larvae molt to the fifth stage (immature adults,
cuspid regurgitation, which, together with pulmonary hyper- 10-18 mm long), return to the wall of the cecum and colon
tension, results in decreased left ventricular preload and via the intestinal arteries, and are encapsulated in subserosal
congestive right ventricular failure. Hepatic congestion is very nodules before returning to the gut lumen as adults, when the
severe, hepatic lymphatics may be distended, and ascites may nodules rupture. The adults require another 6-8 weeks to
occur. Anemia develops because of right-atrial turbulence and reach sexual maturity. The prepatent period of S. vulgaris is
shear-induced mechanical hemolysis, with perhaps microan- thus about 6-7 months.
giopathic hemolysis resulting from platelet activation and Virtually all horses are infected with S. vulgaris and have
fibrin formation. Azotemia develops and death usually occurs arterial lesions resulting from larval migration, although the
in 1-3 days. Phlebosclerosis and thrombosis in the caudal vena prevalence of continuing S. vulgaris infection has been
85.e1
Dirofilariasis
Dog is primary host
Many species accidental hosts
Dirofilaria immitis is genetically heterogeneous
Further reading
Atkins CE, et al. Investigation of caval syndrome in dogs experimentally
infected with Dirofilaria immitis. J Vet Intern Med 1988;2:36-40.
Bazzocchi C, et al. Immunological role of the endosymbionts of Diro-
filaria immitis: the Wolbachia surface protein activates canine neu-
trophils with production of IL-8. Vet Parasitol 2003;117:73-83.
Boreham PFL, Atwell RB, editors. Dirofilariasis. Boca Raton, Fla: CRC
Press; 1988.
Buoro IBJ, et al. Angles of branching and the diameters of pulmonary
arteries in relation to the distribution of pulmonary lesions in canine
dirofilariasis. Res Vet Sci 1983;35:353-356.
Calvert CA, et al. Pulmonary and disseminated eosinophilic granulo-
matosis in dogs. J Am Anim Hosp Assoc 1988;24:311-320.
Cornegliani L, et al. Two cases of cutaneous nodular dirofilariasis in the
cat. J Small Anim Pract 2003;44:316-318.
Frank JR, et al. Systemic arterial dirofilariasis in five dogs. J Vet Intern
Med 1997;11:189-194.
Goggin JM, et al. Ultrasonographic identification of Dirofilaria immitis
in the aorta and liver of a dog. J Am Vet Med Assoc 1997;210:1635-
1637.
Kaiser L, Williams JF. Dirofilaria immitis: worm burden and pulmonary
artery proliferation in dogs from Michigan (United States). Vet
Parasitol 2004;124:125-129.
Kitagawa H, et al. Comparison of laboratory test results before and
after surgical removal of heartworms in dogs with vena caval syn-
drome. J Am Vet Med Assoc 1998;213:1134-1136.
Mar PH, et al. Specific polymerase chain reaction for differential diag-
nosis of Dirofilaria immitis and Dipetalonema reconditum using
primers derived from internal transcribed spacer region 2 (ITS2). Vet
Parasitol 2002;106:243-252.
McCracken MD, Patton S. Pulmonary arterial changes in feline dirofi-
lariasis. Vet Pathol 1993;30:64-69.
Mupanomunda M, et al. Dirofilaria immitis: heartworm infection
alters pulmonary artery endothelial cell behavior. J Appl Physiol
1997;82:389-398.
Peribanez MA, et al. Histochemical differentiation of Dirofilaria immitis,
Dirofilaria repens and Acanthocheilonema dracunculoides microfi-
lariae by staining with a commercial kit, Leucognost-SP. Vet Parasi-
tol 2001;102:173-175.
Rawlings CA, et al. Pulmonary thromboembolism and hypertension
after thiacetarsamide vs melarsomine dihydrochloride treatment of
Dirofilaria immitis infection in dogs. Am J Vet Res 1993;54:920-
925.
Ro JY, et al. Pulmonary dirofilariasis: the great imitator of primary or
metastatic lung tumor. A clinicopathologic analysis of seven cases
and a review of the literature. Hum Pathol 1989;20:69-76.
Strickland KN. Canine and feline caval syndrome. Clin Tech Small Anim
Pract 1998;13:88-95.
86 CHAPTER 1 • Cardiovascular System Arteries
markedly diminished by benzimidazole and macrocyclic embedded. It is usual to find some worms, both fourth-stage
lactone anthelmintics. A degree of host resistance to vermin- larvae and immature adults, in the thrombi, but the number
ous arteritis is slowly acquired under natural conditions, but of worms in any location in any one case varies from a few to
horses of all ages remain susceptible to infection. Lesions several hundred. Following migration of the fifth-stage larvae
range from the very common, but insignificant, tortuous back to the intestine, or destruction of the larvae by anthel-
intimal tracks, to the less common, but more serious, occlusive mintics, the intimal lesions resolve as fibrous intimal thicken-
thrombotic lesions. Lesions of verminous arteritis are often ings, and the luminal diameter will hence increase. The arterial
incorrectly called “verminous aneurysms,” but these dilations wall thickness also decreases.
are usually thick-walled resulting from inflammation and scar- The lesions and accompanying worms are most common in
ring, rather than thinned. Saccular or fusiform aneurysms may the cranial mesenteric artery, although they are also found
occasionally result from weakening of the arterial wall. Lesions elsewhere, including the aorta, the renal arteries, the celiac
occur most frequently in the cranial mesenteric artery and its artery and its branches, and the spermatic vessels. They may
extension, the ileo-cecocolic artery. This apparent larval predilec- be in any branch of the cranial mesenteric artery but are
tion has been suggested to fit a “random-walk” model in which concentrated largely in the right division and the colic artery,
the larvae sense blood vessel curvature, rather than direction which is its continuation, and, to a slightly lesser extent, in
of blood flow, migrate longitudinally along arteries, and are the cranial branch and its continuation, the right colic artery.
essentially trapped in the cranial mesenteric artery because of The worms are rarely found in the aorta caudal to the origin
its perpendicular connection with the aorta, a border which of the renal vessels; they are relatively common about the
most of the larvae do not cross. Larvae that spill over into the origin of the cranial mesenteric and celiac arteries, and less
aorta may be considered as aberrant and lost to their species, common again in the thoracic aorta. Although this statement
in that they are unlikely to return to the cranial mesenteric on the prevalence of lesions in the thoracic aorta applies to
artery and hence to the gut. actively thrombotic lesions containing worms, it is probable
Tortuous intimal tracks consist of fibrin, necrotic debris, that older, warty, mineralized lesions of the type often seen in
and a mixture of inflammatory cells, including eosinophils, in the intima of the aortic arch have this origin; they occur
the intima. The tracks become covered by endothelium, the
fibrin is removed, and the tracks are converted to fibromus-
culoelastic thickenings. More extensive larval migration causes
more extensive thromboarteritis (Figs. 1-88, 1-89). Small
mural thrombi are formed about the larvae attached to the
intima, and there is a reactive leukocytic infiltration, edema,
and resultant degeneration of the elastic and muscle fibers of
the underlying media. The initial acute inflammation persists
as long as the parasite remains but is soon accompanied by a
productive connective-tissue response, initiated by smooth
muscle cells from the media, with attempted organization of
the overlying thrombus and the accumulation of large numbers
of mononuclear leukocytes (Fig. 1-90). The proliferating con-
nective tissues of the intima and adventitia may ultimately
replace the normal structure of the arterial wall with the Figure 1-89 Focally dilated cranial mesenteric artery with hem-
affected walls becoming solid and very thick. The luminal orrhage, ulceration and inflammation of the vessel wall. (Courtesy
surfaces of active arterial lesions are always rough and covered A. G. Armien.)
with layered thrombi in which the parasite is found partially
Figure 1-88 Hemorrhage, ulceration and inflammation of the Figure 1-90 Chronic fibrosing arteritis of the cranial mesenteric
cranial mesenteric artery, with Strongylus vulgaris larva (arrow). artery caused by Strongylus vulgaris infection in a horse, with
(Courtesy University of Minnesota Veterinary Diagnostic larvae present in one of the smaller vessels. Masson trichrome.
Laboratory.) (Courtesy R. Kovi.)
Diseases of the Vascular System Arteries 87
frequently in sites where active lesions occur. The lesions in Onchocerciasis (parasitic aortitis). Onchocerca armillata
the aortic bulb are located immediately proximal to the aortic is a parasite of the wall of the aorta of cattle, water buffaloes,
valves on the cranial wall of the bulb and in the adjacent goats, and camels, in south Asia and equatorial Africa. As with
cranial aortic and caudal right aortic sinuses, but rarely in the other filarids, O. armillata also contains the endosymbiotic
caudal wall and the left sinus. This localization has been bacterium, Wolbachia, whose presence is not only essential for
explained on the basis of the curve of the aortic arch and the the normal development of the parasite larvae and embryo,
axis of systolic ejection, which should, theoretically, provide but also contributes to the pathogenesis of the disease. Several
a zone of turbulence and relatively low velocity of blood flow other Onchocerca spp. are described with tendons and aponeu-
in the cranial segment of the aortic bulb. roses under diseases of muscle in Vol. 1, Muscle and tendon.
The sequelae of verminous arteritis caused by S. vulgaris are The life cycle and vectors involved in the transmission of O.
varied and depend upon the location of the arteritis. Involve- armillata are unknown; however, black flies (Simulium) and
ment of the cranial mesenteric artery is almost constant in midges (Culicoides) are the intermediate hosts of other Oncho-
horses, but untoward sequelae are much less common, no cerca spp.
doubt resulting from the extensive collateral arterial circulation Although virtually all older cattle may be infested in enzo-
to the equine intestine, which may mitigate against the effects otic areas, the lesions produced are apparently not of clinical
of frequent thromboembolic episodes. Colic, which is com- significance. The preferential site is the arch of the aorta. With
monly caused in horses by S. vulgaris if parasite control is poor, chronicity, lesions extend cranially to include the brachioce-
may occur for a number of reasons: thromboembolism and phalic trunk, costocervical arteries, and brachial arteries, and
intestinal ischemia or infarction; interference with innervation caudally to include the abdominal aorta to the level of the
of the gut, resulting from pressure on abdominal autonomic iliac bifurcation. The intima is corrugated, and numerous
plexuses; or, release of toxic products from degenerating larvae. sinuous tunnelings end in small nodules in the intima and media;
Fatal acute intestinal infarction occasionally ensues, with isch- the nodules protrude into the vascular lumen or through the
emia of large areas of the cecum or colon. Thromboembolism adventitia. The males, which are about 7 cm long, inhabit the
of the cecal and colic arteries may also lead to mucosal ulcer- nodules, along with the anterior end of the female, which bears
ation and diarrhea, and occasionally death. Hematochezia has the vaginal opening, and the microfilariae, which escape into
been reported in a horse as a consequence of fistulous con- the bloodstream. The body of the female lies in the sinuous
nections between a verminous cranial mesenteric arterial aneu- tracts, from which the complete specimen cannot be readily
rysm and the cecum and ileum. As a result of successful dissected, but its length is estimated as >100 cm. Parasitic
suppression of S. vulgaris by anthelmintics, drug-resistant cya- tunnels in the inner media have a thin fibrous tissue lining
thostomes (small strongyles) have supplanted S. vulgaris as the without cellular infiltration. There may be acute transmural
most important cause of verminous colic. Coronary arterial aortitis with a predominance of eosinophils, but subacute or
thrombosis and occlusion, which occurs most commonly in the chronic focal granulomatous inflammation is more frequent and
right coronary artery, can lead to myocardial infarction and occurs around tunnels containing dead, degenerate, or mineralized
death; similar consequences follow the development of ver- worms. The granulomas in the media and adventitia become
minous aortic valvular endocarditis, a rare event in strongylosis. encapsulated by fibrous tissue to form nodules of 0.5-2.5 cm
Embolism of the brachiocephalic trunk can occur and is especially diameter containing caseous material and intact and/or dead
significant when the emboli contain larvae that subsequently worms, and eventually dry mineralized debris. The granulo-
migrate in the brain causing encephalomalacia and either matous reaction will resolve with time, and, in very old cattle,
chronic incoordination or progressive fatal encephalitis. Renal the aortic wall becomes thinner, has a corrugated lining with
arterial verminous arteritis and thromboembolism have resulted irregular mineralized ridges, and may develop aneurysms up
in renal infarction and, on rare occasions, passage of larvae in to 3.5 cm in diameter. The suggested causes of the granulo-
the urine. Aortic-iliac thrombosis may be a consequence of matous aortitis include hypersensitivity to the parasite, foreign
strongyle-related thromboembolism, but its pathogenesis body reaction to degenerate and dead onchocercal worms, and
remains uncertain. Thrombosis of the celiac artery and embo- the release of toxic factors from the parasites.
lism of its branches is usually inconsequential. Microfilariae can be found in the blood of infected animals
The major features of Strongylus vulgaris infection are at all times, but there is a tendency to nocturnal periodicity;
shown in eFigure 1-29. infection can be detected by examination of skin snips for
microfilariae. In some bulls with large numbers of circulating
Further reading microfilariae, repetitive episodes of collapse and tetanic con-
vulsion have been observed and attributed to the microfilariae.
Chapman MR, et al. Prevalence of strongyle nematodes in naturally
Some of the bulls showing convulsions eventually developed
infected ponies of different ages and during different seasons of
acute or recurrent ophthalmitis with ophthalmoscopic evi-
the year in Louisiana. J Parasitol 2003;89:309-314.
dence of retinal pigmentary degeneration and other changes
DeLay J, et al. Verminous arteritis in a 3-month-old thoroughbred foal.
similar to those seen in ocular onchocerciasis in humans.
Can Vet J 2001;42:289-291.
Hubert JD, et al. Clinical signs and hematologic, cytokine, and plasma
nitric oxide alterations in response to Strongylus vulgaris infection Further reading
in helminth-naive ponies. Can J Vet Res 2004;68:193-200.
Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
Ogbourne CP, Duncan JL. Strongylus vulgaris in the Horse: Its Biology
tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
and Veterinary Importance. 2nd ed. Farnham Royal, UK: Common-
Parasitol 1990;36:165-170.
wealth Agricultural Bureaux; 1985.
Neary JM, et al. Onchocerca armillata contains the endosymbiotic bac-
Reinemeyer CR, Nielsen MK. Parasitism and colic. Vet Clin North Am
terium Wolbachia and elicits alimited inflammatory response. Vet
Eq Pract 2009;25:233-245.
Parasitol 2010;174:267-276.
87.e1
Strongylus vulgaris
Vasculitis
Further reading
Aref S. A random walk model for the migration of Strongylus vulgaris
in the intestinal arteries of the horse. Cornell Vet 1982;72:64-75.
Drudge JH, Lyons ET. Large strongyles: recent advances. Vet Clin North
Am Equine Pract 1986;2:263-280.
Herd RP. The changing world of worms: the rise of the cyathostomes
and the decline of Strongylus vulgaris. Compend Contin Educ Pract
Vet 1990;12:732-736.
Kiper ML, et al. Hematochezia attributable to cranial mesenteric arterial
aneurysm with connecting tracts to cecum and ileum in a horse.
J Am Vet Med Assoc 1988;193:1278-1280.
Klei TR, et al. Effects of repeated Strongylus vulgaris inoculations and
concurrent ivermectin treatments on mesenteric arterial lesions in
pony foals. Am J Vet Res 1990;51:654-660.
Morgan SJ, et al. Histology and morphometry of Strongylus vulgaris-
mediated equine mesenteric arteritis. J Comp Pathol 1991;104:89-
99.
Morgan SJ, Van Houten DS. The ultrastructure of Strongylus vulgaris-
mediated equine chronic mesenteric arteritis. Vet Res Commun
1990;14:41-46.
Pauli B, et al. Arterial repair after mechanical injury by migrating fourth-
stage larvae of Strongylus vulgaris in the horse. (A light and electron
microscopic study.). Beitr Pathol 1975;155:357-378.
Slocombe JOD, et al. Strongylus vulgaris in the tunica media of arteries
of ponies and treatment with ivermectin. Can J Vet Res 1987;51:232-
235.
Thamsborg SM, et al. Impact of mixed strongyle infections in foals after
one month on pasture. Equine Vet J 1998;30:240-245.
87.e3
Further reading
Atta El, et al. Onchocerca armillata: prevalence and pathology in Suda-
nese cattle. Ann Trop Med Parasitol 1984;78:619-625.
Awad MA, et al. Note on Onchocerca armillata in the Sudanese camel
(C. dromedarius). A histological and anatomo-pathological
approach. Rev Elev Med Vet Pays Trop 1990;43:345-348.
Cheema AH, Ivoghli B. Bovine onchocerciasis caused by Onchocerca
armillata and O. gutturosa. Vet Pathol 1978;15:495-505.
Wahl G, et al. Bovine onchocercosis in north Cameroon. Vet Parasitol
1994;52:297-311.
88 CHAPTER 1 • Cardiovascular System Veins
Ogundipe GA, et al. The prevalence, gross lesions and histopathology survivors, the most important consequence of elaeophorosis
of aortic onchocerciasis in Nigerian cattle. Vet Q 1984;6:85-89. in sheep is filarial dermatosis (sorehead), an often severe exu-
Tamarozzi F, et al. Onchocerciasis: the role of Wolbachia bacterial endo- dative dermatitis affecting the poll, face, abdomen, and lower
symbionts in parasite biology, disease pathogenesis and treatment. parts of the legs, in up to 1% of sheep in enzootic areas. Sto-
Clin Microbiol Rev 2011;24:459-468. matitis and rhinitis also occur. The lesions are due to microfi-
lariae released by adult females located in arteries supplying
the affected areas. Microfilariae can be demonstrated micro-
Elaeophoriasis. The genus Elaeophora is another filarial scopically in the lesions, and they are responsible for intense
parasite. Three species of interest are E. poeli and E. schneideri, leukocytic infiltration, chiefly of eosinophils and mononuclear
which infect ruminants, and E. bohmi, a parasite of horses. cells. There is hemorrhage, vesiculation, and ulceration of the
Elaeophora poeli occurs frequently in the aorta of cattle epidermis with exudation of serum and leukocytes to form
and related species in tropical areas of the Far East, but is of crusts. These lesions have the character of an allergic reaction
little clinical significance. Its life cycle is unknown. These are and are presumably related to the alien nature of the
thread-like worms, the female of which may be up to 30 cm sheep as a host, because they rarely occur in deer. The skin
long. The lesions are found in the aorta and can be distin- lesions are intensely pruritic and often lead to severe self-
guished from those of Onchocerca armillata because the trauma. Lesions often persist for 3-4 years and will regress
females of E. poeli are attached to the vessel by the head, with spontaneously following the death of adult parasites
the body free in the lumen of the vessel (eFig. 1-30). The and microfilariae.
males become encysted in intimal fibrous nodules that also Elaeophora bohmi was found in ~6% of a sample of Aus-
contain the head of the female. In light infestations, the lesions trian horses, the vessels involved being arteries and veins of
are found chiefly on the dorsal wall of the aorta about the the metacarpus, metatarsus, and more distal extremities. The
openings of the intercostal arteries. Heavy infestations are parasites rather selectively involve the media of the vessels
more diffuse and may provoke a prominent fibrous thickening avoiding the intima and adventitia, although the fibrous reac-
of the vessel wall. tion that develops may cause stenosis of the lumen. The
Elaeophora schneideri is commonly found in the arteries worms are coiled and entwined amongst the tissue layers,
of mule deer and black-tailed deer, as well as in white-tailed provoking parasitic granulomas with intense infiltration by
deer, domestic sheep and goats, elk (wapiti), moose, and eosinophils and macrophages. In cases of longer standing,
bighorn sheep in mountainous areas of the western and south- diffuse or nodular fibrous thickenings are visible and palpable
western United States and southwestern Canada, and in in the vessel walls. Microfilariae were found in the blood of
white-tailed deer in the southeastern United States. Mule deer 14 of 161 horses (9%) sampled in Iran. The infection appears
and black-tailed deer are little affected by the parasite, and to be of little clinical significance.
are considered the normal definitive hosts. Horseflies of the
genera Hybomitra and Tabanus are the intermediate hosts.
When the horsefly feeds, infective larvae invade the host and Further reading
migrate to the leptomeningeal arteries, where they develop to Couvillion CE, et al. Elaeophoriasis in white-tailed deer: pathology of
immature adults that migrate against the blood flow to reside the natural disease and its relation to oral food impactions. J Wildl
in the common carotid arteries. The parasites reach sexual Dis 1986;22:214-223. (E. schneideri).
maturity ~6 months later and begin producing microfilariae. LeVan IK, et al. High elaeophorosis prevalence among harvested Colo-
Although adult worms normally inhabit the carotid arteries rado moose. J Wildl Dis 2013;49:666-669. (E. schneideri).
and their branches, they may be found in many other arteries Mirzayans A, Maghsoodloo H. Filarial infection of equidae in the Tehran
through the body. Adult females are 6-12 cm long by area of Iran. Trop Anim Health Prod 1977;9:19-20. (E. bohmi).
0.6-0.9 mm thick, and adult males are 5.5-8.5 cm long by Mtei BJ, Sanga HJ. Aortic onchocercosis and elaeophorosis in tradi-
0.4-0.7 mm thick; adults live 3-4 years. Microfilariae are about tional TSZ-cattle in Tabora (Tanzania): prevalence and pathology. Vet
280 µm long by 18 µm thick, and are found in the capillaries Parasitol 1990;36:165-170. (E. poeli).
of the forehead and face.
When larvae develop in the leptomeningeal arteries of elk,
moose, domestic sheep and goats, sika deer, and possibly
VEINS
white-tailed deer, they can cause ischemic necrosis of brain
tissue, resulting in “clear-eyed” blindness or sudden death. In Venous disorders may be of clinical significance by predisposing
elk, adult worms in the intracranial arteries cause mechanical to thrombosis and subsequent embolism, or by obstructing venous
irritation and hence endothelial damage, intimal proliferation return and hence causing passive congestion of the affected areas.
and fibrosis, thrombosis, and embolism, which result in focal Obstruction of venous outflow may be followed by the devel-
ischemia and infarction in the brain, eyes, optic nerves, ears, opment of collateral venous drainage.
muzzle, nostrils, and other tissues of the head. Adult worms Anomalies of veins occur uncommonly. Arteriovenous fistulas
usually cause only mild intimal sclerosis in deer and sheep, have been discussed previously with arterial anomalies. A
and only rarely do they cause granulomatous verminous variety of congenital portosystemic anastomoses occur in dogs
thrombosis. Microfilariae can cause multifocal myocardial and cats and allow portal blood, with its absorbed toxic sub-
infarction, myocarditis, and fibrosis in deer. Oral food impac- stances, such as ammonia, to bypass the liver and cause hepatic
tions have been associated with E. schneideri in white-tailed encephalopathy. The most common of these defects is persis-
deer, but a causal relationship has not been established. tent ductus venosus a persistence of the normal fetal circulation
Young domestic sheep and goats may develop nervous wherein the umbilical veins enter the ductus venosus, which
signs and die suddenly 3-5 weeks after infection as a result course through the liver to join the caudal vena cava. Other
of thrombosis of cerebral and leptomeningeal arteries. In portosystemic anastomoses occur extrahepatically between
88.e1
Further reading
Boyce W, et al. Elaeophorosis in bighorn sheep in New Mexico. J Wildl
Dis 1999;35:786-789. (E. schneideri).
Hibler CP, Adcock JL. Elaeophorosis. In: Davis JW, Anderson RC, editors.
Parasitic Diseases of Wild Mammals. Ames, Iowa: Iowa State Uni-
versity Press; 1971. p. 263-278.
Kemper HE. Filarial dermatosis of sheep. J Am Vet Med Assoc
1957;130:220-224. (E. schneideri).
Little PB. A Malaysian experience with animal disease. Can Vet J
1979;20:13-21. (E. poeli).
Pessier AP, et al. Probable elaeophorosis in a moose (Alces alces) from
eastern Washington state. J Vet Diagn Invest 1998;10:82-84. (E.
schneideri).
Santin-Duran M, et al. Elaeophorosis in red deer from Spain. J Wildl
Dis 2000;36:779-782. (E. elaphi).
Diseases of the Vascular System Veins 89
the portal vein and various branches of the caudal vena cava
or the azygous vein. As well, portosystemic anastomoses may
be acquired because of portal hypertension, which in turn is
caused by impedance of blood flow through a diseased liver,
an obstructed portal vein, or a kinked intrathoracic caudal
vena cava. Hepatic microvascular dysplasia can occur in dogs
and cats in the absence of macroscopic portosystemic
shunts, and result in similar clinical signs. Portosystemic anas-
tomoses and hepatic encephalopathy are discussed in more
detail in Vol. 3, Liver and biliary system.
Dilation of a vein, variously termed phlebectasia, varicosity,
or aneurysm, occurs but is of little or no importance. A
common type of dilation is the so-called “varicocele” of the
pampiniform plexus. Dilation may also occur because of con-
genital defects, such as venous diaphragms, agenesis, hypopla-
sia, or ectopia, or secondary to trauma, neoplasia, or surgical A
intervention. The initial dilation causes insufficiency of the
venous valves, and the veins may become dilated, elongated,
and tortuous. Thrombosis or sclerosis may be sequelae. The
acquired portosystemic anastomoses noted above usually
result from dilation of pre-existing microscopic venous anas-
tomoses to produce collateral venous drainage.
Hepatic telangiectasis, peliosis hepatis, and hepatic “veno-
occlusive disease” are described with diseases of the liver in
Vol. 3, Liver and biliary system.
Rupture of a large vein, usually the result of physical
trauma, may result in fatal hemorrhage. Spontaneous idio-
pathic rupture of the venae cavae or portal vein of horses
occurs occasionally; rupture of the great coronary vein of the
heart is a rare cause of unexpected death in horses.
Veins may be invaded by neoplasms (Fig. 1-91A, B), which
may then metastasize, and may cause thrombosis or B
obstruction.
Figure 1-91 A. Invasion from adrenal gland tumor (pheochromo-
cytoma) into the caudal vena cava of a dog. B. Vena cava opened
to show invasion of a pheochromocytoma in a dog.
Further reading
Christiansen JS, et al. Hepatic microvascular dysplasia in dogs: a retro-
spective study of 24 cases (1987-1995). J Am Anim Hosp Assoc
cattle recumbent for >4-6 hours results in thrombosis of the
2000;36:385-389.
femoral tributaries (“downer cows”). Venous infarction com-
Koide K, et al. Congenital hepatic arteriovenous fistula with intrahe-
monly ensues, and necrosis of the medial muscle masses and
patic portosystemic shunt and aortic stenosis in a dog. J Vet Med
sciatic nerves causes permanent paraplegia.
Sci 2004;66:299-302.
The thickened, congested, red-black mucosa of the gastric
Leeman JJ, et al. Multiple congenital portosystemic shunts in a dog:
fundus in swine with acute septicemia is a venous infarct result-
case report and literature review. J Am Aim Hosp Assoc 2013;49:281-
ing from thrombosis of veins of the mucosa and submucosa,
285.
probably as a sequel to endothelial damage. Gastrointestinal
Zwingenberger AL, et al. Imaging diagnosis—portal vein aplasia and
infarction and ulceration can occur in phenylbutazone-
interruption of the caudal vena cava in three dogs. Vet Radiol
intoxicated horses as a result of degeneration of veins and
Ultrasound 2011;52:444-447.
phlebothrombosis. Thrombosis of the jugular veins follows
unsuccessful or repeated venipuncture, injection of irritant
solutions, and the use of indwelling catheters, especially if
Phlebothrombosis and thrombophlebitis contaminated with bacteria. Important sequelae to jugular
Venous thrombosis (phlebothrombosis) results from the usual thrombosis are pulmonary embolism, and, if the emboli are
pathogenetic factors and often leads to inflammation of the septic, valvular endocarditis and pulmonary abscessation.
vein wall, and hence becomes thrombophlebitis. Conversely, Endophlebitis may result from the implantation of bacteria
phlebitis inevitably leads to thrombosis. Spontaneous thrombo- carried in the blood stream, as in salmonellosis, and from
sis affects the venae cavae and portal veins occasionally, and the injection of irritant solutions. An important form of
the inciting factors are usually unknown. Neoplastic invasion, acute suppurative endophlebitis is the omphalophlebitis of the
for instance, by pheochromocytoma, is one cause of thrombo- newborn resulting from infection of the uncicatrized umbilical
sis of the caudal vena cava. Thrombosis of the renal vein and cord. The resultant bacteremia may result in acute death
vena cava occasionally occurs in dogs with the nephrotic syn- or give rise to widespread suppurative lesions, often polyar-
drome as a result of urinary loss of antithrombin and resulting thritis. Hepatic thrombophlebitis is especially common in
hypercoagulability of the blood. Stasis of venous blood of “navel-ill.”
89.e1
Further reading
Allen JR, et al. Spontaneous rupture of the great coronary vein in a
pony. Equine Vet J 1987;19:145-147.
Cornelius L, Mahaffey M. Kinking of the intrathoracic caudal vena cava
in five dogs. J Small Anim Pract 1985;26:67-80.
Fernandez del Palacio MJ, et al. Persistent left cranial vena cava associ-
ated with multiple congenital anomalies in a six-week-old puppy.
J Small Anim Pract 1997;38:526-530.
Reimer JM, et al. Diagnosis and surgical correction of patent ductus
venosus in a calf. J Am Vet Med Assoc 1988;193:1539-1541.
Valentine RW, Carpenter JL. Spleno-mesenteric-renal venous shunt in
two dogs. Vet Pathol 1990;27:58-60.
White RN, Burton CA. Anatomy of the patent ductus venosus in the
cat. J Feline Med Surg 2001;3:229-233.
90 CHAPTER 1 • Cardiovascular System Veins
A B
C D
Figure 1-92 The vasculitis of feline infectious peritonitis. A. Renal vasculitis. (Courtesy E. Olson.)
B. Vasculitis within the choroid of the eye. H&E. C. Vasculitis within a small caliber renal vein.
H&E. D. Serial section of (C) immunostained with anti–feline infectious peritonitis virus
antibody.
Further reading
Bressler C, et al. Portal vein and aortic thromboses in a Siberian
husky with ehrlichiosis and hypothyroidism. J Small Anim Pract
2003;44:408-410.
Clements CA, et al. Splenic vein thrombosis resulting in acute anemia:
an unusual manifestation of nephrotic syndrome in a Chinese shar
pei with reactive amyloidosis. J Am Anim Hosp Assoc 1995;31:411-
415.
Grosslinger K, et al. Iliopsoas abscess with iliac and femoral vein throm-
bosis in an adult Siberian husky. J Small Anim Pract 2004;45:113-
116.
Howard J, et al. Blastomycosis granuloma involving the cranial vena
cava associated with chylothorax and cranial vena caval syndrome
in a dog. J Am Anim Hosp Assoc 2000;36:159-161.
Lankveld DP, et al. Factors influencing the occurrence of thrombophle-
bitis after post-surgical long-term intravenous catheterization of
colic horses: a study of 38 cases. J Vet Med A Physiol Pathol Clin
Med 2001;48:545-552.
Meschter CL, et al. Vascular pathology in phenylbutazone intoxicated
horses. Cornell Vet 1984;74:282-297.
Sottiaux J, Franck M. Cranial vena caval thrombosis secondary to inva-
sive mediastinal lymphosarcoma in a cat. J Small Anim Pract
1998;39:352-355.
Van Winkle TJ, Bruce E. Thrombosis of the portal vein in eleven dogs.
Vet Pathol 1993;30:28-35.
Weiss RC, Scott FW. Pathogenesis of feline infectious peritonitis: patho-
logic changes and immunofluorescence. Am J Vet Res 1981;42:
2036-2048.
92 CHAPTER 1 • Cardiovascular System Veins
99 Schistosoma ovuncatum
Schistosoma sinensium
Central and
100 Schistosoma japonicum S. japonicum clade
S. E. Asia
100 Schistosoma malayensis
Schistosoma mekongi
98 Schistosoma edwardiense
Africa S. hippopotami clade
Schistosoma hippopotami
Orientobilharzia turkestanicum Central Asia,
100 Near East Proto - S. mansoni clade
Schistosoma incognitum and E. Europe
100
Schistosoma mansoni
Africa S. mansoni clade
100 Schistosoma rodhaini
Schistosoma nasale
Schistosoma leperi
100
Schistosoma mattheei
100 Schistosoma kisumuensis
97
80 Schistosoma intercalatum Africa S. haematobium clade
84 Schistosoma haematobium
Schistosoma guineensis
100
100 Schistosoma curassoni
99 Schistosoma bovis
Figure 1-94 Schistosoma clades. Summary schematic phylogeny of the interrelationships of members of the species within the Schisto-
soma genus estimated with a Bayesian analysis of combined partial lsrDNA, complete ssrDNA, and partial cox1. cox1, cyclooxygenase 1;
lsr, large subunit ribosomal; ssr, small subunit ribosomal. (From Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit Vectors 2011;4:131-141.)
those that are distributed to other organs die. Schistosoma surrounding fibrosis. The above course of events occurs simi-
nasale develops in the veins of the nasal mucosa; all other larly in urinary schistosomiasis caused by S. mattheei, wherein
species develop in veins of the abdominal cavity, principally hematuria accompanies excretion of eggs in the urine, and
in the portal vessels, until sexual maturity is attained, when granulomatous cystitis and ureteritis result from the host’s
they migrate out to the smaller veins of the mesentery. In immunologic response to the schistosome eggs trapped in the
long-standing infections, S. mattheei may reside in veins of the tissues.
urinary bladder as well as in portomesenteric veins. The pre- Clinical signs of schistosomiasis of portomesenteric distri-
patent period in the mammalian host ranges from 30-77 days. bution include lethargy, anemia, and weight loss. Diarrhea or
As would be expected, not all the eggs move in the proper dysentery occur at the time of patency, persist for a few weeks,
direction. Some break into lymphatics and are conveyed to and, in the absence of reinfection, may be followed by spon-
the regional nodes to produce granulomas but, more impor- taneous recovery as the immune response of the host elimi-
tantly, a great many of them pass to the liver, producing portal nates the parasites and suppresses the egg laying of survivors.
phlebitis and granulomatous hepatitis, in concert with the The eggs can be found in the feces together with some mucus
adult flukes. In heavy infestations and possibly by means of and blood. Blood loss leads to anemia and hypoalbuminemia,
venous shunts developed in the liver, many eggs may pass in which may contribute to the presence of fluid in serous
venous blood to and beyond the lungs, producing granuloma- cavities.
tous endoarteritis and adjacent granulomas wherever they Gross and microscopic findings include thickening of the
lodge. The development of hepatic lesions follows the same wall of the intestine, chiefly the large bowel, by inflammatory
course as for those that develop in the intestinal wall. In the and scar tissue, and the wall may contain small granulomas
liver, the eggs break out of the portal venules to become and lymphoid nodules. Scarring begins in the mucosa and
enclosed by granulomas. Sooner or later, they die and are extends to involve all layers, including the serosa. The mucosa
mineralized, and by that time have provoked extensive may bear polypoid and papillary proliferations. The mesentery
Diseases of the Vascular System Veins 93
is thickened and shortened by fibrous tissue, and the mesen- may be found within thrombi. Adults may similarly cause reac-
teric nodes are enlarged and fibrotic. The adult parasites, tions in veins of the pancreas and the mesenteric and portal
which are about 1-3 cm long, can be found in the mesenteric lymph nodes, and in pulmonary arterioles. Dead parasites are
and portal vessels (eFig. 1-32). There is fibrosis of the liver of removed by a granulomatous reaction that is often followed
variable degree affecting particularly the portal vessels. The by the formation of a grossly visible lymphoid nodule. The
liver may be enlarged or small depending on the course and lumen of the vein may be occluded, and the venous wall
severity of the infestation. On cut surface, the periportal obliterated, by this lymphoid response. There may also be
nature of the fibrosis is quite apparent but, with time and diffuse intimal proliferation and endophlebitis of intrahepatic
more severe infestations, the fibrosis becomes more diffuse portal veins, medial hypertrophy, and adventitial inflammation
and the surface of the liver may have a hobnailed appearance and fibrosis leading to prominent portal fibrosis, which may
or be studded by numerous minute granulomas. appear grossly as “clay pipe-stem” portal fibrosis. Irregular
Proliferative granulomatous nasal lesions produced by S. dilated vascular bypasses develop in the portal areas. The
nasale result in clinical signs of dyspnea and mouth adults ingest erythrocytes and regurgitate hematin pigments,
breathing. which are picked up by the monocyte-macrophage system,
Granulomatous lesions are frequently present in the especially in the regional lymph nodes and liver; these black
urinary bladder and ureters of cattle with S. mattheei infection; iron-porphyrin pigments may be responsible for the gray color
lesions in the ureters, and occasionally renal pelvis, are linear, of the liver and lungs in severe cases of schistosomiasis.
whereas those in the bladder become very extensive and Heterobilharzia americana infection. Heterobilharzia
polypoid. americana, in the family Schistosomatidae, causes schistoso-
The stage of oviposition and extrusion of eggs through the miasis in dogs as an accidental infection. The raccoon is the
tissues and mucous membranes is the stage in which most damage definitive host. Dogs, among many other species, are acciden-
is done. In fact, a host inflammatory response is necessary for tal hosts, including the bobcat, armadillo, Brazilian tapir,
the eggs to move across the mucosa of organs such as the beaver, coyote, mountain lion, mink, nutria, opossum, red
intestine and bladder. The mated schistosomes, in permanent wolf, swamp rabbit, and white-tailed deer. The trematode is
copula, move out into the smallest venous radicles, and the found in the southeastern United States, especially the Gulf
eggs are deposited first in the lumen of the vessel. They adhere coast and southern Atlantic states, and the infection in the
to, and are eventually covered by, the endothelium. The eggs vertebrate host is limited by the geographic distribution of the
of some species are spinous, and this probably facilitates intermediate host. Granulomas incited by H. americana have
passive migration into the tissue. The migration does appear, been reported to occur in the liver, and uncommonly, in other
however, to be partly active by virtue of secretions elaborated tissues of horses.
by the developing miracidium, which diffuse through the shell The life cycle of the trematode is well defined, with the
of the egg into the tissues. These secretions may be also in intermediate host a lymnaeid freshwater snail Bakerilymnaea
part responsible for inciting the inflammatory reaction to the cubensis or Pseudosuccinea columnella. It follows the classic
eggs. Initially, most of the eggs are deposited in the lamina schistosome pathway of cercariae—the cercariae penetrating
propria of the intestine, and break into the lumen with little the skin of the vertebrate host, migrating via the blood to the
more than mechanical injury. Rupture of congested mucosal lungs and liver before finally coming to reside in the mesen-
venules accounts for the characteristic dysentery of schistoso- teric and intrahepatic portal veins, where they mature into
miasis. Also contributing to diarrhea, loss of body condition, adults. Eggs, assisted by the secretion of proteolytic enzymes,
and failure to thrive are ganglionitis and degeneration of the move from the capillary lumen into the intestinal tract and
enteric nervous system, which may result from a localized are expelled in feces. On contact with water, miracidia are
type I hypersensitivity reaction involving mast cell–derived released from the eggs and actively seek the snail intermediate
chemical mediators. host, which completes the life cycle. Clinical signs of the
As the disease progresses and the adults are excluded from infection in dogs include mucoid to bloody diarrhea, lethargy,
smaller venules resulting from endophlebitis, eggs are laid in weight loss, vomiting, anorexia, and ascites. A distinctive
veins in deeper tissues, where antigens released by the mira- finding is the presence of hypercalcemia in >50% of cases,
cidium induce a delayed hypersensitivity response and forma- which is thought to be the result of the synthesis and release
tion of small granulomas (“pseudotubercles”). The granulomas of calcitriol from macrophages as part of the granulomatous
are characterized initially by the infiltration of leukocytes, reaction to egg migration. With or without hypercalcemia,
chiefly eosinophils, and later by the accumulation of mono- there may be areas of dystrophic tissue mineralization, espe-
nuclear leukocytes, epithelioid and giant cells, and reactive cially of schistosome eggs, in the intestine and liver. At post-
fibrosis. Microabscesses occasionally form and rupture into the mortem, the abdominal cavity may contain excess fluid, the
gut lumen. Eggs in submucosal granulomas degenerate and are intestinal wall thickened, and the liver, small, pale, and nodular,
removed, or may be mineralized and remain for a longer containing numerous 1-2 mm pale gray to white areas extend-
period of time. Some of the mature or disintegrating eggs may ing throughout the parenchyma. The lungs and kidneys may
be coated with a bright eosinophilic deposit (the Splendore- contain similar lesions. Histologically, lesions in the liver,
Hoeppli reaction), the result of antigen-antibody complex for- intestinal submucosa, pancreas and lungs are multifocal lym-
mation. The granulomas gradually regress and are replaced by phoplasmacytic, eosinophilic to granulomatous reactions in
fibrous tissue. Host cell responses to eggs are primarily the response to deposited eggs that are sometimes arranged in
result of host hypersensitivity to soluble egg antigens, and, to linear arrays (Fig. 1-95A, B). The eggs are often heavily min-
a much lesser degree, resulting from physical and chemical eralized. The liver, in particular, may exhibit additional lesions
stimuli. of periportal to bridging fibrosis, lobular collapse, nodular
Adult schistosomes in mesenteric and portal veins elicit eosino- regeneration, bile duct hyperplasia, and cholestasis. Confirma-
philic endophlebitis, often with irregular intimal proliferation, and tion of the suspected diagnosis of H. americana, even from
93.e1
Lawton SP, et al. Genomes and geography: genomic insights into the
evolution and phylogeography of the genus Schistosoma. Parasit
Vectors 2011;4:131-141.
Lu DB, et al. Contrasting reservoirs for Schistosoma japonicum between
marshland and hilly regions in Anhui, China—a two-year longitu-
dinal parasitological survey. Parasitol 2010;137:99-110.
Mourão MM, et al. Recent advances in Schistosoma genomics. Parasite
Immunol 2012;34:151-162.
LYMPHATICS
The richness of the lymphatic plexuses in almost all tissues
and their important role as drainage channels for interstitial
fluid makes for almost inevitable involvement of lymphatics
A
by any inflammation and by the many neoplasms that metas-
tasize via lymph channels. In most instances, the lymphatic
lesions are so small as to have no significance, but in some
cases, the consequence of lymphatic involvement may be the
major presenting clinical sign or lesion. Such, for example, is
the case when attention is drawn to papillary carcinoma of
the canine ovary by severe ascites; disrupted portions of the
neoplasm permeate and obstruct the ventral diaphragmatic
lymphatics, which are the main efferent channels of the peri-
toneal cavity.
Lymphedema is defined as swelling of a part of the body by
an increased quantity of lymph resulting from a lymphatic system
disorder. The term should not be used to describe edematous
swellings resulting from venostasis, hypoproteinemia, heart
failure, or cellulitis. Lymphedema may be classified as primary
B or secondary:
• Primary lymphedema, which is usually congenital, and may
Figure 1-95 Heterobilharzia americana infection in a dog. be hereditary, is due to anomalous development of the
A. Liver showing chronic inflammatory reaction, including lymphatic system.
multinucleated giant cells, to H. americana eggs. H&E. B. Close • Secondary lymphedema occurs because of obstruction of
proximity of multinucleated giant cells to parasite eggs. H&E. previously normal lymphatics, resulting from inflamma-
(From an Armed Forces Institute of Pathology Wednesday Slide tion, neoplasia, surgery, or trauma.
Conference, 2011.) Lymphedema is of significance because it may predispose
the affected area, usually a limb, to secondary bacterial infec-
tion and poor wound healing. Prolonged lymphedema leads to
formalin-fixed tissue, can be achieved through the use of PCR fibrosis.
to demonstrate the presence of H. americana–specific small A lymphocele is a lymph-filled space that does not have a
subunit ribosomal RNA. distinct endothelial lining, and may be the result of disruption
of lymphatics by trauma or surgery.
Further reading
Balemba OB, et al. Lesions of the enteric nervous system and the pos-
sible role of mast cells in the pathogenic mechanisms of migration
of schistosome eggs in the small intestine of cattle during Schisto-
soma bovis infection. Vet Parasitol 2000;90:57-71.
Bartsch RC, Van Wyk JA. Studies on schistosomiasis: 9. Pathology of
the bovine urinary tract. Onderstepoort J Vet Res 1977;44:73-94.
Buergelt CD, Greiner EC. Fibrosing granulomas in the equine liver and
peritoneum: a retrospective morphologic study. J Vet Diagn Invest
1995;7:102-107.
De Bont J, et al. The prevalence and pathology of Schistosoma nasale
Rao, 1933 in cattle in Sri Lanka. Parasitol 1989;98(Pt 2):197-202.
Ferreras MC, et al. Histopathological and immunohistochemical study
of lambs experimentally infected with Fasciola hepatica and Schis-
tosoma bovis. J Vet Med B Infect Dis Vet Public Health 2000;47:763-
773.
Ferreras-Estrada MC, et al. A pathological study of experimental long-
standing Schistosoma bovis infection in sheep. J Comp Pathol
1998;119:479-484.
Flowers JR, et al. Heterobilharzia americana infection in a dog. J Am
Vet Med Assoc 2002;220:193-196.
Fransen J, et al. Pathology of natural infections of Schistosoma spindale
Montgomery, 1906, in cattle. J Comp Pathol 1990;103:447-455.
Lawrence JA. The pathology of Schistosoma mattheei infection in the
ox: 1. Lesions attributable to the eggs. 2. Lesions attributable to
the adult parasites. J Comp Pathol 1978;88:1-14, 15-29.
Lindberg R, et al. Experimental Schistosoma bovis infection in goats:
the inflammatory response in the small intestine and liver in various
phases of infection and reinfection. J Parasitol 1997;83:454-459.
Losos GJ. Infectious Tropical Diseases of Domestic Animals. Harlow, UK:
Longman Scientific & Technical; 1986. p. 903-938.
Lu DB, et al. Evolution in a multi-host parasite: chronobiological circa-
dian rhythm and population genetics of Schistosoma japonicum
cercariae indicates contrasting definitive host reservoirs by habitat.
Int J Parasitol 2009;39:1581-1588.
Van Wyk JA, et al. Schistosoma mattheei infection in cattle: the course
of the intestinal syndrome, and an estimate of the lethal dose of
cercariae. Onderstepoort J Vet Res 1997;64:65-75.
Vercruysse J, et al. Pathology of Schistosoma curassoni infection in
sheep. Parasitol 1985;91(Pt 2):291-300.
Vercruysse J, Gabriel S. Immunity to schistosomiasis in animals: an
update. Parasite Immunol 2005;27:289-295.
Diseases of the Vascular System Lymphatics 95
Further reading
Fossum TW, Miller MW. Lymphedema. Etiopathogenesis. J Vet Intern
Med 1992;6:283-293.
Kang JH, et al. Secondary malignant lymphoedema after mastectomy
in two dogs. J Small Anim Pract 2007;48:579-583.
Schacht V, et al. T1α/podoplanin deficiency disrupts normal lymphatic
vasculature formation and causes lymphedema. EMBO J 2003;
22:3546-3556.
Yamaguchi R, et al. Congenital lymphedema in a calf with lymph node
dysplasia or aplasia. J Vet Med Sci 1995;57:797-799.
Further reading
Carmichael NG, et al. Secondary lymphoedema in a dog. J Small Anim
Pract 1986;27:335-341.
Reynhout KM, et al. Lymphocele in a cat. J Am Vet Med Assoc
1994;204:400-403.
Schild AL, et al. Hereditary lymphedema in Hereford cattle. J Vet Diagn
Invest 1991;3:47-51.
van der Putte SCJ. The pathogenesis of congenital hereditary lymph-
edema in the pig. Lymphol 1978;11:10-21.
96 CHAPTER 1 • Cardiovascular System Lymphatics
Further reading
Birchard SJ, et al. Chylothorax in the dog and cat: a review. Lymphol
1995;28:64-72.
Campbell-Beggs CL, et al. Chyloabdomen in a neonatal foal. Vet Rec
1995;137:96-98.
Kull PA, et al. Clinical, clinicopathologic, radiographic, and ultrasono-
graphic characteristics of intestinal lymphangiectasia in dogs: 17
cases (1996-1998). J Am Vet Med Assoc 2001;219:197-202.
Peaston AE, et al. Combined chylothorax, chylopericardium, and
cranial vena cava syndrome in a dog with thymoma. J Am Vet Med
Assoc 1990;197:1354-1356.
White SD, et al. Acquired cutaneous lymphangiectasis in a dog. J Am
Vet Med Assoc 1988;193:1093-1094.
96.e2
Further reading
Hamid ME, et al. Differentiation between Mycobacterium farcinogenes
and Mycobacterium senegalense strains based on 16S-23S ribo-
somal DNA internal transcribed spacer sequences. J Clin Microbiol
2002;40:707-711.
Meschter CL, et al. Intestinal lymphangiectasia with granulomatous
lymphangitis in a dog. J Am Vet Med Assoc 1987;190:427-430.
Tufvesson G. Lymphangitis in horses. Nord Vet Med 1952;4:529-576,
729-744, 817-860, 1047-1058. (Nonspecific Monday-morning
type.).
Diseases of the Vascular System Lymphatics 97
Further reading
Aleman M, et al. Corynebacterium pseudotuberculosis infection in
horses: 538 cases (1982-1993). J Am Vet Med Assoc 1996;209:804-
809.
Costa LR, et al. Comparative molecular characterization of Corynebac-
terium pseudotuberculosis of different origin. Vet Microbiol
1998;62:135-143.
Steinman A, et al. Ulcerative lymphangitis and coronet lesions in an
Israeli dairy herd infected with Corynebacterium pseudotuberculo-
sis. Vet Rec 1999;145:604-606.
98 CHAPTER 1 • Cardiovascular System Vascular Neoplasms
Further reading
Ameni G, Terefe W. A cross-sectional study of epizootic lymphangitis
in cart-mules in western Ethiopia. Prev Vet Med 2004;66:93-99.
98.e2
Further reading
Chansiri K, et al. PCR based method for identification of zoonotic
Brugia malayi microfilariae in domestic cats. Mol Cell Probes
2002;16:129-135.
Denham DA, Fletcher C. The cat infected with Brugia pahangi as a
model of human filariasis. Ciba Found Symp 1987;127:225-235.
Fader RC, Ewert A. Evolution of lymph thrombi in experimental Brugia
malayi infections: a scanning electron microscopic study. Lymphol
1986;19:146-152.
Sakamoto M, et al. Perturbation of lymphatic endothelial cells in exper-
imental Brugia malayi infections. Microcirc Endothelium Lymphatics
1985;2:487-498.
Snowden KF, Hammerberg B. The lymphatic pathology of chronic
Brugia pahangi infection in the dog. Trans R Soc Trop Med Hyg
1989;83:670-678.
Diseases of the Vascular System Vascular Neoplasms 99
• Vascular malformation is obviously a very broad term that of blood vessels and meningothelial cells in the leptomeninges
may be included under the term hamartoma, and may and underlying brain parenchyma.
include arteriovenous fistula in which thick-walled vessels Although most vascular proliferations are idiopathic, there
occur, in contrast to the thin-walled vessels of the other is evidence that various Bartonella spp. (Bartonella vinsonii
benign vascular proliferations. subsp. berkhoffii, B. henselae, B. koehlerae) may contribute to
• Telangiectasis refers to congenital or acquired foci of abnor- the pathogenesis of systemic reactive angioendotheliomatosis
mally dilated capillaries, sinusoids, arterioles, or venules, (and hemangiopericytomas) in animals.
usually seen as small masses in the skin and mucous Formerly thought to be due to neoplastic proliferation of
membranes. endothelial cells and hence termed malignant angioendothelio-
• Angiokeratoma is a rare benign tumor, usually of the nic- matosis, intravascular lymphoma is a rare large cell lymphoma,
titans and conjunctiva of dogs, in which dilated vascular seen in humans, dogs, and a cat, in which neoplastic lympho-
channels are associated with hyperplastic epithelium. cytes proliferate within the lumens of blood vessels. Lympho-
Fortunately, these distinctions, although of pathogenetic matoid granulomatosis (angioinvasive lymphoma) is a rare
interest, are of little practical importance because the lesions pulmonary disorder of middle-aged dogs, characterized by
described are uniformly benign, and excision, if possible, is infiltration of lung and various other organs by neoplastic
curative. mononuclear cells admixed with eosinophils, lymphocytes,
and plasma cells; originally thought to be angiocentric, this
Angioma pulmonary neoplasm is now thought to be an atypical T-cell
Hemangioma is a benign tumor of endothelial cells and may lymphoma that is angioinvasive.
be classified as capillary or cavernous based on the size of the Lymphangioma is a rare, benign tumor that consists of
vascular channels formed. The tumor may be difficult to dif- lymph channels forming capillary, cavernous, or cystic tumors.
ferentiate from vascular malformations and granulation tissue. Lymphangiomas may occur as congenital malformations
Hemangiomas occur most commonly in older dogs, and are (hamartomas) or may develop spontaneously in adults. Cav-
seen less frequently in other species. These tumors arise from ernous and cystic lymphangiomas may progressively enlarge,
vascular endothelium and hence may be found in any site in dissect along fascial planes, and be difficult or impossible to
the body, but are most common in the dermis and subcutis, espe- remove surgically.
cially of the legs, flank, neck, face, and eyelid. The cutaneous Glomangiomas (glomus tumors) of nonhuman primates,
and ocular lesions may arise following exposure to ultraviolet dogs, cats, and horses are rare benign (even more rarely malig-
radiation. Hemangiomas are usually single, ovoid, red-black nant) neoplasms of the neuromyoarterial thermal receptors,
masses of 0.5-3 cm in diameter, which ooze blood when cut. primarily in the digits, characterized by branching vascular
Histologically, blood-filled vascular spaces are lined by a single channels in a fibrous stroma that contains nests of specialized
layer of well-differentiated endothelium, and may be throm- glomus cells, a type of smooth muscle cell. Glomus jugulare
bosed. The vascular spaces are separated by variable amounts and glomus pulmonale tumors have been reported in dogs.
of connective tissue stroma. Hemangiomas are not encapsu- The glomus jugulare and pulmonale are chemoreceptors, and
lated, are not invasive, and do not recur after complete surgical tumors of these bodies resemble other chemodectomas,
excision. A rare form of cavernous hemangioma, analogous to namely, nests of monomorphic rounded cells with scant cyto-
the human hemangioblastoma, is reported in dogs, and is char- plasm separated by thin septa. The tumor is encapsulated and
acterized by thin-walled capillaries separated by pleomorphic grows expansively.
“stromal cells” of indeterminate origin. An epithelioid variant
of hemangioma and hemangiosarcoma has also been described. Angiosarcoma
Disseminated cavernous hemangioma is rare, but has been Hemangiosarcoma (malignant hemangioendothelioma), a
reported in calves, and a similar multifocal hemangioma has malignant tumor of endothelial cells, occurs most frequently
been reported in a pig. Multiple small tumors are present in old dogs, but is less common than hemangioma. German
in skin, subcutis, gingiva, and internal organs. The condition Shepherd dogs (Alsatians) are most commonly affected, and
has been termed generalized congenital hemangiomatosis and some other breeds are over-represented. Hemangiosarcoma
juvenile bovine angiomatosis, to include calves having either occurs infrequently in cats, horses, cows, and sheep.
solitary, for instance, gingival or spinal canal, or multiple angio- There is a current focus on a number of receptor tyrosine
matous lesions. Hemangiomas occur in the urinary bladder of protein kinases, such as platelet-derived growth factor
cattle affected with enzootic hematuria, which is discussed in receptor-β and Src, as well as CD117(c-Kit) and vascular endo-
Vol. 2, Urinary system. thelial growth factor-3, which are overexpressed in hemangio-
A number of hemangioma-like lesions occur in domestic sarcomas. This suggests involvement of growth factor signaling
animals. Bovine cutaneous angiomatosis of adult dairy cows pathways, if not in the genesis, then in the development of the
is reported from Britain, France, and the United States. tumor. The p16-cyclinD1-retinoblastoma pathway has also
Nodular dermal vascular proliferations occur anywhere in the been implicated. There is also increasing evidence that the
skin, but especially along the back, may have a considerable tumor cells arise from hematopoietic stem cell precursors. The
inflammatory component, and resemble “pyogenic granuloma” tumor may arise in any site of the body. The most common
of humans. Varicose tumor of the scrotum of dogs is a benign primary sites in dogs are spleen, skin/subcutis, right atrium, and
vascular proliferation that resembles cavernous hemangioma liver; in cats, spleen, intestines, and subcutaneous tissue; in
when fully developed. Lesions resembling hemangioma occa- horses, ocular, cutaneous, and multicentric. Hemangiosarcoma
sionally develop in the skin of the scrotum or perineum of is the most common primary cardiac tumor of dogs, and the tumor
boars, or the vulva, mammary glands, or ovaries of sows. usually occurs subepicardially in the wall of the right atrium at
Meningioangiomatosis, a rare condition reported in dog, the entrance to the auricle near the coronary groove (Fig. 1-99)
horse, and cow, is characterized by benign focal proliferation or in the auricular appendage. Hemangiosarcoma probably
100 CHAPTER 1 • Cardiovascular System Vascular Neoplasms
arises de novo and not from pre-existing hemangiomas. The rather than either hemangiomas or hemangiosarcomas. The
tumors have a gray to red-black hemorrhagic appearance, and distinction is important because splenic hemangiosarcomas
may reach a diameter of 30 cm in the spleen as a result of carry a very poor prognosis. However, the distinction can often
hemorrhage within the tumor. Large hemorrhagic masses can be difficult because splenic hemangiosarcomas often hemorrhage,
often be found in the spleens of dogs; some are hematomas and if the resultant hematoma is not sampled carefully, its neoplas-
tic origin will be missed. Following rupture, implants of splenic
tissue or tumor may be found on the peritoneum. Hemangio-
sarcomas typically metastasize widely, especially to the lungs
(“cannonball” metastases) (Fig. 1-100A-C). Histologically,
these tumors consist of vascular spaces lined by elongated,
plump, anaplastic endothelial cells (Fig. 1-101A). Vascular
spaces must be identified in tumors with a highly cellular
stroma to differentiate hemangiosarcoma from fibrosarcoma.
Hemorrhage and necrosis commonly occur within these
tumors, and death may occur because of hemorrhage into the
peritoneal cavity, pericardial sac, or brain. When metastases are
widespread, the primary tumor site may be difficult to deter-
mine, and multicentric origin is a possibility. Poorly differenti-
ated hemangiosarcomas may usually be differentiated from
spindle cell sarcomas or other non-endothelial neoplasms by
immunohistochemical staining for factor VIII–related antigen
(Fig. 1-101B), a marker of endothelial cells, and claudin-5
protein, a tight-junction protein normally found on endothelial
cells. Ulex europaeus lectin, a marker of neoplastic human
Figure 1-99 Hemangiosarcoma in the right auricle of a dog. endothelial cells, is unreliable as a marker of canine vascular
(Courtesy D. Hayden.) tumors. Ultrastructurally, Weibel-Palade bodies (granules
A B
C
Figure 1-100 Metastatic hemangiosarcoma in a dog. A. Lung. (Courtesy I. Matise.) B. Liver.
(Courtesy D. Hayden.) C. Brain. (Courtesy M. Bouljihad.)
Diseases of the Vascular System Vascular Neoplasms 101
102
Bone Marrow 103
Hematopoietic
stem cell
Multipotent
Lymphoid Myeloid
precursor
progenitor progenitor
T-cell B-cell
thymus lymphoid CFU-GM CFU-Meg-E
tissue
Mitotic
Committed activity
precursor
Terminally
committed
precursor
Pro- Neutrophil Eosinophil Basophil Mega- Basophilic
monocyte metamyelocyte karyocyte rubricyte
Distinct cell
morphology
Mature
blood cells
covering cortical and trabecular bone surfaces lines the marrow up by adipocytes increases, and in healthy geriatric animals,
cavity containing hematopoietic cells. Endosteal cells are mul- hematopoietic tissue may comprise only 10% of red marrow.
tipotent mesenchymal progenitor cells with ability to give rise Hematopoiesis within the microenvironment of the bone
to osteoblasts, osteocytes, and osteoclasts; all are cells that marrow takes place in the interstitium, and maturing cells
are commonly identified at endosteal surfaces. Together with acquire properties that allow them to transit across a special-
specialized endothelial cells, macrophages and nerve cells, ized blood–bone marrow barrier. This barrier consists of a
endosteal cells comprise a HSC niche or microenvironment. single layer of endothelium and a discontinuous basement
Trabecular bone homeostasis is interconnected with hemato- membrane with adventitial cells, which together regulate
poiesis, and altered hematopoiesis may be associated with cell transition and release into the blood stream. Erythropoi-
changes in density or diameter of the boney trabeculae. Bone esis occurs in discrete clusters, whereas granulopoiesis is
marrow has a vascular supply through nutrient arteries that more dispersed as individual cells throughout the interstitium.
enter through cortical bone, branch to run parallel to the long Megakaryocytes are typically located adjacent to sinusoids.
axis of bone, and give rise to arterioles directed toward the The term “myeloid” refers to all hematopoietic cells in bone
marrow periphery. Anastomosis with venous sinuses leads to marrow exclusive of lymphocytes, but is often also applied
venules that drain into a central longitudinal vein, which in to cells of only the neutrophil lineage or to spinal cord tissue.
turn feeds into nutrient veins. The sinusoidal network in bone Therefore specific terminology such as “granulocytic” and
marrow is extensive, but most sinusoids are very small and “erythrocytic” should be used to describe cells in the marrow.
inconspicuous, and may be entirely inapparent in biopsy sec- Rubriblasts are the first recognizable erythrocyte precursor.
tions. Bone marrow lacks lymphatic vessels. Other compo- Rubriblasts are medium-sized round cells with darkly staining
nents of the hematopoietic microenvironment are nerve cells, cytoplasm, a small Golgi zone, high nuclear-to-cytoplasmic
adventitial barrier cells, adipocytes, macrophages, and mesen- ratio, and one or several nucleoli. With maturation, rubriblasts
chymal cells. progress to rubricytes that progressively synthesize cytoplas-
Mature blood cells are derived from precursor cells through mic hemoglobin, which imparts initially a purple cytoplasmic
orderly and hierarchical maturation under the precise influ- hue and eventually bright orange-pink staining to metarubri-
ence of transcription factors and lineage-specific growth cytes, immature anucleated reticulocytes, and mature anucle-
factors. HSC and committed precursor cells lack distinct mor- ated erythrocytes (Fig. 2-3). Concurrent with homogeneous
phologic features, and are defined by functional assays such as cytoplasmic hemoglobin synthesis, rubricyte nuclei progres-
in vitro colony formation or expression of specific antigens. sively condense and decrease in size. Late-stage rubricytes have
Committed precursor cells are morphologically recognizable as small, round, and intensely dark-staining nuclei that are
rubriblasts, myeloblasts, or megakaryoblasts. Precursor cells expulsed prior to transition across the blood–bone marrow
without distinct morphologic features are infrequent in bone barrier. Rubriblasts and different stages of maturing rubricytes
marrow, and are rarely enumerated for diagnostic purposes. may comprise clusters surrounding macrophages (“nurse
However, during times of hematopoietic stress, HSC may be cells”) that provide trophic factors and iron for synthesis of
mobilized from bone marrow, travel via the circulation to hemoglobin. Rubricyte maturation follows a continuum with
tissues outside the bone marrow, and establish extramedullary mitotic capability throughout, and reliably identifying indi-
foci of hematopoiesis. Healthy animals, particularly dogs and vidual cell stages is challenging. Thus, for practical purposes,
cats, frequently have hematopoietic activity in the red pulp of synchronous erythropoiesis is characterized by low number of
the spleen, and virtually any other tissue, but most commonly rubriblasts and immature large rubricytes with round, cen-
liver and lymph nodes, may acquire hematopoietic activity in trally located nuclei and a moderate amount of blue cyto-
stress or disease states. plasm, and high number of late-stage small rubricytes with
Hematopoiesis is a highly dynamic process, given the short increasingly hemoglobinized cytoplasm. Immature (polychro-
life-span of blood cells. Neutrophils circulate for 8-10 hours matophilic) erythrocytes are difficult to distinguish from mature
after release from bone marrow, platelets for 10-14 days, and erythrocytes in hematoxylin and eosin (H&E)-stained sec-
erythrocytes for 70 (cats) to 150 days (cows). Hence it is tions, but are readily identified on cytology preparations.
common to observe mitotic activity in bone marrow samples Maturation from rubriblast to reticulocyte takes ~6 days
from healthy animals, which may be markedly increased under homeostatic conditions, but may be accelerated relative
during sustained inflammation, or in response to blood loss or to the degree of hypoxic stress. Rubricytes are not normally
premature destruction of blood cells. Chronic blood loss or released from bone marrow, and their presence in blood in the
inflammation in an otherwise healthy animal may increase the absence of regenerative anemia suggests altered blood–bone
proportion of marrow hematopoietic relative to adipose tissue marrow barrier function, abnormal splenic erythropoiesis, or
from ~50% to >90% within a few weeks. Further prolonged lead toxicity. Specific causes of altered blood–bone marrow
increased demand for blood cells results in progressive conver- barrier function include injury caused by hyperthermia or
sion of adipose tissue first in distal trabecular bone regions of chemotherapy, and disruption resulting from granulomatous
the metaphysis, and then in areas lacking trabecular bone inflammation, hematopoietic neoplasia, myelofibrosis, or met-
toward the diaphysis. Such expanded hematopoiesis depends astatic neoplasia.
on formation of new HSC niches through interaction with Myeloblasts are the precursors of neutrophils, eosinophils, and
endosteal cells, and is grossly apparent as a red line along the basophils. They are larger than rubriblasts, have pale-staining
endosteal surface of long bones. High proliferative capacity and abundant cytoplasm, and have one large nucleolus, or,
also renders hematopoietic tissue uniquely susceptible to more commonly, several small nucleoli. Myeloblasts are con-
injury from cytotoxic drugs, toxins, and infectious agents. The centrated adjacent to trabeculae (Fig. 2-4) and generate
ratio of hematopoietic to adipose tissue in red marrow is differentiating granulocytes of progressive maturity toward
80-90% to 10-20% in healthy animals <1 year of age (Fig. 2-2). the sinusoids in the center of the marrow cavity. Recogniz
With progressive age, the proportion of marrow space taken able sequential stages of granulocyte differentiation are
Bone Marrow 105
A B
C D
E F
Figure 2-2 Bone marrow biopsy sections from a healthy young dog. A. Bone marrow is comprised
of ~70% hematopoietic and 30% adipose tissue. B. Myeloblasts are concentrated adjacent to tra-
beculae, erythrocytes are inconspicuous, and hemosiderin is not yet apparent given the age of the
dog. C. Periodic acid–Schiff stain highlights megakaryocyte and granulocyte cytoplasm. D. CD31
immunohistochemistry identifies small collapsed sinusoids that are difficult to appreciate on H&E
stains. E. Silver impregnation for reticulin is negative in normal bone marrow. F. Masson trichrome
stains erythrocytes and granulocyte and megakaryocyte nuclei red. Extracellular collagen is absent.
106 CHAPTER 2 • Hematopoietic System Bone Marrow
# *
* *
*
A
Figure 2-3 Bone marrow aspirate with erythroid hyperplasia.
Rubriblast has dark basophilic cytoplasm (#). Promyelocytes have
slightly granular and light blue cytoplasm (*). Metarubricytes
(arrows) are frequent.
Further reading
Auler P, et al. Myeloid metaplasia in canine mixed mammary tumors:
occurrence and characterization. Vet Q 2011;31:173-177.
Mochizuki H, et al. Demonstration of the cell clonality in canine hema-
topoietic tumors by X-chromosome inactivation pattern analysis.
Vet Pathol 2015;52:61-69.
Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic
stem cells. Nature 2014;505:327-334.
Tefferi A. The forgotten myeloproliferative disorder: myeloid metapla-
sia. Oncologist 2003;8:225-231.
Wilkins BS. Pitfalls in bone marrow pathology: avoiding errors in
bone marrow trephine biopsy diagnosis. J Clin Pathol 2011;64:
380-386.
Wilkins BS, Clark DM. Making the most of bone marrow trephine
biopsy. Histopathol 2009;55:631-640.
110 CHAPTER 2 • Hematopoietic System Bone Marrow
epithelial cells. In cattle, an adjuvanted inactivated BVDV membrane interactions with heterochromatin, and contrib-
vaccine administered to breeding age cows in Europe and utes to nuclear segmentation, is mutated. Identical morpho-
New Zealand caused a widespread condition termed “bovine logic changes in granulocytes of animals suggest that mutation
neonatal pancytopenia” in offspring. Approximately 50% of is LBR is also the cause of PHA in animals, but the actual
affected calves died because of massive internal and external genetic defect remains to be mapped. In PHA, neutrophil and
hemorrhage. Affected animals also had an increased incidence eosinophil nuclei are hyposegmented but have condensed
of infectious diseases. Detailed analysis of hematologic find- clumped chromatin like normal mature granulocytes. PHA is
ings showed that affected calves had predominantly thrombo- usually an incidental finding on a complete blood count
cytopenia and neutropenia, and became anemic as a result of (CBC), given that the hyposegmented granulocytes are not
hemorrhage. Allo-immunization against polymorphic antigens functionally impaired. PHA has been reported in multiple dog
incorporated into the vaccine from in vitro producer cells was breeds, a few cats, and 2 Arabian horses, and is inherited as a
considered to be the cause of this neonatal immune-mediated dominant or co-dominant trait. Homozygous mutation of the
cytopenia. LBR gene in people results in more severely hyposegmented
Several genetic causes of congenital neutropenia have been nuclei, skeletal abnormalities, and frequent fatality, and a
identified. Trapped neutrophil syndrome occurs in Border similar phenotype occurs in homozygous cats. Absence of
Collies across the world, and is caused by an autosomal reces- toxic changes in neutrophils and clinical signs of infection
sive deletion in the gene coding for vesical protein sorting 13B distinguish PHA from a severe left shift. Acquired PHA, also
(VPS13B). The carrier rate of the mutation is 4-8%, and called pseudo-PHA, is also characterized by hyposegmented
affected dogs have neutropenia, slender extremity bones, poly- granulocyte nuclei, but in the absence of bacterial or fungal
arthritis, and microencephaly. The cause of the neutropenia is infection. Acquired PHA has been described in association
unclear, but is likely related to impaired generation and trans- with retroviral infection, chemotherapy, myeloid neoplasia,
port of neutrophil granules. Canine cyclic hematopoiesis occurs and myelodysplastic syndrome. Thorough clinical history,
in Collie-like dogs and is the result of an autosomal recessive repeat CBCs, and hematologic evaluation of related animals
insertion into the gene coding for an adapter protein subunit will distinguish the different entities.
important in trafficking of vesicles and proteins, such as neu- Overall, genetic causes of neutropenia and abnormal neu-
trophil elastase. Concentration of all blood cells, not just neu- trophil morphology or function are rare in animals, but serve
trophils, fluctuates in this condition, and affected animals also as useful models of corresponding human conditions.
have limited melanin pigmentation of hair follicles resulting Some agents infect neutrophils and cause profound neu-
in a “gray” phenotype. trophilia. Hepatozoon is a large genus of hemogregarine para-
Abnormally large granules in neutrophils and other cells sites for which vertebrates serve as the intermediate host and
occur in animals with Chediak-Higashi syndrome (CHS). invertebrates as the definitive host. Hepatozoon gamonts infect
CHS is caused by mutations in the lysosomal trafficking regu- leukocytes in mammals and birds, and erythrocytes in reptiles.
lator LYST gene that result in reduced or absent formation, Dogs infected with H. canis or H. americanum have marked
migration, and exocytosis of lysosomes. Mutations that pro- neutrophilia. Hepatozoon parasites have a life cycle distinct
foundly reduce the LYST protein correlate with a more severe from other vector-borne protozoa because they are acquired
clinical phenotype than those that generate a truncated by vertebrates through ingestion of an invertebrate host such
protein. Abnormal granule formation may be observed in as a tick containing oocysts, rather than being transmitted via
many cell types. In neutrophils, lack of transcellular movement saliva by a tick during a bite.
and extrusion of abnormally large lysosomes impairs Hepatozoon canis is prevalent in Africa, Asia, southern
phagosome-lysosome fusion and microbial killing. Affected Europe, and South and North America, and causes predomi-
animals generally have normal neutrophil counts but reduced nantly infection of hemolymphoid organs. H. americanum
innate immunity. Granules of cytotoxic and natural killer lym- occurs in dogs in the southern and central United States, and
phocytes also are not extruded properly; platelets have causes myositis and severe lameness. Several ticks, including
reduced dense granules, impairing aggregation and resulting in Rhipicephalus sanguineus in Europe and Amblyomma ovale in
a bleeding diathesis; and animals with CHS have partial or South America, transmit H. canis. Sporozoites ingested with
complete albinism from reduced transfer of melanin- the tick migrate through the intestinal wall of the dog, invade
containing granules. The condition occurs in cattle, cats, mink, mononuclear cells and disseminate via blood or lymph to
humans, mice, and other species. CHS has been described in hemolymphatic organs, liver, kidney, and lungs. Merogony
Hereford, Brangus, and Japanese black cattle that have partial with formation of micromerozoites and macromerozoites
oculocutaneous albinism and leukocyte and platelet defects. occurs in host tissues, and mature meronts released from
CHS is the cause of the blue smoke fur color variant in Persian tissues invade neutrophils and monocytes to develop into
cats and the light blue-grey fur color in Aleutian mink. Affected gamonts that can be observed on blood smears. The tick
mink have normal neutrophil and platelet number, giant neu- Amblyomma maculatum transmits H. americanum, but it
trophil granules, and reduced platelet aggregation. All mink appears that H. americanum can also be acquired by predation
are susceptible to infection by a parvovirus that results in of other infected mammalian hosts and through intrauterine
neuropathy, hyperglobulinemia, anemia, and progressive transmission.
weight loss. Mink with the Aleutian trait have particularly Infection of dogs with H. canis can result in subclinical
severe and fatal disease, and it has been speculated that the illness or severe life-threatening cachexia, lethargy, and
cause is defective innate immune function as a result of CHS. anemia. A mild subclinical infection is most common and
Pelger-Huët anomaly (PHA) is caused by a genetic muta- associated with <5% of leukocytes on blood films containing
tion that in heterozygotes manifests with band-shaped or H. canis gamonts and mild anemia. Severe illness with marked
bilobed instead of segmented granulocyte nuclei. In affected parasitemia and neutrophilia occurs in immunocompromised
humans, the lamin B receptor (LBR) that stabilizes nuclear or debilitated dogs, or with concurrent other infections. Other
Bone Marrow 111
abnormalities in H. canis infection are polyclonal hyperglobu- Other vector-borne rickettsial infections of domestic
linemia, and increased creatine kinase and alkaline phospha- animals, such as salmon poisoning disease caused by Neorick-
tase activity. Periostitis is uncommon. Diagnosis is usually ettsia helminthoeca and equine neorickettsiosis (Potomac horse
based on observing gamonts on blood films, or meronts in fever, also called equine monocytic ehrlichiosis), caused by
tissue biopsies. Neorickettsia risticii, are covered in later sections of this
Infection with H. americanum results in more severe chapter and other chapters.
disease and is fatal after several months unless treated. Target Lymphopenia is most often the result of redistribution of
organs of H. americanum are skeletal and cardiac muscle lymphocytes to lymphoid organs rather than an absolute
where infected macrophages form cysts composed of zoites decrease in body lymphocytes. Causes for such altered distri-
surrounded by layers of glycosaminoglycan. Merogony fol- bution include increased endogenous and exogenous gluco-
lowed by rupture of the cyst and release of merozoites causes corticoids, and acute bacterial or viral infection. Absolute
intense myositis. Massive neutrophilia of up to 200 × 109/L is lymphopenia may result from intestinal loss of lymphatic fluid
observed in H. americanum infection, although the number of in lymphangiectasia or severe enteropathy, immunosuppres-
infected neutrophils on blood smears is typically <0.1%. sion, chemotherapy, and radiation. Rare causes of absolute
Hence diagnosis may require biopsy of affected muscle for lymphopenia are congenital severe combined immunodefi-
demonstration of cysts. Affected dogs have fever, muscle pain ciency caused by impaired DNA repair in Arabian horses, or
and atrophy, mucopurulent ocular discharge, and bone pain. lack of cytokine signals in various dog breeds as a result of
Chronic infection with persistent hyperglobulinemia may mutation in the cytokine receptor subunit shared by IL-2,
result in renal amyloidosis, glomerulonephritis, and uveitis. IL-4, IL-7, IL-9, IL-15, and IL-21. Of note, blood lymphocyte
Untreated infection with H. americanum results in debilitation concentration is generally higher in healthy young than adult
and death. animals; hence lymphopenia in young animals should prompt
Hepatozoonosis has been reported in cats from several assessment of immune competency.
countries with H. canis infection, but neither the species of A common cause of lymphocytosis is endogenous catechol-
Hepatozoon nor the definitive host is identified. Infection was amine release. Hypoadrenocorticism in dogs, and infections
associated with meronts in myocardium and skeletal muscle, with bacterial and protozoal agents, such as Ehrlichia, Ana-
and low levels of parasitemia. plasma, Theileria, and Babesia, may manifest with lymphocy-
Another vector-borne agent of leukocytes is Anaplasma tosis. Retroviruses such as feline leukemia virus (FeLV), equine
phagocytophilum, which is the current name of the former infectious anemia virus (EIAV), FIV, and bovine leukemia
Ehrlichia equi, Ehrlichia phagocytophila, and human granulo- virus (BLV) establish permanent infections that may result in
cytic ehrlichiosis agent. Anaplasma phagocytophilum is a widely transient lymphocytosis. Lymphocyte concentration is gener-
distributed, obligate intracellular, gram-negative bacterium ally lower in BLV-seropositive than seronegative healthy cows,
transmitted by various ixodid ticks. The bacterium infects and but ~30% of infected cows develop persistent non-neoplastic
survives in neutrophils by interfering with phagocytosis, oxida- B-cell lymphocytosis. Neoplastic lymphocytosis occurs in leu-
tive burst, motility, and endothelial adhesion. Groups of aggre- kemic lymphoma or leukemia.
gated bacteria in endosomes of neutrophils may be observed Causes of monocytosis are chronic infections, excess glu-
during acute infection and are called morulae. Infection can cocorticoids, histiocytic proliferative diseases, and myelopro-
variably cause fever, leukopenia, thrombocytopenia, edema, liferative neoplasia.
petechiation, and reluctance to move. Infection in domestic Eosinophilia can be seen in animals with extensive tissue
and nondomestic ruminants in Europe with A. phagocytophi- parasite migration, allergic responses, or as a paraneoplastic
lum is called tick-borne fever. Equine granulocytic anaplasmosis condition. Blood eosinophil transit can be very brief as
is associated with fever, neutropenia, thrombocytopenia, reflected by blood concentrations that are normal or only
ataxia, and icterus. Experimentally infected dogs have tran- slightly increased despite substantial tissue eosinophil accu-
sient high fever, thrombocytopenia, and leukopenia. In immu- mulations. This is considered to result from prolonged tissue
nocompetent animals, infection with A. phagocytophilum is eosinophil survival in the presence of cytokines such as IL-5.
self-limiting and induces robust antibody responses. Infection Massive blood eosinophilia and tissue eosinophil infiltrates are
is diagnosed by observing morulae on blood films, rising anti- observed in cats, and distinction between reactive and neo-
body titers, and PCR detection of bacterial nucleic acids. plastic proliferation may be difficult in these cases.
Canine monocytotropic ehrlichiosis is caused by Ehrlichia Basophilia is rarely observed in animals, and is associated
canis, which is transmitted by the brown dog tick Rhipicepha- with parasitic and neoplastic conditions such as heartworm
lus sanguineus. Infection of dogs, and rarely cats, occurs world- infection, or mast cell and myeloproliferative neoplasms.
wide. German Shepherd dogs are suggested to be particularly
susceptible to infection. Acute infection is similar to that with
A. phagocytophilum, except that ophthalmic lesions are more Further reading
common and consist of anterior uveitis, chorioretinitis, papill- Allen KE, et al. Hepatozoon spp infections in the United States. Vet
edema, and retinal hemorrhage, and thrombocytopenia is Clin North Am Small Anim Pract 2011;41:1221-1238.
moderate to severe. Infection progresses from an acute phase Allison RW, Little SE. Diagnosis of rickettsial diseases in dogs and cats.
to a subclinical phase, and in some cases to a chronic phase. Vet Clin Pathol 2013;42:127-144.
Dogs in the chronic phase of monocytotropic ehrlichiosis are Anistoroaei R, et al. A frameshift mutation in the LYST gene is
severely ill and have marked weight loss. Morulae may be responsible for the Aleutian color and the associated Chediak-
observed in monocytes on blood films during the acute phase. Higashi syndrome in American mink. Anim Genet 2013;44:
In dogs with advanced disease, marked lymphocytosis com- 178-183.
posed of large granular lymphocytes has been observed, which Baneth G. Perspectives on canine and feline hepatozoonosis. Vet Para-
is an immune, rather than a neoplastic, response. sitol 2011;181:3-11.
111.e1
Further reading
Aroch I, et al. Clinical, biochemical, and hematological characteristics,
disease prevalence, and prognosis of dogs presenting with neutro-
phil cytoplasmic toxicity. J Vet Intern Med 2005;19:64-73.
Baird JD, Arroyo LG. Historical aspects of Potomac horse fever in
Ontario (1924-2010). Can Vet J 2013;54:565-572.
Dallap Schaer BL, et al. Identification of predictors of Salmonella shed-
ding in adult horses presented for acute colic. J Vet Intern Med
2012;26:1177-1185.
de Caprariis D, et al. Evolution of clinical, haematological and bio-
chemical findings in young dogs naturally infected by vector-borne
pathogens. Vet Microbiol 2011;149:206-212.
Deshuillers P, et al. Pelger-Huët anomaly in a cat. Vet Clin Pathol
2014;43-337-341.
Dotta L, et al. Clinical, laboratory and molecular signs of immunodefi-
ciency in patients with partial oculo-cutaneous albinism. Orphanet
J Rare Dis 2013;8:168.
Harrus S, Waner T. Diagnosis of canine monocytotropic ehrlichiosis
(Ehrlichia canis): an overview. 2011;187:292-296.
Meng R, et al. Neutrophil elastase-processing defect in cyclic hemato-
poietic dogs. Exp Hematol 2010;38:104-115.
Perkins GA, et al. Ulcerative dermatitis, thrombocytopenia, and neu-
tropenia in neonatal foals. J Vet Intern Med 2005;19:211-216.
Petterino C, et al. Paraneoplastic leukocytosis in a dog with a renal
carcinoma. Vet Clin Pathol 2011;40:89-94.
Shearman JR, Wilton AN. A canine model of Cohen syndrome: trapped
neutrophil syndrome. BMC Genomics 2011;12:258.
112 CHAPTER 2 • Hematopoietic System Bone Marrow
Brovik L, et al. Pelger-Huët anomaly and a mild skeletal phenotype tive anemia is usually macrocytic and hypochromic. Hemorrhage
secondary to mutations in LBR. Am J Med Genet A 2013; into tissues results in recycling of the iron in hemoglobin, and
161A:2066-2073. therefore a more robust regenerative response than hemor-
Carrade DD, et al. Canine granulocytic anaplasmosis: a review. J Vet rhage into the gastrointestinal tract or other external sites with
Intern Med 2009;23:1129-1141. loss of iron.
Demasius W, et al. Bovine neonatal pancytopenia (BNP): novel insights Chronic blood loss leads to iron deficiency. Dietary iron
into the incidence, vaccination-associated epidemiological factors deficiency is the most common human nutritional disorder in
and a potential genetic predisposition for clinical and subclinical the world. Diets for domestic animals are generally iron
cases. Res Vet Sci 2014;96:537-542. replete, therefore iron deficiency in adult animals is rare and
Gleich S, Hartmann K. Hematology and serum biochemistry of feline virtually always the result of whole-body blood loss. Iron
immunodeficiency virus-infected and feline leukemia virus-infected metabolism is tightly regulated: dietary iron is absorbed by
cats. J Vet Intern Med 2009;23:552-558. duodenal enterocytes, and transferred from enterocytes to
Mason SL, et al. Presentation and management of trapped neutrophil plasma through interaction with ferriportin and oxidative
syndrome (TNS) in UK border collies. J Small Anim Pract 2014; enzymes. In plasma, iron is bound to transferrin and trans-
55:57-60. ported to rubricytes and macrophages for incorporation into
Nagahata H. Bovine leukocyte adhesion deficiency (BLAD): a review. J hemoglobin and storage, respectively. Free iron is highly toxic;
Vet Med Sci 2004;66:1475-1482. therefore iron is always bound to proteins such as ferritin, and
Reissmann M, Ludwig A. Pleiotropic effects of coat colour-associated blood ferritin concentration is a good indicator of body iron
mutations in humans, mice and other mammals. Semin Cell Dev stores. Intracellular partially degraded ferritin aggregates into
Biol 2013;24:576-586. hemosiderin granules. The iron in hemosiderin reacts with
Swenson CL, et al. Impact of bovine leukemia virus infection on neu- potassium ferrocyanide and turns blue-black, which is the
trophil and lymphocyte concentrations in dairy cattle. J Am Vet Med Prussian blue stain reaction. Multiple additional proteins regu-
Assoc 2013;243:131-135. late iron transport within and across cells. Hepcidin is a central
Zimmerman KL, et al. Leukocyte adhesion deficiency type I in a mixed- regulator of iron metabolism. Increased hepcidin inhibits iron
breed dog. J Vet Diagn Invest 2013;25:291-296. transfer from enterocytes into plasma, and iron release from
macrophages, leading to loss of iron with enterocyte sloughing
and iron retention in macrophages. In iron-replete states, hep-
Disorders of erythrocytes cidin concentration is high, which limits iron absorption and
Anemia is a reduction in the red blood cell (RBC) mass and iron mobilization from macrophage stores. In iron-deficient
therefore in oxygen-carrying capacity. Causes of anemia are states, hepcidin concentration is low, which enhances iron
reduced erythrocyte production, premature destruction, and transfer from enterocytes. However, hepcidin is also increased
blood loss (Table 2-2). The degree of anemia is generally cat- in chronic inflammation and disease, which inhibits enterocyte
egorized as mild, moderate, or marked if the hematocrit is iron transfer and iron mobilization from storage in macro-
within 13 , within 2 3 , or > 2 3 below the lower reference interval, phages, leading to the conundrum of abundant stainable
respectively. Anemia is further characterized as regenerative if iron in bone marrow and spleen despite a functional iron-
there is an increased concentration of polychromatophilic limited anemia. Anemia of chronic inflammation and disease
RBC or reticulocytes in blood and an increased proportion of is most common in dogs, but is also seen in other domestic
rubricytes in bone marrow, or as nonregenerative if production species.
of RBCs is not increased. Mechanistically, there are 3 main Iron deficiency resulting from blood loss develops gradu-
categories of anemia: blood loss, hemolytic, and decreased ally, usually weeks to months. With modern hematology ana-
production. lyzers, changes in erythrocytes caused by iron-limited
erythropoiesis can be detected long before there is iron defi-
Blood loss anemia ciency characterized by lack of stainable iron in bone marrow
Acute blood loss anemia is usually the result of trauma. Most and spleen, and reduced blood iron and ferritin concentration.
external blood loss is readily identifiable, whereas internal Neonatal animals have very limited iron stores, and milk is
blood loss may be obscured. In both instances, there is a rapid low in iron, resulting in physiologic iron deficiency during the
shift of water from the interstitial fluid compartment into the first few months of life. By 4-6 months of age, bone marrow
vasculature to restore blood volume, which results in hemo- and/or spleen iron stores become apparent, and persistent lack
dilution and a lowered hematocrit and protein concentration. of stainable iron and anemia are abnormal. The most common
Reduced oxygen delivery stimulates erythropoietin produc- cause of anemia in juvenile animals is blood loss caused by gas-
tion in the kidney, which in turn increases proliferation of trointestinal parasites, such as strongyles in horses, Haemonchus
committed erythroid progenitor cells in bone marrow. Newly contortus and Trichostrongylus spp. in ruminants, and hook-
released erythrocytes appear in blood in 3-5 days, depending worms and ascarids in dogs and cats. Heavy ectoparasite infes-
on the intensity of the erythropoietic stimulus and the capac- tation can also cause iron deficiency anemia. Piglets in intensive
ity of the host to respond. Horses release very few reticulocytes production systems are born severely iron deficient and gener-
from bone marrow in regenerative anemia; these few reticulo- ate iron stores very slowly; therefore, despite routine paren-
cytes may be detectable with automated analyzers that scru- teral iron supplementation, piglets remain highly susceptible
tinize large numbers of cells, but they are typically not to debilitating or fatal anemia from blood loss. In adult pet
identified on blood smear review. However, newly released dogs and cats, iron deficiency anemia is most often secondary
erythrocytes in horses and other species are larger than mature to a bleeding gastrointestinal neoplasm. Internal bleeding and
erythrocytes and have lower hemoglobin concentration, trans- epistaxis associated with vascular erosion in guttural pouch
lating to higher mean cell volume (MCV), and lower mean mycosis may cause anemia, and occasionally iron deficiency
cell hemoglobin concentration (MCHC). Therefore regenera- anemia, in horses. Bleeding into the esophagus, stomach, and
Bone Marrow 113
Table • 2-2
Classification of anemia by mechanism
Mechanism Hematologic and clinical findings Examples, affected breeds
Blood Loss
Acute Low to normal hematocrit, low to normal plasma Trauma with external blood loss
protein concentration, normal MCV
Chronic Low hematocrit, normal plasma protein concentration, Gastrointestinal or urogenital bleeding
low to normal MCV
Hemolysis
Immune- Marked anemia, spherocytosis, agglutination, marked Primary (autoimmune), drug-induced, transfusion
mediated jaundice, splenomegaly, hemoglobinuria reaction, infectious agents, paraneoplastic
Infectious Mild to marked anemia, spherocytosis, mild or absent Babesiosis, anaplasmosis, cytauxzoonosis, hemotropic
jaundice, mild or absent splenomegaly mycoplasmosis, equine infectious anemia
Mechanical Mild to moderate anemia, poikilocytosis, RBC Endocardiosis, endocarditis, vasculitis, intravascular
trauma fragmentation, mild or absent jaundice coagulation, burns
Toxic injury Mild to moderate anemia, poikilocytosis, Heinz bodies, Oxidant injury, clostridial sepsis, leptospirosis,
mild or absent jaundice hyperglycemia, snake venom
Hereditary Pyruvate kinase (PK) deficiency—dog: mild to moderate Various small to medium-sized dog breeds; Somali,
hemolytic anemia, persistent reticulocytosis, Abyssinian, and domestic shorthair cats
splenomegaly, develop myelofibrosis and
osteosclerosis; cat: mild or absent anemia, persistent
reticulocytosis
Phosphofructokinase (PFK) deficiency: mild to moderate Spaniel-type dogs, Whippets, mixed-breed dogs
anemia worsened by exercise, persistent
reticulocytosis
Glucose-6-phosphate dehydrogenase (G6PD) deficiency: American Saddlebred
episodic mild to moderate anemia, jaundice
Erythrocyte flavin adenine dinucleotide (FAD) deficiency: Spanish Mustang, Kentucky Mountain Saddle Horse
eccentrocytosis, pyknocytosis, methemoglobinemia,
normal hematocrit
Cytochrome b5 reductase deficiency: normal Multiple dog breeds, domestic shorthair cats
hematocrit, methemoglobinemia, cyanosis
Stomatocytosis: mild to moderate anemia Standard Schnauzer, Alaskan Malamute, Patrijshond
Spherocytosis: mild to moderate anemia Golden Retriever
Elliptocytosis: normal hematocrit Various dog breeds
Decreased Production
Chronic inflammation with iron sequestration: Cancer, polyarthritis, enteritis, etc.; common in dogs;
normocytic normochromic or microcytic hypochromic uncommon in other species
anemia
Iron deficiency: macrocytic or normocytic hypochromic All species; most common in dogs
anemia progressing to microcytic hypochromic
anemia
Erythropoietin deficiency: normochromic normocytic Chronic kidney disease; all species
anemia
Cobalamin deficiency: mild to moderate anemia, Giant Schnauzer, Australian Shepherd, Border Collie,
leukopenia, megaloblastic change in hematopoietic Shar Pei, Beagle
cells
Immune or toxin-mediated progenitor cell injury: Pure red cell aplasia (lack of RBC production);
moderate to severe anemia +/− other cytopenia aplastic anemia (lack of production of all
hematopoietic cells); all species
Primary hematopoietic neoplasm: acute myeloid or All species and ages
lymphoid leukemia, myelodysplasia,
myeloproliferative neoplasm; marked cytopenia of
one or several cell lineages
Metastatic hematopoietic neoplasm: mild cytopenia Myeloma, carcinoma, mast cell tumor
MCV, mean cell volume; RBC, red blood cell.
114 CHAPTER 2 • Hematopoietic System Bone Marrow
Further reading
Powers JM, Buchanan GR. Diagnosis and management of iron defi-
ciency anemia. Hematol Oncol Clin North Am 2014;28:729-745.
Bone Marrow 115
A B
C D
Figure 2-7 Samples from a dog with immunohemolytic anemia and intravascular hemolysis.
A. There are numerous ghost cells (arrows), spherocytes (arrowheads), and polychromatophilic
erythrocytes in the blood smear. The nucleated cell is a rubricyte. B, C. The bone marrow aspirate
and section show marked rubricyte hyperplasia but orderly maturation. D. Renal tubules contain
heme pigments reabsorbed from urinary filtrate.
administration of blood or virus. Infected horses are the sole febrile period and is accompanied by pallor of mild to marked
source of viral transmission. degree. The febrile periods may progress to death in less than
Infection causes acute severe illness that may be fatal, then a week, or regress and recur at irregular intervals. Rarely, an
cycles of illness characterized by thrombocytopenia and acute episode is followed by many years of an asymptomatic
anemia, and eventual asymptomatic infection. However, even carrier state.
horses without clinical signs of illness remain a reservoir of During acute illness anemia is severe and sufficient to cause
infectious virus. The cyclic nature of infection corresponds to death, with hemoglobin of 25-50 g/L, and hematocrits of
an intense immune response that drives selection of viral 0.08-0.15 L/L. There is consistent thrombocytopenia during
escape mutants in a manner akin to immunity to the human febrile periods, with resulting petechiae. Anemia is initially
immunodeficiency virus in humans. regenerative as indicated by anisocytosis and macrocytosis,
EIAV infects cells of the monocyte-macrophage system, and the and later becomes nonregenerative. There may also be leuko-
mechanism for thrombocytopenia and anemia is thought to penia as a result of neutropenia and lymphopenia, and at
be a combination of premature removal of platelets and eryth- least a relative monocytosis. Monocytes may contain ingested
rocytes coated with immune complexes, and direct infection erythrocytes (sideroleukocytes) within 2-3 days of a febrile
of megakaryocytes. Hemolysis is predominantly intravascular, episode. Grossly, horses that die or are euthanized have edema
and during chronic infections, the bone marrow becomes of the ventral abdominal wall and in the suspensory ligaments
hypoplastic with plasma cell hyperplasia. Acute disease is of the viscera. The spleen is enlarged, turgid, and fleshy with
characterized by pyrexia and marked depression, with capsular hemorrhages; a bulging but not oozing cut surface;
anorexia, jaundice, weight loss, and pitting and dependent and inapparent lymphoid follicles. The liver is enlarged,
edema. There are petechial hemorrhages on the ventral surface dark, and turgid, with a fine lobular pattern and focal capsular
of the tongue but also on ocular and vulvar mucosae that hemorrhages. Petechial hemorrhages are present on the
reflect thrombocytopenia. Mild icterus develops after a short renal capsules and in the perirenal tissues. On cut surface,
116 CHAPTER 2 • Hematopoietic System Bone Marrow
Further reading
Issel CJ, et al. A perspective on equine infectious anemia with an
emphasis on vector transmission and genetic analysis. Vet Microbiol
1998;17:251-286.
Payne SL, Fuller FJ. Virulence determinants of equine infectious anemia
virus. Curr HIV Res 2010;8:66-72.
Bone Marrow 117
However, marked bilirubinemia results in bilirubinuria, which Although cattle are not susceptible to A. ovis, sheep and goats
gives an intense yellow-brown color to urine. Hemoglobin develop a latent infection if inoculated with A. marginale. The
concentration may be as low as 30-40 g/L, and hematocrit economic impact of widespread ovine anaplasmosis on sheep
0.10-0.15 L/L, and there typically is a leukocytosis because of production has not been fully determined.
neutrophilia. About 1 week after onset of parasitemia, eryth-
rocyte regeneration appears on blood smears. Clinical illness
consists of fever, weight loss, reduced milk production, abor- Further reading
tion, lethargy, and death, in particular in animals older than 2 Kocan KM, et al. The natural history of Anaplasma marginale. Vet
years. Mortality rates of 50-60% are observed in naive adult Parasitol 2010;167:95-107.
animals first infected with A. marginale, although this varies Renneker S, et al. Can Anaplasma ovis in small ruminants be neglected
by bacterial strain, geographic region, and nutritional status of any longer? Transbound Emerg Dis 2013;60(Suppl. 2):105-112.
cattle. High-producing dairy cows appear most susceptible to
severe illness and high mortality from acute anaplasmosis.
Animals resist movement, have a rapid heart rate and increased Babesiosis. The apicomplexan protozoan Babesia parasit-
respiratory rate, and may have incoordination. Cattle that izes erythrocytes of a wide range of mammals, including humans.
survive become persistently immune carriers with cyclical Similar to Anaplasma, Babesia infects and replicates exclu-
low-level parasitemia and do not develop clinical illness upon sively in erythrocytes. The number of Babesia spp. recognized
reinfection. has increased dramatically over the past decade, given applica-
Anaplasmosis, distinct from babesiosis, does not cause tion of molecular tools, and morphologically similar organisms
intravascular erythrocyte lysis, and therefore no hemoglobin- may be genetically distinct. Classification of Babesia is not
uria. Recycling of iron and globins by splenic and hepatic reviewed here, but rather the pathogenesis and pathology of
macrophages is considered to be the main reason for more natural infections. Babesia has high host specificity, and is
effective erythrocyte regeneration in anaplasmosis relative to transmitted by ticks. During the tick bite, sporozoites are
babesiosis, in which hemoglobin is lost externally via the injected with tick saliva into the host and directly infect eryth-
urinary system. Erythrocytes are the only target cell of A. rocytes. Sporozoites in erythrocytes divide asexually into 2 or
marginale, and are frequently sphered in acute disease, likely 4 pear-shaped merozoites (“piroplasm”) that are then capable
because of removal of parasitized erythrocyte membrane com- of infecting new erythrocytes (Fig. 2-9). Some merozoites
ponents by splenic macrophages. Identifying organisms on develop into extracellular gametocytes, which if ingested by
blood smears is a useful diagnostic test in acute infection, but ticks replicate in their gut. Some Babesia spp. have transovarial
in chronically infected carrier animals, very few erythrocytes transmission in the tick, implying potentially prolonged sur-
contain organisms, and other tests such as ELISA or PCR must vival in ticks without feeding on vertebrate hosts. Transmission
be applied. by biting insects or contaminated instruments appears to be
There are no pathognomonic gross lesions of anaplasmosis. less common than for Anaplasma, which may be because
There is pallor of all tissues and mild to marked icterus, with of preferential location of erythrocytes in capillaries rather
relatively good body condition in those animals dying acutely, than veins.
and cachexia in chronic cases. The lungs are pale and discol- The severity of the disease produced in the mammalian
ored and may have bullous emphysema if there has been host depends more on the strain and species of infecting
severe terminal dyspnea. There are frequently ecchymotic Babesia than on the number of organisms inoculated. Patho-
hemorrhages on the epicardium, and the heart is flabby and genic effects are, in most infections, related directly to lysis of
dilated. The liver is pale and icteric, and the gallbladder is red cells by emerging parasites, but other mechanisms, including
usually distended. The spleen is enlarged, turgid, and con- sludging of infected red cells, hemoglobinuric nephrosis, and
gested in acute cases, and firm, dark red, and fleshy in chronic release of vasoactive peptides, contribute to the signs and are
ones. The enteric tract is unremarkable, and the bladder may
contain deeply bilirubin-stained urine. The marrow hemato-
poietic space is variably expanded, depending on the stage
of the disease, and there may be serous atrophy with
chronicity.
Anaplasma centrale produces a natural infection of cattle,
but is also used, being a mild pathogen, as an immunizing
agent against A. marginale in some areas of endemic infection.
A. centrale infection usually produces a mild disease, although
sometimes it can be severe, with fever and anemia but no
icterus. Immunity to A. centrale does not protect against infec-
tion by all strains of A. marginale, and coinfections have been
reported. A. centrale also causes a persistent infection.
Anaplasmosis in sheep and goats is caused by A. ovis. A.
ovis is highly prevalent in sheep in many Eurasian and south-
ern European countries, but rarely associated with overt clini-
cal disease unless animals have concurrent other infections,
debilitation, or poor nutrition. However, infection of goats
more often results in anemia and clinical disease, and there
are reports of infection of humans in Cyprus with an Ana- Figure 2-9 Blood smear from a cow with Babesia bigemina
plasma organism genetically similar to A. ovis via tick bite. infection.
117.e1
Further reading
Stuen S, Longbottom D. Treatment and control of chlamydial and
rickettsial infections in sheep and goats. Vet Clin North Am Food
Anim Pract 2011;27:213-233.
118 CHAPTER 2 • Hematopoietic System Bone Marrow
responsible for death. The severity of anemia and illness is expected of an acute hemolytic disease. There is variably
enhanced by splenectomy, which is used commonly in patho- severe hemoglobinuric nephrosis with severe congestion, focal
genetic studies. Splenectomy is a risk factor for human babe- hemorrhage and hemosiderin in tubular epithelium, and
siosis, and likely also for some veterinary infections. B. bovis diffuse vacuolar degeneration with interstitial mixed mono-
merozoites are smaller than those of B. bigemina. nuclear cell reaction. There is hepatic periacinar congestion
“Tick fever” in cattle is caused by one or several of A. with uninfected red cells, and vacuolar degeneration in
marginale, B. bovis, and B. bigemina. Babesia bovis causes the midzone and periacinar hepatocytes, accompanied by cana-
most severe disease. Bos indicus cattle breeds are relatively more licular cholestasis. There is hemosiderin accumulation in both
resistant to the effects of this parasite than Bos taurus, which hepatocytes and Kupffer cells, and the latter contain both
has led to the suggestion that the organism evolved in these infected and noninfected red cells. Lymphocytes and plasma
breeds. Young cattle have pronounced resistance to severe cells accumulate in portal areas and around central veins.
infection. Colostral antibodies transiently protect young Parasitized erythrocytes may be seen in vessels in all tissues, but
calves, and infection of young animals induces long-term they are particularly common in interstitial capillaries in the
immunity. Hence, in endemic areas, there often is a high level kidney, in the gray matter of the brain, in the heart, and espe-
of herd immunity, and outbreaks result from interruption in cially in skeletal muscle; in these locations, nearly every eryth-
exposure to ticks or introduction of naive animals. For these rocyte packed into the distended capillaries appears to contain
reasons, the disease is mostly seen in adult cattle recently 1-2 parasites. The organisms are faint blue in routine sections,
introduced from tick-free areas, or in areas of greatly fluctuat- and are best demonstrated in imprint preparations of fresh tissue.
ing tick populations. In sections, Giemsa stain demonstrates them as small paired
Infection by B. bovis causes severe febrile illness, which or single spherical bodies with denser staining at one pole. In
begins ~2 weeks after exposure to ticks. The animal may well-fixed fresh brain of acute cases, there may be edema of
become extremely ill before severe anemia, parasitemia, or the neuropil around the clogged capillaries.
hemoglobinuria are apparent, and sometimes the clinical Animals that die with peracute disease have necrosis of
picture is dominated by neurologic signs such as seizures, lymphocytes in germinal centers of node and spleen, although
hyperesthesia, and paralysis, likely associated with the ten- there may be some degree of recovery in animals surviving a
dency for parasitized red cells to sludge in cerebral capillaries. week, and general depletion of lymphocytes in those dying
Animals progress to weakness, fever, hemoglobinuria, and after protracted illness. Characteristic changes in the medul-
anemia; the latter is more severe in animals surviving more lary region of nodes include sinus histiocytosis with extensive
than a week. Causes of death are shock and respiratory dis- erythrophagocytosis. The histology of the spleen is often
tress. The parasite is never numerous in circulating erythro- unhelpful, the organ being so suffused with intracorpuscular
cytes, rarely being seen in >5% of circulating erythrocytes. and extracorpuscular hemoglobin that evidence of erythro-
Parasitized erythrocytes are more likely to be found in smears phagocytosis is obscured. There is little extramedullary hema-
of blood prepared from cut skin capillaries than in routine topoiesis in liver or spleen. The bone marrow has hyperplasia
blood samples from large veins. Recovery is usually fairly of immature rubricytes and, in animals that survive the acute
rapid in animals that survive the acute phase, although chronic stage, there is strong reticulocytosis and slow recovery of
ill thrift has been described. Photosensitization may occur anemia. There is increased hemosiderin in bone marrow, sug-
in the convalescent phase, probably as a result of reduced gesting that marrow is also a site of erythrolysis.
excretion of phylloerythrin in animals with severe Babesiosis results in metabolic disease more complex than a
hyperbilirubinemia. simple syndrome of intravascular hemolysis. Severely affected
The most typical postmortem findings are those to be expected animals may die before significant anemia has set in, and in
of an acute intravascular hemolytic crisis. There is anemia, vari- these cattle, the intense visceral congestion and pulmonary
ably severe jaundice and hemoglobinuria, and the kidneys are edema suggest that death may be at least partly the result of
deep red-brown throughout as a result of hemoglobin staining circulatory shock. This has been supported by studies that
and intense congestion of capillaries. There is capillary conges- have shown that the parasite is the source of proteases that
tion of most organs; the spleen is grossly swollen, soft, and activate plasma kallikrein, which, as well as being a hypoten-
dark; and the liver is acutely congested and may be heavily sive agent, may activate bradykinin, another potent vasodila-
stained with bile pigment. The gallbladder is distended with tory agent. Rather unexpectedly, metabolic alkalosis occurs in
thick, dark, viscous bile. B. bovis infections, whereas acidosis is the rule in severe B.
In some acute cases, the lungs are congested and edema- canis infections. The result of these profound metabolic upsets is
tous, and the larger airways contain stable foam. Recent hem- a syndrome of circulatory failure, likely because of extensive
orrhages are common in the thoracic serosal membranes. The plugging of microvasculature by sequestered red cells. The
most characteristic macroscopic feature of B. bovis infections is apparent anemia is therefore caused in considerable measure
striking, uniform congestion of the gray matter throughout the by the vasodilatory effects of kallikrein and shift of red cells
brain, imparting to it a dramatic, deep pink color (the cerebral away from large veins. Although plasmin activation occurs, the
flush), which contrasts strongly with the white matter; the effects on the coagulation system are unlikely to be a signifi-
latter is often stained faint yellow by unconjugated bilirubin. cant factor in the pathogenesis because hemorrhage is not a
In some peracute cases, there is minimal hemoglobinuria or major part of the morbid picture.
jaundice, but the brain still has characteristic capillary conges- The actual mechanism of penetration of red cells by the mero-
tion, and imprint preparations yield many intraerythrocytic zoites of Babesia is unclear. Parasites remodel the erythrocyte
organisms. surface with their variable erythrocyte surface antigen (vesa)
Histologically, there is thickening and congestion of pulmo- proteins, which changes the membrane mechanical and adhe-
nary capillaries with hemosiderin in intravascular macro- sive properties. The organism causes complement activation
phages. Kidneys and liver have the histologic lesions to be by the alternative pathway, and by C3b achieves adherence
Bone Marrow 119
and later invasion. The mechanism of hemolysis is also obscure. infection, as most clinically normal carriers of this organism
Immune mechanisms do not appear to play a significant role have some parasitized erythrocytes in this site.
in the early stages of the disease, but they may be a factor in In the last 2 decades, it has been recognized that canine
delayed recovery. Osmotic fragility is markedly increased in babesiosis is caused by different organisms transmitted by spe-
nonparasitized cells. Generation of intravascular fibrin may cific vectors and has highly variable pathogenesis. Large babe-
contribute to capillary erythrocyte sludging. sial organisms in dogs include B. canis, B. rossi, B. vogeli, and an
Babesia bigemina infection may be transmitted by the as yet unnamed Babesia in North America. B. canis occurs
same tick as B. bovis, and both parasites may cause losses in mostly in southern and central Europe, is transmitted by Der-
the same geographic area. B. bigemina, however, usually causes macentor reticulatus and causes disease of variable severity
much less severe illness, although parasitized erythrocytes cir- consisting of fever, hemolytic anemia, and jaundice in adult
culate early, sometimes before clinical signs are apparent, and dogs, and less severe disease in young dogs. B. rossi is restricted
in much greater numbers than in B. bovis infection. B. bigemina to sub-Saharan Africa, is transmitted by Haemaphysalis ellip-
also causes erythrocyte destruction, but this appears to be tica, and causes severe peracute and acute illness with 10-20%
directly proportional to the level of parasitemia, unlike B. bovis mortality. Clinical disease results from severe hemolytic
infection. There are few of the vasoactive and erythrocyte anemia, acid-base derangement, hypoxia, and a systemic
adherence effects, thus profound shock-like signs are usually inflammatory response. Death is attributed to multiple organ
absent. Anemia in severe cases may be marked before the failure as manifested by hepatopathy and hypoglycemia, acute
animal becomes ill and, as in any case of severe anemia, death kidney failure, cerebral ischemia, and respiratory distress. Con-
may occur suddenly as a result of myocardial failure. Fever is trary to most babesial infections, B. rossi affects young dogs as
not usually as severe as in B. bovis infection. severely as adult dogs. B. vogeli occurs in tropical and sub-
The pathology of B. bigemina and B. bovis infections is tropical regions of most continents, including North America,
similar, except that in B. bigemina infection there is little capil- and is transmitted by the brown dog tick Rhipicephalus san-
lary congestion of the viscera and none of the cerebral gray guineus. Disease associated with B. vogeli infection is less
matter impact, the presence or absence of the cerebral flush being severe than that of other large babesial organisms in dogs, and
the most reliable gross feature for differentiating the 2 infections. may be subclinical in immunocompetent animals. However,
Pulmonary edema may be more often seen in fatal cases of B. young dogs are also more likely to be clinically ill with hemo-
bigemina infections, probably because the greater severity of lytic anemia and thrombocytopenia. The unnamed large
anemia causes terminal left ventricular failure. babesial organisms in dogs were identified in splenectomized
Babesia divergens and B. major are more or less restricted or immunosuppressed animals in North America and Britain,
to northern and western Europe and Asiatic Russia and, for and were also associated with severe anemia and thrombocy-
the most part, are of relatively minor importance to the cattle topenia. Large babesial organisms in dogs are morphologically
industries there, although significant outbreaks of disease and indistinguishable.
death may occur. Although B. divergens is small and resembles Small Babesia of dogs were until recently thought to all
B. bovis in size, and B. major is as large as B. bigemina, the be B. gibsoni, but are now recognized to belong to at least 5
pathology and pathogenesis of the disease produced by these different taxa: B. gibsoni (sensu stricto), B. conradae, a B.
organisms is apparently very similar to that produced by B. microti–like organism, Theileria annae, and an unnamed Thei-
bigemina. Thus there is intravascular hemolysis with little or leria spp. The number of organisms in erythrocytes is often
no capillary agglutination of erythrocytes, and death results high, but disease associated with small babesial organisms in
primarily from severe anemia. Spontaneous splenic rupture has dogs is usually mild. Anemia results mostly from extravascular
been reported in B. major infections, a complication rarely, if erythrocyte removal and not intravascular hemolysis.
ever, reported in other bovine babesial infections. In dogs with pathogenic babesiosis at postmortem, there
Differential diagnosis of bovine babesial infections in coun- is staining of tissues with both bilirubin and hemoglobin.
tries where more than one species of Babesia is present is impor- The kidneys are dark brown, and there is splenomegaly and
tant and at times difficult, and may be complicated by dual copious thick bile in the gallbladder. In addition, there is evi-
infections and by the additional possibility of Anaplasma dence of vascular injury in the form of hemorrhages and
infection. B. bovis and B. bigemina may be distinguished from edema, which may be severe in the lung (eFig. 2-1). Parasit-
one another in well-prepared blood smears, but erythrocytes ized erythrocytes may be found plugging capillaries in smears
parasitized by B. bovis are rare in jugular blood, or even in and sections of cerebral cortex, reminiscent of B. bovis infec-
blood from deep skin punctures. They are best demonstrated tion, but the phenomenon is never as severe as in that disease.
in smears of blood expressed from a superficial skin scrape; Disseminated intravascular coagulation is a consistent occur-
this is most conveniently obtained from the tail-tip in the live rence in severe B. rossi and B. canis infection, and is presum-
animal. B. bigemina–containing erythrocytes, on the other ably related to, and is likely to aggravate, the hemolysis and
hand, are quite numerous in circulating blood while clinical the vascular damage. Microthrombi can be demonstrated in
signs are severe. The morphology of the parasites will usually many tissues.
be insufficiently preserved in postmortem material to allow Piroplasmosis in horses is caused by Theileria equi and
distinction, but the preference of B. bovis for capillaries of Babesia caballi. T. equi was previously classified as B. equi, but
organs such as kidney, heart, and brain will, in most cases, serve is molecularly distinct from other Babesia spp. and was reclas-
to distinguish the infections. It must be remembered that sified. Also, during initial infection, T. equi sporozoites invade
Sarcocystis spp. may be present in smears of myocardial blood. lymphocytes, monocytes, and macrophages, and develop
Serologic tests are available for antemortem diagnosis, and PCR schizonts and then merozoites in those cells. Merozoites are
tests for postmortem samples. It is necessary to demonstrate released to invade erythrocytes. This property is more like
a very heavy parasite burden in cerebral capillaries if brain other Theileria spp. than Babesia spp. Infection with either
smears are to be relied on as evidence of active B. bovis organism is widespread, and their distinct ixodid ticks are also
119.e1
B
eFigure 2-1 Babesiosis in a dog. A. Babesia canis can be detected
as single or paired, piriform organisms within erythrocytes in a
vessel within the stomach. B. Centrilobular congestion and hepa-
tocellular degeneration and extramedullary hematopoiesis. (Cour-
tesy E.P. Lane.)
120 CHAPTER 2 • Hematopoietic System Bone Marrow
widely distributed. North America is generally considered free the tick vector, in addition to clades of distinct Theileria and
of equine piroplasmosis, although sporadic outbreaks have Cytauxzoon organisms.
occurred in Florida and Texas. T. equi infection is considered Cytauxzoon felis is naturally transmitted by ixodid ticks,
to be more widespread and causes more severe disease. Clini- and can be transmitted experimentally by fresh and cryopre-
cal disease in acute infection with either organism is similar, served blood or tissue homogenates from infected animals.
and consists of fever, lethargy, petechiation, ventral and peri- Infection of domestic cats results in acute febrile illness and
orbital edema, thrombocytopenia, jaundice, hemoglobinuria, death in ~19-21 days. Clinically ill cats have fever, depression,
splenomegaly, and intravascular hemolysis leading to anemia. pallor, icterus, dark urine, and occasionally dyspnea. Hematol-
T. equi are small piroplasms, and 1-5% of erythrocytes may ogy is characterized by nonregenerative anemia and frequently
contain organisms during acute infection, whereas B. caballi neutropenia and thrombocytopenia. Lack of erythrocyte regen-
are large piroplasms, and <1% of erythrocytes are infected. eration and neutropenia distinguish C. felis from hemotropic
Mortality is low in immunocompetent horses, but experimen- Mycoplasma infection. Babesia felis piroplasms are indistin-
tal infection of foals with severe combined immunodeficiency guishable from C. felis, but infection with the former is not
results invariably in fulminant infection and death. Following usually characterized by leukopenia (Fig. 2-10). Cytauxzoon
acute infection, most horses become persistently infected organisms in erythrocytes are variable in shape, but most
clinically inapparent carriers resistant to illness from subse- common are signet ring forms with a thickened nuclear area
quent exposure. Such horses constitute a source of infection at one point of the ring. The level of parasitemia is low, with
for naive animals. It has been suggested that some horses clear piroplasms in 1-4% of peripheral blood erythrocytes, but in
B. caballi infection over time without treatment. Immunity to terminal stages of illness; infected macrophages may be in
one organism does not cross-protect against infection by the blood samples from larger veins and therefore on blood films.
other piroplasm. Macrophages containing schizonts can be readily identified in
Babesial infection of cats is uncommon worldwide except imprints from virtually any organ at postmortem, in particular
in southern Africa. The small B. felis piroplasm causing infec- lung and spleen. In the early hemolytic stages of the disease,
tion in those areas induces severe hemolytic anemia. Several the urine is highly concentrated, acidic with high levels of
other small and large piroplasms have been reported in domes-
tic and nondomestic cats, but neither disease association nor
classification is well established.
Babesial infections of other species are for the most part
mild or clinically inapparent. The course of these diseases in
general follows the pattern described for B. bigemina infection,
in that there is quite severe parasitemia, anemia caused by
intravascular hemolysis, with hemoglobinuria in acute cases.
At autopsy, there is splenomegaly and variably severe jaundice
and, in some cases (notably B. trautmanni infection in pigs),
edema, and petechiae. An organism resembling B. divergens
may infect white-tailed deer, and mice are susceptible to
numerous Babesia organisms.
Further reading
Gohil S, et al. Bovine babesiosis in the 21st century: advances in
biology and functional genomics. Int J Parasitol 2013;43:
125-132. A
Penzhorn BL. Why is Southern African canine babesiosis so virulent?
An evolutionary perspective. Parasit Vectors 2011;4:51.
Schnittger L, et al. Babesia: a world emerging. Infect Genet Evol
2012;12:1788-1809.
Wise LN, et al. Equine piroplasmosis. Vet Clin North Am Equine Pract
2014;30:677-693.
Further reading
Johnsson NN, et al. Productivity and health effects of anaplasmosis and
babesiosis on Bos indicus cattle and their crosses, and the effects
of differing intensity of tick control in Australia. Vet Parasitol
2008;155:1-9.
Short MA, et al. Outbreak of equine piroplasmosis in Florida. J Am Vet
Med Assoc 2012;240:588-595.
Bone Marrow 121
protein and large amounts of bile and blood, including intact The trypanosomes important to human and animal health
red cells and bilirubin crystals. Consistent with a rapidly fatal are transmitted by insects that carry the metacyclic stages in
course of disease, animals at postmortem are generally in good either their oral or anal tracts. Thus, Trypanosoma cruzi, the
body condition with adequate adipose tissue. There is exten- cause of Chagas disease in humans and animals in South
sive vascular obstruction from schizont-containing macro- America, is known as a stercorarian parasite because it is
phages, leading to congested edematous lungs, reddened spread by passage in the feces of the reduviid insects (Triato-
lymph nodes, petechial and ecchymotic hemorrhages, and minae subfamily); after the insects bite (often around the
pleural, pericardial, and peritoneal effusion. mouth or eye), they defecate, and the trypanosomes gain entry
North American bobcats are considered to be a reservoir to the host through the bite wound, often assisted by the host
of C. felis, and generally do not become ill after experimental scratching. The important African trypanosomes of animals
tick infection. Inoculation of cats with blood from parasitemic (T. congolense, T. vivax, T. brucei brucei) and of humans
bobcats induces parasitemia in cats, but not severe illness. This (T. brucei rhodesiense and T. brucei gambiense) are called sali-
is thought to be because transferred piroplasms are unable to varian parasites because of their transmission through the
undergo schizogony in recipient cats without a developmental salivary glands of the tsetse fly. Other biting and sucking
stage in ticks. Other nondomestic cats also harbor C. felis insects, such as tabanids, stable flies or fleas, and vampire bats
without apparent clinical illness. may transmit trypanosomes mechanically. Infection of the
The host-pathogen relationship between C. felis and definitive host, the tsetse fly, is probably lifelong.
domestic cats appears to evolve. Recently, infection in domes- Trypanosoma equiperdum, the cause of dourine, does not
tic cats has been identified over an expanded range of the require a vector host but is transmissible by direct contact
southern and midwestern United States, and domestic cats with mucous membranes. It is described in Vol. 3, Female
have been recognized as parasitemic over several years but genital system.
healthy. Anecdotally, cats that have survived C. felis infection Not all species of Trypanosoma of mammals are pathogenic,
may be resistant to subsequent challenge, and immunosup- and among the common nonpathogenic species of veterinary
pressive treatment may increase parasitemia. These findings interest are T. melophagium, ubiquitous in sheep and trans-
suggest that a more benign host-pathogen relationship of C. mitted by the ked, Melophagus ovinus; T. theileri, which is
felis and domestic cats may be emerging. widespread in cattle and transmitted by several types of biting
flies, including Tabanidae; T. theodori, which occurs in goats
in the Middle East, transmitted by the hippoboscid fly, Lipo-
Further reading ptena caprina, and probably synonymous with T. melophagium;
Meinkoth JH, Kocan AA. Feline cytauxzoonosis. Vet Clin North Am and T. lewisi of rats, which is of much interest as a convenient
Small Anim Pract 2005;35:89-101. subject for research on the genus. T. rangeli of South Ameri-
Rizzi TE, et al. Prevalence of Cytauxzoon felis infection in healthy cats can cats, dogs and humans is also apparently nonpathogenic
from enzootic areas in Arkansas, Missouri, and Oklahoma. Parasit to the vertebrate hosts but differs from the above in that it
Vectors 2015;8:13. can be transmitted by inoculation or contamination, the
vector being the triatomine Rhodnius prolixus. The species of
trypanosomes listed above, although widespread in their hosts,
Trypanosomiasis. Trypanosomes are insect-transmitted are ordinarily sparse in blood and seldom observed unless
protozoa, uniform in type but varying in morphologic details. specifically looked for in thick smears, after splenectomy, or
Some species are morphologically stable, whereas others are by culture. Occasionally, however, T. melophagium and T. thei-
polymorphic, and the differentiation of species by morphol- leri are found in very large numbers in the blood of cattle and
ogy is challenging (Fig. 2-11). sheep suffering from a primary and usually an immunosup-
pressive disease. It is not clear whether T. theileri may become
pathogenic in the compromised host; however, its increase in
number in association with other diseases suggests that it may
be of secondary importance.
In endemic areas, the incidence of infection by pathogenic
species varies depending on such factors as the availability of
mammalian reservoirs, the density of vector tsetse flies, and
the systems of husbandry adopted, but, as a rule, domestic
animals and trypanosomes cannot coexist. Trypanosomiasis pro-
hibits domestication of livestock in perhaps 1 4 of the total land
surface of Africa. Knowledge of host-parasite relationships is
not fully understood, neither for the vector nor the mamma-
lian hosts. Within a species of the organism, local strains may
be distinct in their basic and predominant antigens, but within
the host in the course of chronic infections, a series of geneti-
cally regulated antigenic variants appears in succession so that
the animal exhausts itself without clearing the infection. Suc-
cessive waves of parasite and antibody dominance account for
the characteristic recrudescences of the infection and for the
known difficulty in producing an effective vaccine.
Figure 2-11 Trypanosoma vivax trypomastigote in blood smear The pathogenic trypanosomes differ widely in virulence and
from a cow. are apparently nonpathogenic in mammalian reservoir hosts.
122 CHAPTER 2 • Hematopoietic System Bone Marrow
Most of them are parasites of a variety of domestic and wild somes, and as a product of direct injury from parasite-derived
animals, in some of which they produce fulminating disease, neuraminidases, such as trans-sialidases. There may be competi-
in some chronic disease, and in others mild or unapparent tion among precursor cells for erythroid and granulocytic differ-
infections. Strains within a species of the parasite also differ entiation, which may explain the clinical finding that animals
greatly in virulence, some strains producing rapidly fatal infec- with severe anemia are more susceptible to secondary infection
tions, some producing chronic infections with premunition, by bacteria and viruses. A dilutional component to the anemia
and some allowing complete recovery and acquired immunity. has been suggested, but no increase in blood volume has been
Much of the knowledge of trypanosomiasis has been gained detected. Calves infected during the first week of life have less
by studies of T. brucei, which conveniently infects dogs, rabbits, severe hematologic disease than calves infected at 6 months
rats, and mice, and poses little problem of dissemination in or older. Some of these animals become cachectic and die,
developed countries, where it has served as a research model. although it appears that infection at an early age results in a
In terms of the overall problem, T. brucei is not nearly as more tolerant host-parasite relationship that is less injurious
important as T. vivax and T. congolense and the pathogenic to the host. T. vivax and T. congolense differ in that T. vivax
trypanosomes of humans. Of the latter organisms, only T. tends to circulate relatively freely and uniformly in the vascu-
congolense is studied with any frequency outside their natural lar system, and, in this respect, the level of parasitemia gives
habitats because the other trypanosomes are thought to con- a reasonable estimate of the total parasitic burden. In contrast,
stitute too great a hazard of dissemination, even under condi- T. congolense “homes” to the microvasculature of the brain and
tions of laboratory restraint. Most of the research on T. vivax skeletal muscle, and the paucity of organisms in the peripheral
and T. congolense has been directed at defining the disease in blood makes diagnosis and estimates of total burden difficult.
British breeds of cattle. Efforts are now being made to under- It appears that the tissue tropism of T. congolense is a response
stand the host-parasite relationship in indigenous species of to developing immunity and is antibody mediated. It is not
animals, such as the Thomson’s gazelle, wildebeest, Cape known why brain and muscle are selectively parasitized, but
buffalo, and eland, which are heavily exposed and apparently the phenomenon may be related to trypanosomal energy
carry the organisms, but rarely, if ever, have clinical disease. requirements, because the endothelial cells in these areas tend
The components of pathogenicity of trypanosomes are largely to have more mitochondria than in other tissues.
unknown. Their effects vary with their tissue tropism. The Trypanosoma vivax is more virulent than T. congolense.
edema and interstitial reactions caused by T. brucei are the Whereas both cause anemia and cachexia, infection with T.
result of the fact that this parasite resides in perivascular congolense regularly results in chronic disease, and in a high
tissues, in contrast to the more serious pathogens of humans percentage of animals infected with T. vivax, there is sudden
and animals, which are obligate intravascular parasites. In death from salmonellosis or other infections. Infected animals
many respects, bovine trypanosomiasis is similar clinically and are moderately stunted in growth, although this effect is less
pathogenetically to equine infectious anemia in that infection apparent on body weight than on dressed weight (the part of
is followed by an asymptomatic period until antibody devel- the carcass that is edible). This disparity is the result of the
ops. There is then anemia and generalized compensatory fact that infected animals pool fluid in the intestinal tract and
hyperplasia of the mononuclear phagocyte system, which ulti- become pot-bellied while failing to deposit muscle and fat.
mately results in cachexia and hematopoietic and lymphoid When viewed from behind, infected animals have poorly
exhaustion. covered bony prominences, poor “spring of rib,” and a deep
Bovine trypanosomiasis. In cattle, parasitemia occurs a and pendulous abdomen. The skin is scurfy and rough, par-
week after inoculation with 105 or more organisms that have ticularly about the head, ears, and hindquarters. There is
been passed in rats and column separated (see Fig. 2-11). By chronic low-grade pyrexia with intermittent temperature
the second week of infection, there is a sharp drop in the red increases, and periodic watery diarrhea with passage of poorly
cell count and hemoglobin levels, accompanied by an ery- digested ingesta of normal color. There is irregular oculonasal
throid shift and macrocytosis, anemia being the predominant discharge, but no loss of appetite, and the animals continue to
aspect of the disease. There is concurrent thrombocytopenia of eat. There is mild mucosal pallor without petechial hemor-
moderate degree and hypocomplementemia. Fibrinogen is rhages, and the urine may be dark but never blood tinged. The
reduced to about half of normal levels, and there is irregular heart and respiratory rates are not remarkably altered under
appearance of fibrin degradation products as animals go laboratory conditions but are increased in nonspecific response
through febrile periods. Kinetically, the erythrocyte life-span to anemia under field conditions, and animals may show open-
is reduced to a half or less of normal, and iron utilization is mouth breathing on forced exercise. In the absence of second-
initially rapidly increased, but slows down with cachexia and ary infection, there is little or no depression or abnormal
inhibition of the erythroid response because of inflammatory behavior despite high levels of cerebral parasitism.
changes. The platelet life-span is not shortened in infections Anemia is of moderate degree, with hemoglobin generally
with T. congolense, although it may be with T. vivax. In the between 50 and 80 g/L, is initially macrocytic and normo-
former, the truncation appears to result from proliferation of chromic, and later becomes normochromic, normocytic, and
marrow megakaryocytes that are impaired in their maturation poorly responsive. In the well-developed disease, there are
and produce fewer platelets that survive normally, thus con- always some hypochromic red cells and at least mild poikilo-
stituting an ineffective response. The disease tends to stabilize cytosis. In the early stages of infection, the radio-iron uptake
at ~4-6 weeks in well-fed animals under laboratory conditions, time is reduced from a normal of ~3 hours to about half that
and to proceed to death from secondary causes in animals that figure but in chronic disease is only mildly reduced. There is
are forced to forage for feed as well as maintain their immune increased osmotic fragility of red cells without spherocytosis.
defenses. The platelets are 100-200 × 109/L and are often lower during
Red cells are destroyed by erythrophagocytosis as a result intercurrent infection. The leukocyte count is reduced to
of adsorbing toxic and metabolic products of the trypano- about half of normal (5-6 × 109/L) as a result of an absolute
Bone Marrow 123
reduction in both neutrophils and lymphocytes. Changes are level, and the nuclei are increased in diameter, but the cyto-
less severe in neonatally infected animals. Biochemical changes plasmic volume is reduced, indicating ineffective thrombopoi-
consist of a reduction in total protein, largely because of esis. There is a mild generalized increase in endothelial and
reduced albumin, but there are no consistent changes in trans- true reticular cells in bone marrow, but myelofibrosis is not
aminases or bilirubin. There is a consistent reduction in total severe. Trypanosomes may be found free and phagocytosed in
serum lipids, cholesterol, and triglyceride, and erythrocyte small vessels throughout the body, but are most commonly
phospholipid levels are consistently elevated, which may indi- observed in the liver and cerebral cortex. Hepatic changes
cate that there is an acquired injury to red cell membranes are constant, and consist of atrophy of hepatocellular cords
that contributes to shortened life-span. Aspirated marrow is with sinusoidal dilation and periportal lymphoplasmacytic
hypercellular with an erythroid shift that drops the proliferation. There is increased interstitial stroma, without
granulocytic:erythrocytic ratio to 0.4 or lower in animals change in lobular organization, and generalized Kupffer cell
infected with T. congolense. There is a less marked erythroid hyperplasia.
response in T. vivax infection. Changes in the lymphoid tissue are remarkable and constant
There are no pathognomonic gross lesions of trypanosomiasis. in all areas of the body. There is first follicular hyperplasia, with
Chronically affected animals are cachectic and have a rough a competent response and the formation of large and densely
haircoat, and there is increased clear fluid in body cavities. cellular germinal centers. These changes are accompanied by
There is generalized lymph node enlargement to 2-4 times variable paracortical hyperplasia, and the paracortex has a
normal, and the hemal nodes become prominent in subcuta- moth-eaten appearance because of the many large lympho-
neous areas and in association with the para-aortic and pelvic blasts and tingible body macrophages. At this time, the lymph
nodes, where they may reach 1 cm in diameter or larger. The nodes are physically enlarged, and there is thinning of the
lungs are heavy and have increased density on palpation, and capsules with focal colonization of perinodal fat and a histo-
may show intercurrent cranioventral bronchopneumonia. The logically compressed peripheral sinus. In chronic disease, the
heart is generally flabby, with serous atrophy of pericardial fat, nodes remain enlarged, but this is due, at least in part, to a
and there may be white foci 1-2 mm in diameter on the epi- marked increase in capsular and intranodal stroma with
cardium and on the cut surface. The liver and kidneys are numerous collagenous septa extending from the medulla to
symmetrically enlarged and constitute a greater than normal the capsule. The medullary follicles remain, but their cellular-
percentage of body weight. The liver is unusually firm and not ity is reduced, and there is marked atrophy of paracortical
easily penetrated by digital pressure, and there is a fine lobular areas. Concurrently, there is sinus histiocytosis and at least
pattern visible through the capsule and on cut surface. Renal some degree of hemosiderosis without medullary cord hyper-
medullary fat has serous atrophy. There are fine focal, raised, plasia. The changes are thus those of continuing stimulation with
reddened areas 1-2 mm in diameter throughout both layers an initial competent response followed by hyperplasia, then
of the omentum. The enteric tract is unremarkable, except atrophy and sclerosis.
that the small intestine is atonic and contains an excessive Concurrent with the changes in lymph nodes, there is
amount of normal-appearing fluid content. The most remark- remarkable atrophy of the thymus, with the reduction most
able changes occur in lymph nodes, which have generalized prominently affecting cortical regions. With the loss of cortical
medullary pigmentation, and in bone marrow, where there is volume, there is a reduction in cell density and an increase in
a regular increase in hematopoietic areas, which may occupy size of nuclei in cortical thymocytes. The splenic lymphoid
all of the cancellous and diaphyseal fatty areas in animals that changes reflect those in other areas of the body, with atrophy
have been infected 6 months or more. The spleen is uniformly of periarteriolar cuffs and the formation of large hypocellular
enlarged and bulges, but does not ooze blood, on cut surface. follicles, occasionally with “target” ringing of mantle cell and
The Malpighian corpuscles are generally visible grossly. marginal zone layers. The number of follicles is not increased.
Microscopically, there is a generalized increase in septal The most marked splenic change is sinus hyperplasia charac-
width in the lungs and accumulation of intravascular terized by a marked increase in fixed cells in the Billroth cord
hemosiderin-bearing macrophages. There are multifocal areas (splenic cord, red pulp cord) areas, which contain within their
of fiber atrophy with sclerosis and lymphoplasmacytic prolif- interstices many macrophages and plasma cells, with increased
eration in the myocardium, most prominently in those animals hemosiderin and an irregular appearance of extramedullary
that have succumbed to the disease. The bone marrow goes thrombopoiesis and erythropoiesis. Renal changes consist of a
through a cycle of changes similar to those in equine infec- moderate generalized increase in interstitial connective tissue
tious anemia. There is early conversion of fatty to hematopoi- with mild epithelial atrophy and the appearance of large lym-
etic marrow with high cell density, erythroid shift, and phoid cuffs around arterioles at the corticomedullary junction.
plasmacytosis, followed by a reduction in cellular packing and Glomeruli are regularly increased in diameter and in cellular-
dilation of sinusoids, and ultimately by reduction in hemato- ity and occasionally contain hemosiderin-laden macrophages.
poiesis and serous atrophy of the remaining tissue. The rubri- There are focal adhesions between the visceral and parietal
cytes are increased in number and are relatively synchronous layers of Bowman’s capsule, and a mild epithelioid appearance
in maturation with numerous mature cells, suggesting late to the central areas of the tuft. The nuclei of the juxtaglo-
asynchrony associated with poor availability of iron. There is merular cells are unusually prominent, and there is mild pig-
a variable degree of hemosiderosis, depending on the duration mentation by both iron and bilirubin in the proximal
of the disease, and erythrophagocytosis may be observed in epithelium. The overall changes in glomeruli are compatible
the marrow. Marrow granulocyte reserves are reduced, and, as with membranoproliferative glomerulonephritis.
a result, there is mild early asynchrony, although it is likely Subtle changes are consistently present in skeletal muscu-
that with the expanded volume of hematopoietic marrow lature and consist of an overall hypercellularity with a mild
there is a normal volume of granulopoietic tissue. Megakaryo- reduction in fiber diameter and increased perivascular lym-
cytes are increased in number to about twice the normal phocytes. The reddened foci in the omentum consist of focal
124 CHAPTER 2 • Hematopoietic System Bone Marrow
venous ectasia with mild interstitial sclerosis and perivascular form, the disease is characterized by invasion of mesodermal
lymphoplasmacytic reaction. tissues, and the growth therein of the leishmanial forms of the
Trypanosomiasis in other species. Trypanosoma brucei organism, which show a preference for cardiac and skeletal
rhodesiense and T. b. gambiense are human pathogens causing muscle. It has been suggested that, because the cysts are focal
African sleeping sickness and are not important in domestic and the interstitial reaction may be widespread and diffuse,
animals, although T. gambiense has produced meningoenceph- there may be an autoimmune component to the myocarditis
alitis in experimental goats and cats. These trypanosomes are associated with release of fiber proteins associated with para-
morphologically indistinguishable from each other and from sitic injury.
T. brucei, from which they are presumed to have evolved.
Trypanosoma brucei brucei is a cause of nagana in most
domestic species in Africa; humans are refractory to infec Further reading
tion. Transmission is by Glossina spp. or mechanical. Equids, Guegan F, et al. Erythrophagocytosis of desialylated red blood cells is
small ruminants, camels, and dogs are very susceptible; the responsible for anaemia during Trypanosoma vivax infection. Cell
disease is more chronic in cattle; and pigs may recover. Inco- Microbiol 2013;15:1285-1303.
ordination and spinal paralysis are reported in horses and dogs. Omotainse SO, Anosa VO. Comparative histopathology of the lymph
Dogs may also develop parasitism and inflammation of the nodes, spleen, liver and kidney in experimental ovine trypanosomo-
anterior segments of the eye. The neurologic signs are undoubt- sis. Onderstepoort J Vet Res 2009;76:377-383.
edly the result of invasion of cerebrospinal fluid and to inflam- Van den Bossche P, et al. A changing environment and the epidemiol-
mation of meninges, brain, and cord. Diagnosis depends on ogy of tsetse-transmitted livestock trypanosomiasis. Trends Parasitol
demonstration of the organism in blood in acute or relapsing 2010;26:236-243.
febrile cases, or otherwise in lymph nodes by direct smear,
inoculation into the very susceptible laboratory mouse, or
cultivation. Hemotropic mycoplasmas. Hemotropic mycoplasmas, also
Trypanosoma evansi was originally shown to be the cause called hemoplasmas, are cell wall–less unculturable bacteria
of surra in horses and camels, but it is pathogenic for most that attach to erythrocyte membranes and cause variably
domestic species and distributed in North Africa, Asia, and severe anemia. The organisms were previously known as
Central and South America. Transmission is mechanical, Eperythrozoon or Haemobartonella spp., but based on nucleic
chiefly by Tabanidae, but also by other blood-sucking flies, and acid sequences, they are most similar to Mycoplasma, and
apparently by vampire bats in the Americas. The disease in have all been renamed as such. All hemotropic mycoplasmas
horses and dogs is severe, and probably uniformly fatal in the are considered to be vector transmitted, although the specific
absence of adequate treatment. Cattle are mildly affected and vector has been identified in only a few cases. Based on
act as reservoirs, although acute disease may occur in suscep- sequence analysis, multiple mycoplasmal agents are identified
tible cattle introduced to endemic areas. in blood in most species, but association with disease is infre-
Trypanosoma equinum occurs in South America as the quent. Mycoplasmas are at or below the limit of resolution of
cause of mal de caderas of horses, a disease that resembles light microscopy, and identification of organisms on blood
surra. The parasite is transmitted mechanically by tabanids. It films is an insensitive method of diagnosis (Fig. 2-12).
is probably a stable variant of T. evansi. In cats, there are currently 3 hemoplasmas: M. haemofelis,
Trypanosoma suis is a West African species transmitted M. turicensis, and M. haemominutum. Only M. haemofelis is
by tsetse flies. It produces a nagana-like disease in pigs but is consistently associated with anemia, and can be identified by
apparently nonpathogenic for other domestic animals. light microscopy as rings or short chains of perimembranous
Trypanosoma simiae was originally isolated from African organisms. M. turicensis and M. haemominutum are only identi-
monkeys. Although its pathogenicity for pigs is unpredictable, fied by PCR. Cats that survive acute infection with M. hae-
it is ordinarily highly virulent and causes death in a few days. mofelis mount an immune response coincident with increase
Pathogenicity for other domestic species is insignificant. Trans- in hematocrit and disappearance of organisms from blood
mission is cyclical in tsetse flies. Trypanosomes of the species smears. It is unclear whether cats subsequently clear infection
T. congolense, T. dimorphon, T. vivax, and T. uniforme are causes or become subclinical carriers. Dogs are also host to multiple
of nagana in Africa. Most domestic species are susceptible to hemoplasmas, but only M. haemocanis has been associated
infection, although dogs are resistant to T. vivax. There is with anemia, and only in splenectomized or immunosup-
considerable variation in the pathogenicity of different strains, pressed dogs. Cattle are host to M. wenyonii and M. hemobos.
especially of T. congolense. M. wenyonii has been associated with anemia, edema, lymph-
Trypanosoma cruzi is the cause of American trypanoso- adenopathy, and fever in dairy cattle. The pathogenicity of M.
miasis (Chagas disease), which is an uncommon illness of hemobos is unclear. Similarly, infection of sheep with M. ovis
children, although infection of human adults and animals is only rarely causes hemolytic anemia. M. haemolamae is preva-
apparently common. The reservoir hosts are chiefly wild lent in llamas and alpacas, and acute infection or infection in
species, but cats, dogs, and pigs can be infected and act as crias or stressed adults may cause anemia with a large number
reservoirs. Sheep and goats are susceptible to experimental of erythrocyte organisms (see Fig. 2-12).
infections. This trypanosome is of zoologic interest because, Acute infection with M. suis in young pigs results in illness
both in the tissues of the vertebrate host and in the alimentary characterized by fever, hemolytic anemia, and hypoglycemia.
canal of the vector, it forms developmental phases resembling Older pigs may be infected, but clinical disease is usually
the other genera Leptomonas, Crithidia, and Leishmania of the not apparent. As for other erythrocytic infectious agents, M.
family Trypanosomatidae. suis-induced anemia is multifactorial, and physical damage
Whereas some of the manifestations of T. cruzi infection leading to premature splenic removal, induction of immune
may be attributable to parasitemia with the trypanosomal responses to erythrocyte and parasite components, eryptosis,
124.e1
Further reading
Anosa VO, et al. The haematology of Trypanosoma congolense infec-
tion in cattle. I. Sequential cytomorphological changes in the blood
and bone marrow of Boran cattle. Comp Haematol Int
1997;7:14-22.
Batista JS, et al. Highly debilitating natural Trypanosoma vivax infec-
tions in Brazilian calves: epidemiology, pathology, and probable
transplacental transmission. Parasitol Res 2012;110:73-80.
Forsberg CM, et al. The pathogenesis of Trypanosoma congolense
infection in calves. IV. The kinetics of blood coagulation. Vet Pathol
1979;16:229-242.
Gutierrez C, et al. Trypanosomosis in goats. Ann N Y Acad Sci
2006;1081:300-310.
Magona JW, et al. A comparative study on the clinical, parasitological
and molecular diagnosis of bovine trypanosomosis in Uganda.
Onderstepoort J Vet Res 2003;70:213-218.
Bone Marrow 125
A A
10 m
B B
Figure 2-12 A. Mycoplasma haemofelis are minuscule epicel- Figure 2-13 Rangelia vitalii cytoplasmic zoites in bone marrow
lular erythrocyte bacteria associated with regenerative anemia. cell (A) and in an endothelial cell (B) from a dog. (Courtesy
B. M. haemolamae can cause massive parasitemia in young or A.P. Loretti.)
debilitated camelids.
and endothelial activation from attachment of infected cells Sykes JE. Feline hemotropic mycoplasmas. Vet Clin North Am Small
all likely contribute to disease. Anim Pract 2010;40:1157-1170.
Rangelia vitalii is a tick-transmitted piroplasmic proto-
zoon that infects endothelial cells and hematopoietic cells of
dogs in South America. Infection is frequently fatal in domes- Mechanical, physical, and chemical causes of hemolytic
tic dogs, and the most prominent clinical feature is bleeding anemia. Hemolytic anemia from mechanical trauma is caused
from pinnae. An unusual feature of R. vitalii infection is pre- by physical damage to erythrocytes in vessels where turbulent
dominant targeting of endothelial rather than hematopoietic blood flow and pressure gradients exert shear forces. This
cells. As a result, organisms are present in low number or may be observed in animals with disseminated intravascular
transiently in erythrocytes or leukocytes, although infected coagulation (DIC), vasculitis, endocarditis, endocardiosis,
dogs have immunohemolytic anemia with splenomegaly and hemangiosarcoma, and burn wounds. DIC is characterized
jaundice. Thrombocytopenia is variable, and not considered by microangiopathy with luminal narrowing from fibrin
to be the primary cause of bleeding. Organisms are most strands and platelet aggregates, which generates fragmented
readily identified in capillaries of lymph node and other tissues erythrocytes (schistocytes) that are removed prematurely by
(Fig. 2-13). splenic macrophages. Anemia caused by mechanical trauma is
generally only mild, and jaundice is absent or mild. Both
intravascular and extravascular hemolysis induce erythropoi-
Further reading etic stress.
França RT, et al. Canine rangeliosis due to Rangelia vitalii: from first Many substances have the ability to cause oxidative injury.
report in Brazil in 1910 to current day—a review. Ticks Tick Borne Hemoglobin, normally maintained in a reduced state by eryth-
Dis 2014;5:466-474. rocyte enzymes, is an abundant target for substances with
Hoelzle LE, et al. Pathobiology of Mycoplasma suis. Vet J 2014; oxidative potential. Oxidized hemoglobin undergoes confor-
202:20-25. mational change and forms membrane-bound precipitates
125.e1
Further reading
dos Santos AP, et al. Complete genome sequence of Mycoplasma
wenyonii strain Massachusetts. J Bacteriol 2012;194:5458-5459.
126 CHAPTER 2 • Hematopoietic System Bone Marrow
Further reading
Auza NJ, et al. Diagnosis and treatment of copper toxicosis in rumi-
nants. J Am Vet Med Assoc 1999;214:1624-1628.
Harvey JH. Pathogenesis, laboratory diagnosis, and clinical implications
of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet
Clin Pathol 2006;35:144-156.
Bone Marrow 127
A B
C D
Figure 2-16 Bone marrow biopsy sections from an older dog with aplastic anemia. A, B. The bone
marrow is profoundly hypocellular, sinusoids are prominent, and there are lymphocytes and plasma
cells. C. CD3-positive lymphocytes around blood vessels. D. Occasional CD79a-positive B
lymphocytes.
with known potential to cause hematopoietic precursor cell tion. Physiologic erythrocytosis results from hypoxic stimula-
injury are chloramphenicol, phenylbutazone, trimethoprim- tion of erythropoietin production in animals with chronic
sulfamethoxazole, and cephalosporins. Prolonged high estro- cardiac or pulmonary disease. Paraneoplastic erythrocytosis is
gen concentration, either from endogenous production by the result of ectopic production of erythropoietin by malig-
Sertoli cell tumors in dogs, granulosa cell tumors in horses and nant tumors, most often carcinomas. Lymphoid tumors, and
other species, adrenal tumors in ferrets, or from exogenous specifically renal lymphoma in dogs, have also been shown to
administration, may cause precursor cell injury and bone produce erythropoietin and induce erythrocytosis.
marrow hypoplasia or aplasia. Bracken fern (Pteridium aquili-
num) ingestion causes hematuria (enzootic bovine hematuria)
and bone marrow suppression in ruminants caused by ptaqui- Further reading
loside toxin. Antiproliferative therapy with chemotherapeutic Fyfe JC, et al. Selective intestinal cobalamin malabsorption with pro-
agents or irradiation also affects bone marrow. Neutropenia is teinuria (Imerslund-Gräsbeck syndrome) in juvenile Beagles. J Vet
the main manifestation of toxicity, and to a lesser degree Intern Med 2014;28:356-362.
thrombocytopenia, reflecting their 8-hour and 10-day life- Weiss DJ. Bone marrow pathology in dogs and cats with non-
spans, respectively. Overall, hematopoietic stem cells are regenerative immune-mediated haemolytic anaemia and pure red
thought to be highly resistant to fatal injury, and with suffi- cell aplasia. J Comp Pathol 2008;138:46-53.
cient time, protection from opportunistic infections and cell
replacement through transfusion, there can be recovery of
normal hematopoiesis in many instances. Disorders of platelets
Erythrocytosis is most often the result of dehydration, and Platelets are produced as cytoplasmic fragments of bone
may be very severe in animals with extreme external loss of marrow megakaryocytes and function in primary hemostasis,
free water or internal water sequestration. Neonatal bovine inflammation, and repair (see also later section, Disorders of
diarrhea, parvoviral enteritis, and equine salmonellosis are hemostasis). Platelet number on the complete blood count
conditions typically associated with severe hemoconcentra- (CBC) is the most widely used indicator of adequate platelets,
128.e1
Further reading
Aroch I, et al. Peripheral nucleated red blood cells as a prognostic
indicator in heatstroke in dogs. J Vet Intern Med 2009;23:
544-551.
Chalhoub S, et al. Anemia of renal disease: what it is, what to do and
what’s new. J Fel Med Surg 2011;13:629-640.
Cortinovis C, Caloni F. Epidemiology of intoxication of domestic animals
by plants in Europe. Vet J 2013;197:163-168.
Dandrieux JR, et al. Canine breed predispositions for marked hypoco-
balaminaemia or decreased folate concentration assessed by a labo-
ratory survey. J Comp Pathol 2013;54:143-148.
Durno AS, et al. Polycythemia and inappropriate erythropoietin con-
centrations in two dogs with renal T-cell lymphoma. J Am Anim
Hosp Assoc 2011;47:122-128.
Seguro AC, Andrade L. Pathophysiology of leptospirosis. Shock
2013;39:17-23.
Shmukler BE, et al. Cation-leak stomatocytosis in Standard Schnauzers
does not cosegregate with coding mutations in the RhAG, SLC4A1,
or GLUT1 genes associated with human disease. Blood Cells Mol
Dis 2012;48:219-225.
Waldner CL, Blakley B. Evaluating micronutrient concentrations in liver
samples from abortions, stillbirths, and neonatal and postnatal
losses in beef calves. J Vet Diagn Invest 2014;26:376-389.
Bone Marrow 129
but as for erythrocytes, platelet volume is variable in health, platelet number does not consistently correlate with increased
higher in recently released platelets, and lower in iron defi- plateletcrit, and clinical associations of thrombocytosis have
ciency and immune-mediated destruction. Therefore platelet- not clearly been identified.
crit (analogous to hematocrit) is actually a more meaningful
indicator of total platelet mass, and its use will become more
widespread because modern automated hematology analyzers Further reading
determine plateletcrit, platelet number, and platelet volume. Fielding CL, et al. Rattlesnake envenomation in horses: 58 cases (1992-
Thrombocytopenia results from increased consumption, pre- 2009). J Am Vet Med Assoc 2011;238:631-635.
mature destruction, or decreased production. Increased con- Schwartz D, et al. Platelet volume and plateletcrit in dogs with pre-
sumption occurs in conditions such as hemorrhage, enteritis, sumed primary immune-mediated thrombocytopenia. J Vet Intern
anticoagulant toxicity, pancreatitis, necrosis, endotoxemia, Med 2014;28:1575-1579.
envenomation, and vasculitis, and usually causes mild throm-
bocytopenia. Many hemotropic infectious agents can infect all
blood cells, including platelets; Anaplasma platys specifically Hematopoietic neoplasia
targets platelets. Bovine viral diarrhea virus (BVDV) has Integration of cellular, genetic, molecular, and immunologic
tropism for megakaryocytes, and either direct toxicity or features of primary hematopoietic neoplasms with prognosis
immune-mediated injury render thrombocytopenia a common over the past decade has established 3 main categories in
feature of BVDV infection. FeLV infection of megakaryocytes people: acute myeloid leukemia (AML), myeloproliferative neo-
may also cause thrombocytopenia. plasm (MPN, formerly called “chronic leukemia”), and myelo-
Immune-mediated thrombocytopenia (IMT) is a relatively dysplastic syndrome (MDS). Despite limited knowledge about
common primary autoimmune disease in dogs. The pathogen- genetic and molecular features, most myeloid neoplasms in
esis involves premature removal of antibody-coated platelets animals can be grouped into one of these broad categories,
by splenic macrophages. The nature of antigens targeted by based on careful morphologic and immunochemical charac-
antibodies is poorly characterized. Platelet concentration and terization (Table 2-3).
plateletcrit in IMT are usually very low, and megakaryocytes Acute myeloid leukemia. Animals with AML are usually
in bone marrow sections are markedly increased. Concurrent acutely but nonspecifically ill and have profound cytopenia in
immune destruction of erythrocytes and platelets (Evans syn- one or several cell lines. Undifferentiated blast cells may be
drome) also occurs in dogs. IMT in cats is also most commonly absent in peripheral blood or may comprise a massive leuko-
of an autoimmune nature, and often part of a generalized cytosis. By definition, either bone marrow or blood, or both,
antihematopoietic cell immune response, leading to multiple contain >20% blast cells for a diagnosis of AML. Blast cells are
cytopenias. Treatment with immune suppression appears to large cells with round to oval nuclei, 1 or 2 nucleoli, and
be more effective in dogs than cats. IMT in horses is more basophilic cytoplasm. Blast cells lack differentiated features
commonly associated with the use of drugs such as penicillin, such as granules that would allow classification into lineage.
cephalosporins, and sulfonamides, which are presumed to act Identification and enumeration of blast cells is best accom-
as a hapten for induction of antiplatelet antibody responses. plished on cytology; determining the extent of myelophthisis
Decreased platelet production is most often the result of and presence of myelofibrosis or myelonecrosis requires
myeloproliferative or infiltrative bone marrow diseases, such histopathology. Thus accurate diagnosis and classification of
as leukemia or myeloma. Regeneration of platelets can be AML requires, at minimum, a CBC, bone marrow cytology,
monitored in a similar manner as for erythrocytes by detecting and histopathology. Bone marrow films should be differen-
increased mean platelet volume (MPV). tially counted (500 nucleated cells) to determine the propor-
Thrombocytosis is a frequent finding in dogs with a variety tion of blast cells, the proportion of differentiated granulocytic
of illnesses, including inflammation and cancer. Increased and erythrocytic cells, and the granulocytic:erythrocytic (G : E)
Table • 2-3
Categories of myeloid neoplasms
Category Definition Subcategory
Acute myeloid leukemia Cytopenia and ≥20% blast According to cell morphology and/or immunophenotypic
(AML) cells in blood or bone features of cells: acute undifferentiated leukemia (AUL);
marrow AML with neutrophilic differentiation; AML with
granulomonocytic differentiation; AML with
megakaryoblastic differentiation; etc.
Myeloproliferative neoplasms Cytosis of mature appearing According to cell morphology: polycythemia vera (PV); essential
(MPN, old term = chronic cells in blood, hypercellular thrombocythemia (ET); chronic neutrophilic leukemia (CNL);
leukemia) bone marrow, <5% blasts chronic monocytic leukemia (CMoL); mastocytosis; etc.
Myelodysplastic syndrome Nonregenerative cytopenia, According to most pronounced cytopenia, termed: refractory
(MDS) dysplasia, 5-20% bone anemia with excess blasts (RAEB); refractory neutropenia
marrow blast cells, with excess blasts (RNEB); refractory thrombocytopenia with
+/− myelofibrosis excess blasts (RTEB)
129.e1
Further reading
O’Marra SK, et al. Treatment and predictors of outcome in dogs with
immune-mediated thrombocytopenia. J Am Vet Med Assoc 2011;
238:346-352.
130 CHAPTER 2 • Hematopoietic System Bone Marrow
ratio. Concurrent assessment of CBC and bone marrow cytol- tions identified in the oncogenes RAS, FLT3, and C-KIT, trans-
ogy is essential for interpreting bone marrow histopathology, location of BCR to ABL, copy number changes in PTEN and
and at times serial CBCs and repeated bone marrow biopsies BRCA1, and large deletions. Clonality in AML and other
are required to arrive at a definitive diagnosis. Recovery from hemolymphatic tumors has been identified in dog tissues with
hematopoietic stem cell injury, parvovirus, and acute feline a PCR assay targeting polymorphic regions of the androgen
immunodeficiency virus (FIV) infection can cause transient receptor gene located on the X chromosome. Usefulness of
cytopenia and excess bone marrow blast cells, which needs to this assay is currently limited because ~50% of female dogs
be distinguished from AML by repeated CBCs. normally lack heterozygosity at this gene locus.
AML is a highly heterogeneous cancer. In some cases, the Practically, once a diagnosis of AML has been derived by
entire bone marrow consists of blast cells, and animals have the above criteria, the cancer should be subcategorized based
severe cytopenia; in other cases, blast cells encompass only on morphology (Figs. 2-19, 2-20; see Table 2-3). In cases of
20-30% of bone marrow cells, with partial differentiation into acute undifferentiated leukemia, flow cytometric analysis of
granulocytes or rubricytes (Figs. 2-17, 2-18). There usually is fresh aspirated bone marrow cells may be useful to rule out
lack or severe decrease in rubricytes, granulocytes, or mega- lymphoid cell type, and to classify blast cells as monocytic
karyocytes. Although animals are presented with acute illness, (CD11c/CD14/major histocompatibility complex II [MHC
retrospectively, cytopenia has often existed for weeks or II]), granulomonocytic (CD4/CD11b/CD11c), or megakaryo-
months before diagnosis of AML. Bone marrow cellularity in cytic (CD9/CD41/CD61). Detection of CD34 is consistent
AML is also highly variable and can range from 10-100%. with acute leukemia, but does not differentiate between acute
Investigations in people have shown that the molecular lesions myeloid or acute lymphoid leukemia. Specialized laboratories
in AML are heterogeneous and mirror the variable clinical and performing flow cytometry generally apply a panel of 10-20
morphologic features of this cancer. Some understanding of antibodies and derive interpretation about blast cells from
the molecular basis of AML in dogs is emerging with muta- detecting presence or absence of a combination of antigens.
A B
C D
Figure 2-17 Acute myeloid leukemia with neutrophilic differentiation in a dog. A. The blood
smear shows anemia, neutropenia, thrombocytopenia, and numerous blast cells. B. Bone marrow
aspirate has lack of rubricytes and segmented neutrophils, and increased immature granulocytes.
C, D. There were green masses throughout the mesentery and in kidney. (Courtesy R. Fraser.)
Bone Marrow 131
E F
Figure 2-17, cont’d E, F. Bone marrow sections have a predominance of blast cells with single
or multiple nucleoli, and reduced metamyelocytes and band neutrophils.
A B
C D
Figure 2-18 Samples from a dog with acute myeloid leukemia with rubricytic differentiation.
A. Bone marrow aspirate is devoid of granulocytes; blast cells are sparse in this field. B. The pro-
portion of blast cells is >20%, there is differentiation to rubricytes, granulocytes are rare. C. The
spleen is enlarged, mottled, and firm. D. There are clusters of rubricytes in many tissues; shown
here is a pulmonary arteriole.
132 CHAPTER 2 • Hematopoietic System Bone Marrow
A A
B B
Figure 2-19 Acute myeloid leukemia with neutrophilic differen- Figure 2-20 Undifferentiated acute myeloid leukemia, in a dog.
tiation, in a dog. A, B. Blast cells comprised 25%, but differentia- A, B. Blast cells comprise >80% of cells, and mitotic figures are
tion to band and segmented neutrophils is apparent. frequent. At low power, individual rubricytes and granulocytes are
apparent, but megakaryocytes are absent.
IHC is useful to differentiate acute T-lymphocyte (CD3 posi- cancer, response to therapy and prognosis are also very vari-
tive) or B-lymphocyte (CD79a or CD20 positive) leukemia able. Although many cases of AML have life-threatening
from AML, but few additional antibodies specific for leuko- thrombocytopenia or neutropenia at diagnosis, and the animal
cyte antigens are reactive with formalin-fixed tissue. Antibody dies within days despite therapy, survival in dogs of a year and
to canine CD18 reactive with formalin-fixed tissue labels all longer has also been reported. Organomegaly caused by leu-
leukocytes, but granulocytic and monocytic cells stain more kemic infiltrates is usually subtle, and in decreasing order of
intensely than lymphocytes. Some antibodies to canine MHC frequency involves spleen, liver, lymph nodes, and any other
II are also reactive with formalin-fixed tissue, and label mono- tissue. Several subcategories of AML have been reported in
cytic cells and macrophages (Fig. 2-21). Infidelity in antigen horses, and clinical presentation usually consisted of hemor-
expression on neoplastic leukocytes is relatively common in rhage and thrombocytopenia.
human leukemia, and has also been described for leukemic Acute lymphoid leukemia (ALL) arises from large precur-
cells of dogs. Hence interpretation of antigen expression sor lymphocytes in bone marrow. Morphologically, lympho-
should always be based on absence or presence of multiple blasts and myeloblasts are indistinguishable, but in most cases,
antigens, and not only a single antigen. ALL cells express markers such as CD3, CD4, CD5, CD8,
All subcategories of AML (see Table 2-3) have been CD20, CD21, or CD79a to indicate lymphoid origin. Dogs
reported in dogs and most other domestic animals. Granulo- with ALL are more likely to have severe neutropenia and
monocytic and megakaryoblastic AML appear to be more thrombocytopenia than dogs with AML. B-ALL is more com-
common than neutrophilic or other subcategories in dogs, monly reported than T-ALL in dogs, but it is unknown whether
whereas erythroblastic AML in association with FeLV infec- there are differences in natural history for either subcategory
tion was most common in cats. However, overall data on (Fig. 2-22). The mean age of dogs with ALL is higher (8.0
prevalence of well-characterized AML cases in animals are years) than that of dogs with AML (6.3 years). Canine mul-
sparse, and much remains to be learned about this cancer. As ticentric stage V leukemic lymphoma may be challenging to
might be expected for a morphologically heterogeneous distinguish from ALL with enlarged lymph nodes. Usually,
Bone Marrow 133
A A
B B
C C
Figure 2-21 Acute myeloid leukemia with monocytic differentia- Figure 2-22 B-lymphocyte acute myeloid leukemia, in a dog.
tion in a dog. A. Blood smear shows pancytopenia with occasional The dog had mild anemia and no morphologically abnormal cells
monocytes. B. Bone marrow section has predominance of large on the blood smear. A. Bone marrow aspirate shows a uniform
blast cells with a single nucleolus. C. Immunohistochemistry for population of hyperchromatic blast cells and many lysed cells
major histocompatibility complex II expression labels approxi- (arrowheads). B. Bone marrow section is >80% cellular, and mega-
mately half of the blast cells. karyocytes and hemosiderin are rare. C. Cells have indistinct
cytoplasm, uniformly round nuclei, and prominent central
nucleoli.
dogs with stage V lymphoma have greater tissue tumor burden in dogs and cats AML is slightly more commonly reported
than those with ALL, and lymph nodes are more massively than ALL. Infection of cats with certain strains of FeLV results
enlarged. Also, expression of CD34 on leukemic cells is very in relatively frequent AML, most commonly of erythroblastic
strongly suggestive of ALL rather than stage V lymphoma. In type (erythremic myelosis), but monoblastic AML and ALL
horses, ALL is more commonly reported than AML, whereas have also been described.
134 CHAPTER 2 • Hematopoietic System Bone Marrow
Further reading
Comazzi S, et al. Acute megakaryoblastic leukemia in dogs: a report
of three cases and review of the literature. J Am Anim Hosp Assoc
2010;46:327-335.
Comazzi S, et al. Immunophenotype predicts survival time in dogs with
chronic lymphocytic leukemia. J Vet Intern Med 2011;25:
100-106.
Juopperi TA, et al. Prognostic markers for myeloid neoplasms: a com-
parative review of the literature and goals for future investigation.
Vet Pathol 2011;48:182-197.
Novacco M, et al. Prognostic factors in canine acute leukaemias: a
retrospective study. Vet Comp Oncol 2015 Jan 26. [Epub ahead of
print].
Tan E, et al. Automated analysis of bone marrow aspirates from
dogs with haematological disorders. J Comp Pathol 2014;151:
A
67-79.
Usher SG, et al. RAS, FLT3, and C-KIT mutations in immunophenotyped
canine leukemias. Exp Hematol 2009;37:65-77.
Vernau W, Moore PF. An immunophenotypic study of canine leukemias
and preliminary assessment of clonality by polymerase chain reac-
tion. Vet Immunol Immunopathol 1999;69:145-164.
Willmann M, et al. Chemotherapy in canine acute megakaryoblastic
leukemia: a case report and review of the literature. In Vivo
2009;23:911-918.
Further reading
Adam F, et al. Clinical pathological and epidemiological assessment of
morphologically and immunologically confirmed canine leukaemia.
Vet Comp Oncol 2009;7:181-195.
Figueiredo JF, et al. Acute myeloblastic leukemia with associated
BCR-ABL translocation in a dog. Vet Clin Pathol 2012;41:
362-368.
Fischer C, et al. Erythroleukemia in a retrovirus-negative cat. J Am Vet
Med Assoc 2012;240:294-297.
Giantin M, et al. Evaluation of tyrosine-kinase receptor c-KIT (c-KIT)
mutations, mRNA and protein expression in canine leukemia: might
c-KIT represent a therapeutic target? Vet Immunol Immunopathol
2013;152:325-332.
Mochizuki H, et al. Demonstration of the cell clonality in canine hema-
topoietic tumors by X-chromosome inactivation pattern analysis.
Vet Pathol 2015;52:61-69.
Valentini F, et al. Use of CD9 and CD61 for the characterization of
AML-M7 by flow cytometry in a dog. Vet Comp Oncol
2011;10:312-318.
Wilkerson MJ, et al. Lineage differentiation of canine lymphoma/
leukemias and aberrant expression of CD molecules. Vet Immunol
Immunopathol 2005;106:179-196.
134.e2
Further reading
Cruz-Cardona JA, et al. BCR-ABL translocation in a dog with chronic
monocytic leukemia. Vet Clin Pathol 2011;40:40-47.
Perez M, et al. Partial cytogenetic response with toceranib and pred-
nisone treatment in a young dog with chronic monocytic leukemia.
Anticancer Drugs 2013;24:109-1103.
Bone Marrow 135
A A
B B
Figure 2-24 Myeloproliferative neoplasm, mastocytosis in a dog.
The dog had mild anemia and a low number of mast cells on
routine blood smear review. A. Bone marrow shows rubricytes,
granulocytes, megakaryocytes, and a moderate number of round
granular cells. B. Toluidine blue staining identifies numerous mast
cells.
Further reading
Perez-Alenza MD, et al. Clinico-pathological findings in cattle exposed
to chronic bracken fern toxicity. N Z Vet J 2006;54:185-192.
Weiss DJ, Aird B. Cytologic evaluation of primary and secondary myelo-
dysplastic syndromes in the dog. 2001;32:67-75.
Bone Marrow 137
a rare MPN in dogs and cats not associated with solid mast
cell tumors. Animals have gradually progressive myelophthisis
(see Fig. 2-24).
Multiple myeloma. Multiple myeloma (MM) is a malignant
tumor of plasma cells that occurs in older animals. In dogs and
horses, the tumor is most often located in the medullary cavity
of bones with active bone marrow, and frequently at multiple
sites. Animals with MM are usually presented with a history
of lameness or paresis secondary to spinal cord compression,
or the neoplasm may be suspected from the radiographic
evidence of multiple foci of bone lysis. Other clinical signs are
usually nonspecific and include lethargy, weakness, and
anorexia. Hypercalcemia may occur in the course of disease
as a result of bone lysis, and polyuria, polydipsia, and kidney
disease occur secondary to hypercalcemia and light-chain pro-
A teinuria. Bleeding diatheses, including epistaxis, gingival bleed-
ing, retinal hemorrhage, and, less frequently, melena or
hematuria, are common. In cats, malignant plasma cell tumors
are more often located at extramedullary sites, either in
abdominal organs or skin. In most MM, the neoplastic cells
secrete a clonal immunoglobulin (also called paraprotein or M
protein) that is detectable by serum electrophoresis as a mono-
clonal protein. Free light chains readily cross the glomerulus;
therefore, in many cases, urine protein electrophoresis is a
sensitive means of identifying clonal immunoglobulin light
chains (Bence Jones proteins) that may not accumulate in
serum.
Diagnostic criteria for MM in people are applicable to dogs,
and require presence of neoplastic cells in bone marrow plus either
serum or urine monoclonal proteins or osteolytic lesions. In cats,
diagnostic criteria for MM are presence of a plasma cell tumor,
either in abdominal organs or bone marrow, plus monoclonal
B proteins detected in serum or urine. Lytic bone lesions are
uncommon in cats. Cutaneous plasma cell tumors in cats may
also be associated with monoclonal gammopathy, and have a
better prognosis than those involving abdominal organs. The
diagnosis of MM is usually made by fine-needle aspiration or
bone marrow core biopsy from an area of bone lysis. Immu-
noglobulin G (IgG) followed by IgA gammopathies are most
common.
Nonsecretory MM has been reported, and differentiation
from plasmacytoid lymphoma is based on the location of
MM in the bone medullary cavity causing bone lysis. Cellular
features of MM are similar to those of plasma cells, and
can include binucleation or multinucleation and moderate
anisokaryosis and anisocytosis. Some infectious agents such
as Ehrlichia and Leishmania may induce clonal immunoglobu-
lin production, which needs to be differentiated from MM
C by identifying morphologically abnormal and highly frequent
plasma cells, and with serologic assays. Plasma cell features
Figure 2-27 Myelofibrosis in a dog. A. The dog had anemia, in bone marrow supportive of a diagnosis of MM are propor-
and teardrop-shaped (arrowhead) and oval (arrows) erythrocytes tion >5% of nucleated cells, occurrence in clusters, and abnor-
in the blood smear. B, C. Bone marrow was patchy with fibrous mal morphology, such as binucleation or multinucleation,
tissue and areas of hematopoietic cells. anisocytosis, and anisokaryosis. Clustering of bone marrow
plasma cells is best identified on histopathology, and in
some cases proximity to osteoclasts indicates bone lysis
(Fig. 2-28).
Mastocytosis. Bone marrow involvement in mast cell neo- Circulating nonhematopoietic neoplastic cells. Cancers
plasia of dogs is most often the result of metastatic spread of that metastasize via the blood stream frequently shed low
high-grade solid mast cell tumors to multiple hemolymphatic numbers of cells that may be detectable in blood with highly
sites. Mastocythemia in cats is rare, and in most instances sensitive techniques such as flow cytometry. Sufficient
reflects release of cells from visceral (usually splenic) or cuta- numbers to be apparent on routine review of blood smears
neous mast cell tumors. Primary bone marrow mastocytosis is may occur with disseminated histiocytic sarcoma, high-grade
138 CHAPTER 2 • Hematopoietic System Lymphoid Organs
Further reading
Campbell MW, et al. Chronic lymphocytic leukaemia in the cat: 18
cases (2000-2010). Vet Comp Oncol 2013;11:256-264.
Comazzi S, et al. Immunophenotype predicts survival time in dogs with
chronic lymphocytic leukemia. J Vet Intern Med 2011;25:
100-106.
Giraudel JM, et al. Monoclonal gammopathies in the dog: a retrospec-
tive study of 18 cases (1986-1999) and literature review. J Am Anim
Hosp Assoc 2002;38:135-147.
Mellor PJ, et al. Myeloma-related disorders in cats commonly present
as extramedullary neoplasms in contrast to myeloma in human
patients: 24 cases with clinical follow-up. J Vet Intern Med
2006;20:1376-1783.
Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-
stratification, and management. Am J Hematol 2014;89:915-925.
A
LYMPHOID ORGANS
The lymphatic system consists of lymphatic organs and a
conducting network of lymphatic vessels that carry the circu-
lating lymph directly toward the heart. Because the lymphatic
vessels are a major component of the circulatory system, they
have been discussed in the chapter on cardiovascular diseases.
The bone marrow, lymph nodes, spleen, thymus are classified
in the Nomina Anatomica Veterinaria as lymphoid organs.
However, these organs are also part of the immune system,
which is more complex and includes a number of other organs
and tissues. Central or primary lymphoid organs provide lym-
phoid precursor cells that circulate and take up residence in
peripheral or secondary lymphoid organs. In most domestic
B animals, the bone marrow and the thymus as well as the liver
are considered primary lymphoid organs. Peripheral lymphoid
organs include the spleen and the lymph nodes, which are
responsible for production of antibodies and cell-mediated
immune responses. Furthermore, there are numerous types
of mucosa-associated lymphoid tissues (MALTs) that repre-
sent local collections of lymphoid tissue that underlie the
submucosa, such as the gastrointestinal tract–associated lym-
phoid tissue (GALT) or the bronchus-associated lymphoid
tissue (BALT). Other such locations of lymphoid tissues at
various sites of the body include the conjunctival-associated
lymphoid tissue (CALT); the nasal-associated lymphoid tissue
(NALT); the larynx-associated lymphoid tissue (LALT); the
duct-associated lymphoid tissues (DALT) of different salivary
glands, including mammary glands; and the skin-associated
lymphoid tissue (SALT). MALT can be further divided into
C organized tissues that include the tonsils and Peyer’s patches
and diffuse lymphoid cells in epithelial layers and their under-
Figure 2-28 Multiple myeloma in a dog. A. Plasma cells in bone lying connective tissue that are not organized into a structure
marrow aspirate are morphologically normal but very numerous. such as the SALT. The Peyer’s patches are a major site of
B. Bone marrow biopsy shows uneven cell density at low magni- B- and T-cell production after thymic involution, and can
fication. C. At high magnification, plasma cells predominate in therefore be classified as primary and secondary lymphoid
dense areas. organs.
In other chapters, pathologic changes have been character-
ized based on primary or secondary disease processes affecting
a particular organ system. This is extremely difficult for the
mast cell tumors, and widely metastatic carcinomas. In most lymphoid organs because they play a central role in many
instances, prominent neoplastic cells on blood or bone marrow immune-mediated disease processes that manifest in nonlym-
films reflect bone marrow metastases and advanced cancer. phoid organs. In most disease processes, the lymphoid organs
Morphology is generally sufficient for distinction from neo- have a vital immunologic function; however, the pathophysi-
plastic leukocytes. ologic processes of the lymphoid cells do not necessarily
138.e1
Further reading
Amati M, et al. Carcinocythaemia (carcinoma cell leukaemia) in a dog:
an acute leukaemia-like picture due to metastatic carcinoma. J
Small Anim Pract 2012;53:476-479.
Blackwood L, et al. European consensus document on mast cell
tumours in dogs and cats. Vet Comp Oncol 2012;10:e1-e29.
Cian F, et al. Leukemic small cell lymphoma or chronic lymphocytic
leukemia in a horse. Vet Clin Pathol 2014;42:301-306.
Geigy C, et al. Multiple myeloma in a dog with multiple concurrent
infectious diseases and persistent polyclonal gammopathy. Vet Clin
Pathol 2013;42:47-54.
Hikasa Y, et al. Connective tissue-type mast cell leukemia in a dog. J
Vet Med Sci 2000;62:187-190.
Piviani M, et al. Significance of mastocytemia in cats. Vet Clin Pathol
2012;42:4-10.
Ramos-Vara JA, et al. Immunohistochemical detection of multiple
myeloma 1/interferon regulatory factor 4 (MUM1/IRF-4) in canine
plasmacytoma: comparison with CD79a and CD20. Vet Pathol
2007;44:875-884.
Weiss DJ. Bone marrow pathology in dogs and cats with non-
regenerative immune-mediated haemolytic anaemia and pure red
cell aplasia. J Comp Pathol 2008;138:46-53.
Workman HC, Vernau W. Chronic lymphocytic leukemia in dogs and
cats: the veterinary perspective. Vet Clin North Am Small Anim Pract
2003;33:1379-1399.
Lymphoid Organs 139
manifest as changes in the lymphoid organs themselves. For Agammaglobulinemia is characterized by lack of all types
those diseases, the reader is referred to the appropriate chapter of major immunoglobulins and an absence of mature B cells
with the manifestation of the immunologic function within and plasma cells. It occurs in male foals, and affected horse
that organ. Furthermore, the bone marrow is also the major breeds include Thoroughbreds, Quarter Horses, and Standard-
component of the myeloid tissues and has therefore been breds. Equine agammaglobulinemia resembles Bruton con-
discussed previously. However, the division of myeloid and genital X-linked agammaglobulinemia of human infants in
lymphoid organs is arbitrary given that some disorders of both expression and progression. In humans, there is a muta-
erythrocytes are caused by antibody formation and could also tion in the BTK gene encoding Bruton tyrosine kinase, which
be classified as a disease of lymphocytes. The liver, together is closely related to the Src kinase family. This kinase is
with the yolk sac, plays a major part as the primary site of required for B-cell maturation, and B-cell development is
blood cell formation during early ontogeny and may be, arrested in the pre-B stage. Histologically, there is an absence
together with bone marrow, the primary site of maturation or of plasma cells and germinal centers in lymph nodes, Peyer’s
production of B lymphocytes in mammals. This is evidenced patches, and tonsils, but the thymus is normal.
by the large number of islets of hematopoietic cells within the Selective deficiencies of immunoglobulins can be observed
parenchyma of the fetal liver. Similarly, the yolk sac may also in any class of immunoglobulins, but selective IgM and IgA
represent a site of production of immature hematopoietic deficiencies have been reported in dogs and horses. These
cells. Regardless, detailed discussions of the liver, the yolk sac, diseases are characterized by serum levels of the affected
and the MALT can be found in the appropriate chapters. This immunoglobulin being at least 2 standard deviations below
section will only discuss disease processes that manifest within normal values, but B-cell counts are normal. Clinical signs
the thymus, spleen, and lymph nodes. commonly manifest after degradation of maternal antibodies.
An IgM deficiency occurs in foals of Quarter Horse and Arabian
breeding, and both sexes are affected. IgM deficiencies
Developmental diseases of are very rare in humans. In affected foals, immunoglobulin
the lymphoid system levels vary from undetectable to 10% of normal, and the
Immunodeficiency lymphocyte counts are normal, with normal proportions of
Immunodeficiency syndromes are characterized by an B- and T-derived classes. These animals have neutrophilic leu-
increased risk of the host becoming infected by various patho- kocytosis without anemia and are presented for examination
gens, including less virulent or even commensal organisms or at 4-8 months of age with febrile disease involving the respira-
uncommon pathogens, and to be less responsive to standard tory tract. Most animals die as a result of septicemia or pneu-
antimicrobial therapies. These syndromes are a reflection of monia before 10 months of age. The few surviving horses will
the immune system’s inability to protect the host against have recurrent respiratory infections, and most die before
infectious disease or the development of neoplastic diseases. reaching full adulthood. In dogs, an IgA deficiency has been
In general, antibody deficiencies are associated with bacterial reported in Beagles, German Shepherd dogs, Irish Setters, and
infections, and cell-mediated deficiencies are associated with Shar Peis. IgA deficiencies are the most common deficiency in
protozoal, fungal, viral, or obligate intracellular bacterial infec- humans in the United States. They are usually asymptomatic,
tions. The vast majority of immunodeficiencies are caused by but can be associated with autoantibodies to IgA, recurrent
an acquired impairment of the immune system that can be respiratory diseases, allergies, and autoimmune diseases. In
caused by malnutrition, aging, neoplastic or infectious dis- dogs, affected animals may have disease manifestation in the
eases, or chronic diseases. Such immunodeficiencies are also skin, gastrointestinal tract, or respiratory tract. Atopy is
referred to as secondary immunodeficiencies. In contrast, primary common. The number of lymphocytes, and plasma cells in
immunodeficiencies are caused by genetic or congenital defects. affected dogs appear normal, suggesting an inability to produce
Most of these deficiencies manifest themselves early in life, or secrete IgA.
and the affected animal is often clinically described as “poor Severe combined immunodeficiency. Severe combined
doing” or failing to thrive. However, in some animals, primary immunodeficiency (SCID) describes a group of diseases that
immunodeficiencies may manifest clinically only later in life. are characterized by defects in both humoral and cellular immu-
The type of infection in affected animals often indicates which nity. In most cases, both B- and T-cell lineages are affected,
component of the immune system may be defective. This and animals with SCID have lymphopenia, nonresponsiveness
chapter will only discuss primary immunodeficiencies character- of lymphocytes to antigen stimuli, and minimal levels of
ized by an absence or defect in a class or subclass of lymphocytes immunoglobulins or responses to immunization. Although
derived either from bone marrow or thymus. Primary immuno- numerous defects have been shown to cause SCID in humans,
deficiencies caused by defects of phagocytic cells, or of com- and mouse models of SCID have been developed, in domestic
plement, or secondary immunodeficiencies, or the failure to animals, SCID has only been described in foals, primarily of
passively transfer immunoglobulin from dam to offspring are the Arabian breed, and Basset hounds, Cardigan Welsh Corgi,
not included in this chapter. Primary defects in adaptive and Jack Russell Terrier dogs.
immune response can be partial or combined, affecting either SCID occurs in ~2% of Arabian and Arabian-crossbred foals,
only T cells or B cells or both. Such conditions usually lead to but the incidence of phenotypically normal heterozygotes will
severe combined immunodeficiency. be much higher. Both sexes are affected, and the disease is the
Immunoglobulin deficiencies. These primary immunode- result of an autosomal recessive trait expressed as an absence of
ficiencies are characterized by an immunoglobulin deficiency both B- and T-lymphocyte functions. The genetic defect is a
that can affect all 3 types of major immunoglobulins (agam- spontaneous frame-shift mutation of the PRKDC gene encod-
maglobulinemia) or appear as selective deficiencies of indi- ing the catalytic subunit of DNA-dependent protein kinase
vidual classes of immunoglobulins (selective immunoglobulin (DNA-PKcs) located on chromosome 9. The mutation causes
deficiency). a complete loss of function of DNA-PKcs, which is required
140 CHAPTER 2 • Hematopoietic System Lymphoid Organs
for formation of functional V regions during recombination of nodes, particularly from the mediastinal area, may have corti-
immunoglobulin heavy-chain and T-cell receptor genes. This cal microabscesses. Follicles are absent, and the cortex consists
results in an inability to produce functional T and B cells. of a reticular framework in which there are small foci of lym-
Furthermore, DNA-PKs have an important function in DNA phocytes around small arterioles. Postcapillary venules have
repair, and affected horses have been shown to have defects high vesicular endothelium and are usually well demonstrated
in their DNA repair mechanism. Homozygous horses rarely because of the lack of perivascular and intramural lympho-
live beyond 5 months of age; heterozygous horses have a cytes. Medullary cords are collapsed, and medullary sinuses
higher risk of developing equine sarcoids in the skin. Whether are dilated and contain neutrophils and macrophages. If
a single allele mutation in PRKDC predisposes such horses to thymus can be identified, it consists of small lobules of 1-2 mm
the development of neoplastic disease is unknown as is the diameter surrounded by normal fat. The lobules have normal
potentially synergistic effect of the mutation and bovine papil- stromal capsulation and consist almost entirely of medullary
lomavirus 1 and 2 infection, which has been associated with structures with central Hassall’s corpuscles and a vesicular
the development of equine sarcoids. reticular network with a very low lymphocyte population. The
Foals with SCID are normal at birth, but at ~10 days of presence of the Hassall’s corpuscles is worthy of note because,
age develop a range of diseases, including pneumonia and besides identifying the tissue as thymus, their presence also
diarrhea, that are commonly associated with equine adenovi- indicates that there has been successful embryologic migration
ruses, Cryptosporidium parvum, and Pneumocystis carinii infec- of the epithelial duct system. In human infants, the corpuscles
tions. Foals commonly develop bilateral nasal discharge that are present only in SCID patients with an enzyme deficiency
becomes sufficiently profuse to impair suckling. There is pro- of adenosine deaminase (ADA), whereas in X-linked SCID
gressive weight loss and intermittent pyrexia with coughing, the thymus only contains lobules of undifferentiated epithelial
depression, and rough haircoat. Intractable respiratory disease cells resembling fetal thymus.
is the most common clinical sign, but diarrhea and swollen joints An X-linked SCID has been reported in Basset Hounds and
are also observed. In spite of intensive therapy, affected foals Cardigan Welsh Corgi dogs that is characterized by defects in
die at 3-5 months of age. the gene encoding the gamma chain that is common to the
Hematologically, the animals are profoundly lymphopenic, receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and
and it is suggested that counts of <1 × 109/L are diagnostic for IL-21. Affected dogs therefore cannot complete the signal
the disease. Lymphopenia is present from birth and is constant transduction pathways of any of these interleukins. Different
throughout life. Because IgM is synthesized by the normal mutations in the gamma chain of the IL-2 receptor are also
equine fetus, absence of IgM from serum of foals that have not the most common mutations encountered in SCIDs in
suckled supports a diagnosis of SCID. In animals from 1-100 humans. Similarly, different mutations have been detected in
days of age, the serum IgM and IgA levels are low and remain Basset Hounds (4 base-pair deletion in exon 1) and Cardigan
between 0.2 and 0.6 g/L. The IgG, which is maternally Welsh Corgi dogs (single base-pair insertion in exon 4), and
derived, progressively drops from 8.0 g/L shortly after birth the location of the mutation within target genes influences
to 2.0 g/L in foals that approach 100 days of age. There is the spectrum of diseases observed in affected animals. Because
usually mild anemia that increases in severity with resistant the mechanisms of gene rearrangement are not impaired,
and repeated infections, but is often masked by dehydration. affected dogs have lymphocytes that express mature T- and
Leukocyte counts are highly variable, being primarily depen- B-cell markers. Therefore this variant of SCID is characterized
dent on the numbers of neutrophils. Reduced lymphocyte by only moderate lymphopenia, with normal percentages of
levels in blood are usually more than compensated by neutro- circulating B lymphocytes and low to normal percentages of
philia, so that total leukocyte counts are usually in the normal mature, but nonfunctional, T cells. There is a decrease in cir-
range. culating CD8-positive cells, and the ratio of CD4 to CD8 cells
The characteristic lesions in foals with SCID are bilateral is ~15 : 1 compared to 2 : 1 in normal dogs. Affected dogs also
cranioventral bronchopneumonia in association with hypoplasia have normal serum level concentrations of IgM. In contrast,
of all lymphoid tissue, including thymus, lymph nodes, and spleen. serum IgG and IgA concentrations are significantly reduced or
The thymus is identified only as a thin mediastinal raphe not detectable, respectively. Only antibodies of the IgM class
cranial to the heart. The bone marrow is unusually reactive are produced, which is consistent with an inability to class-
for the age of the animal, and hematopoiesis persists in cancel- switch to IgG and IgA. Affected puppies fail to produce anti-
lous bone and partially occupies the central femoral cavities. bodies in response to immune stimuli, including vaccination
Terminally, areas of marrow that appear red grossly may be and are highly susceptible to bacterial and viral infections.
hypoplastic with dilated sinusoids. Histologically, the lesions They rarely live more than 3-4 months. As with SCID in
in the lung are typical of a suppurative bronchopneumonia, horses, lymphoid organs are severely hypoplastic, and tonsil,
but basophilic adenoviral inclusion bodies are usually present thymus, Peyer’s patches, or lymph nodes are often grossly
in the epithelial nuclei of bronchi and bronchioles as well as undetectable. The histologic changes are similar to those
other organs. The primary SCID lesion is marked lymphoid described in horses. The small lobules of the thymus have few
hypoplasia of all lymphoid organs. The spleen has no lymphoid to no lymphocytes, and there is no corticomedullary demarca-
follicles, the small arterioles are devoid of lymphocytic cuffs, tion. The ratio of CD8 to CD4 lymphocytes has markedly
and there are no plasma cells. The lack of connective tissue shifted toward CD8-positive cells. Similar to human X-linked
stroma in follicular sites helps to differentiate this hypoplastic SCID, Hassall’s corpuscles are not detectable.
lesion from atrophy. Some spleens have increased extramedul- An autosomal recessive SCID as a result of a mutation in
lary hematopoiesis. The lymph nodes consist of a stromal DNA-PKcs has also been described in Jack Russell Terriers
framework that is essentially an unoccupied superstructure. (Fig. 2-29). Both the mechanisms and the pathology, including
The capsule is delicate, with the peripheral sinus often heavily adenoviral hepatitis, are similar to reports in Arabian foals. A
colonized by macrophages and granulocytes. Some lymph single litter of Rottweiler puppies was suspected to have SCID
Thymus 141
Further reading
Bell TG, et al. Autosomal recessive severe combined immunodeficiency
of Jack Russell terriers. J Vet Diagn Invest 2002;14:194-204.
B Don-van’t Slot HP, van der Kolk JH. Severe combined immunodeficiency
disease (SCID) in the Arabian horse. Tidschr Diergeneeskd
Figure 2-29 Severe combined immunodeficiency (SCID) in a
2000;125:577-581.
dog. A. Thymic hypoplasia characterized by small lobules that
Flaminio MJ, et al. Common variable immunodeficiency in horses is
have few to no lymphocytes and no corticomedullary demarca-
characterized by B cell depletion in primary and secondary lymphoid
tion. B. Immunohistochemistry for CD3 highlights the loss of T
tissues. J Clin Immunol 2009;29:107-116.
cells.
Perryman LE. Molecular pathology of severe combined immunodefi-
ciency in mice, horses, and dogs. Vet Pathol 2004;41:95-100.
Tallmadge RL, et al. Expression of essential B cell development genes
based on few T cells and few follicles with B cells in lymphoid in horses with common variable immunodeficiency. Mol Immunol
tissues and abnormally low IgA levels. The mechanisms of this 2012;51:169-176.
syndrome were not investigated. Verfuurden B, et al. Severe combined immunodeficiency in Frisian
T-cell immunodeficiency. Rare T-cell immunodeficiencies Water Dogs caused by a RAG1 mutation. Genes Immun
have been reported in dogs and cattle. In Weimaraners, a 2011;12:310-313.
growth hormone deficiency has been reported that was associ-
ated with constant severe bacterial infections and poor growth
rates. Affected puppies not only had decreased levels of
growth hormones, but also low T-cell counts. The thymus was THYMUS
small, and there was loss of corticomedullary delineation Structure and function of the normal thymus
because of the absence of T cells. Affected puppies had normal The thymus is a composite organ of epithelial and lymphoid
leukocyte counts and gammaglobulins and were able to tissues, both of which have distinct developmental origins. The
produce antibody in response to bacterial challenges. The thymic anlage develops from the third paired branchial (pha-
underlying mechanisms are unknown. Treatment with bovine ryngeal) pouch of the foregut endoderm. Endodermal diver-
growth hormone was beneficial. In humans, mutations in the ticula arise bilaterally from the middle series of the branchial
STAT5b gene have been described causing a combined phe- pouches. Following outgrowths of the epithelial component to
the cranial mediastinal area, the ducts connecting the diver-
notype of growth hormone insensitivity and immunodefi-
ticula to the pharynx soon disappear, setting the thymus anlage
ciency because of T-cell lymphopenia. Clinical findings free. While extending laterally and backward, the diverticula
included congenital growth hormone deficiency that mani- grow into the surrounding mesoderm and neural crest–derived
fested as persistently low growth rate, severely delayed bone mesenchyme of the branchial arch and give rise to the capsule,
age, and postnatal growth failure as well as recurrent infec- trabeculae, and blood vessels. The diverticula lose their lumina,
tions of the skin, severe chronic lung disease, and multiple and their lower ends enlarge and migrate caudally toward the
141.e1
Further reading
Crisman MV, Scarratt WK. Immunodeficiency in horses. Vet Clin North
Am Equine Pract 2008;24:299-310.
Felsburg PJ, et al. Canine X-linked severe combined immunodeficiency.
Vet Immunol Immunopathol 1999;69:127-135.
Fox-Clipsham LY, et al. Population screening of endangered horse
breeds for the foal immunodeficiency syndrome mutation. Vet Rec
2011;169:655.
Hutchison JM, et al. Immunodeficiency syndrome associated with
wasting and opportunistic infection in juvenile llamas: 12 cases
(1988-1990). J Am Vet Med Assoc 1992;201:1070-1076.
Meek K, et al. SCID dogs: similar transplant potential but distinct intra-
uterine growth defects and premature replicative senescence with
SCID mice. J Immunol 2009;183:2529-2536.
Moroff SD, et al. IgA deficiency in Shar-Pei dogs. Vet Immunol Immu-
nopathol 1986;13:181-188.
Nolte T, et al. Oxazolone and ethanol induce colitis in non-obese
diabetic-severe combined immunodeficiency interleukin-2R (null)
mice engrafted with human peripheral blood mononuclear cells.
Clin Exp Immunol 2013;172:349-362.
Roth JA, et al. Thymic abnormalities and growth hormone deficiency
in dogs. Am J Vet Res 1980;41:1256-1262.
Tallmadge RL, et al. Fell Pony syndrome: characterization of develop-
mental hematopoiesis failure and associated gene expression pro-
files. Clin Vaccine Immunol 2012;19:1054-1064.
Taylor SD, et al. Protective effects of broadly neutralizing immuno-
globulin against homologous and heterologous equine infectious
anemia virus in horses with severe combined immunodeficiency.
J Virol 2011;85:6814-6818.
142 CHAPTER 2 • Hematopoietic System Thymus
thorax and become the thoracic lobes. The upper ends either blood islands of the primordial yolk sac. A further cell type,
atrophy or persist as cervical lobes. In ruminants and pigs, both which resembles striated muscle fibers, is of indefinite origin, but
large cervical lobes and thoracic lobes exist, whereas the cervi- has importance in the pathogenesis of myasthenia gravis.
cal lobes vary in size in cats, are small in horses, and absent in These relationships are pertinent to the histologic interpreta-
dogs. The thoracic lobe develops in all domestic animals in the
tion of the thymus in pathologic states; as in dysplasia, atrophy,
ventral portion of the cranial mediastinum, except in rumi-
nants, where it can be found dorsally.
regeneration, and hyperplasia, these components recapitulate
their embryologic relationships.
There are 2 streams of epithelial migration, with that from In most species, the thymus reaches maximal development
the uppermost part of the pharyngeal pouch forming the at about the time of puberty. It can become hyperplastic,
thymic duct epithelium and later the Hassall’s (thymic) cor- and in calves given repeated injections of endotoxin can
puscles, and that from the lower part of the pouch forming extend from the rami of the mandibles to the base of the
the reticular epithelial component of the cortex and medulla of heart. Normally, the thymus regresses in adult life, and this
the adult thymic lobule. Embryologically, the reticular epithe- regression may be accelerated during severe or chronic illness,
lial component first invades the mediastinal interstitium with but it never entirely disappears. Even a very small organ
irregular, solid, rosette-like buds that enlarge to form the pri- weighing <10 g can be immunologically potent in autoim-
mordial lobules. This reticular epithelium forms loose cuffs mune dysfunction.
around small vessels that persist in adult life and become The thymus differs from the spleen and lymph nodes in a
obvious following lymphoid atrophy. The second component number of important aspects: There are no lymphoid follicles
migrates as a system of branching ducts that ramify in the and B lymphocytes in the normal thymus; there are no affer-
interlobular stroma and penetrate the lobules to form a central ent lymphatics, and the cortex is composed of small, densely
cord that broadly communicates between the lobules of a packed T-cell precursors and T lymphocytes at various stages
single lobe. In early development, this tubular system has a of proliferation and differentiation as well as apoptotic cells;
basement membrane and layered epithelium that becomes the medulla does not contain sinusoids, but instead represents
solid and cystic and loses the outer membrane in the mature a mesenchymal-endothelial reticular network that contains
thymic medullary corpuscle. In terms of induction, it appears Hassall’s corpuscles and large numbers of lymphocytes (Fig.
that these medullary ducts are essential to colonization of the 2-30, eFig. 2-2). The thymic epithelial cells are best high-
thymic anlage by thymocytes (T lymphocytes at different lighted by immunohistochemistry for cytokeratins; pancyto-
stages of development), and are the source of trophic thymic keratin antibodies MNF116 or AE1/AE3 are most commonly
hormones. The colonizing lymphocytes are derived from used to detect the different subpopulations of epithelial cells
Thymic cortical
epithelial cell Trabeculae
Thymocyte Capsule
Subcapsular
epithelium
Cortex
Corticomedullary
junction
Medulla
Macrophage Hassall’s
Thymic medullary
(bone marrow origin) corpuscle
epithelial cell
Figure 2-30 Normal thymus in a dog. The illustration on the left depicts the thymic structure
and cell populations; the image on the right parallels the microscopic appearance of these
structures.
142.e1
and to visualize their multiple delicate interconnecting cyto- expression of CD2 and CD44, and such cells are termed
plasmic processes. The lymphoid component is best character- “triple-negative” as they do not yet express CD3, CD4, or
ized immunohistochemically by CD3. Cortical thymocytes CD8. Most T cells develop a TCR heterodimer composed of
(immature T lymphocytes) will have cytoplasmic expression, α and β chains, and a much smaller proportion develop the
whereas medullary thymocytes are usually positive for both γδ TCR configuration. This rearrangement process brings vari-
membranous and cytoplasmic CD3. CD1a is only available able (V), diversity (D), and joining (J) gene segments together.
for frozen sections, and antibodies against terminal deoxynu- The numerous combinations among the V, D, and J segments,
cleotidyl transferase (TdT) or CD99 have only been estab- together with non–template-encoded nucleotides (N) by ter-
lished in humans for cortical thymocytes. There is also an minal deoxynucleotidyl transferase, for instance, V-N-D-N-J,
appreciable number of CD20-positive B lymphocytes in the create the large repertoire of T-cell types within the αβ and
medulla that may be the cells from which mediastinal large γδ T-cell lineages. Although intrathymic dendritic cells were
B-cell lymphomas arise. These cells commonly synthesize IgG, originally thought to derive from progenitors with lymphoid
IgM, and IgD. potential, it has recently been shown that thymic dendritic
Thymic cortical lymphocytes are small cells with nuclei cells are also derived from myeloid-restricted progenitors.
slightly larger than erythrocytes, little internal nuclear detail, Besides becoming CD3-positive with this level of maturation,
and minimal cytoplasm. Despite their small size and lack of the young thymocytes expressing the αβ form of TCR also
nucleoli, there is intense lymphopoiesis in the peripheral express CD4 and CD8 molecules and are known as double-
thymic cortex and continual migration of cells to the periph- positive cells during the time they express both molecules.
ery from this area. Most (99%) of this proliferation is ineffec- Those cells that recognize antigen in association with class II
tive and balanced by a high rate of cell death, apparently in a MHC gain additional CD4 expression and lose CD8. Simi-
process of immunologic selection. A complete turnover of larly, those cells that recognize antigen in association with class
cells is believed to occur within 3-4 days. In normal states, I MHC persist as CD8-positive cells. A much smaller popula-
cortical lymphocytes are closely packed so that the cortex tion of γδ T cells form a cytotoxic T-cell population as mature
appears uniformly dark histologically. In conditions of stress cells. Thymocytes that do not pass the applied selection crite-
and atrophy, cortical epithelial cells and phagocytes become ria usually die through apoptosis.
prominent, and these larger cells with ingested nuclear debris Prothymocyte development is believed to occur within the
give the cortex a moth-eaten appearance. caveolae of the large epithelial “nurse cells.” Nurse cells tend to
Thymic medullary lymphocytes are larger than their corti- express either MHC II, primarily in the cells of the outer
cal precursors and have a more vesicular nucleus with small cortex and dendritic cells of the inner cortex, or, in association
nucleoli and more cytoplasm. They appear less tightly packed with the more flattened reticular epithelium of the medulla,
than the cortical cells and, with the higher density of epithelial expressing both type I and II determinants. This close apposi-
cells and the greater variability in nuclear size and shape, cause tion of epithelium and young lymphocytes permits the trans-
the medullary areas to appear less dense histologically, giving mission of inductive signals for proliferation and development,
the thymus its characteristic corticomedullary differentiation. In or for death of the great majority of the cells produced. The
many disease states where the animal is faring poorly, this thymic nurse cells themselves produce interleukin-1 (IL-1),
corticomedullary boundary is indistinct and blurred by dilu- which drives lymphoproliferation, and in the course of matu-
tion of the cortical cells and an increase in macrophages in ration, the T cells acquire receptor and production capability
both regions. In normal states, the squamous ductal epithe- for IL-2, as well as other reactive lymphokines.
lium is obvious in central medullary areas, but the reticular The progeny of this system are the recognition and regulation
epithelium of the cortex and medulla is not apparent in the specialists of the adult immune system. They identify antigens
background of cells and only becomes apparent following presented to them by other cells as having either the MHC I
atrophy of the lymphocyte population. or II determinants, and determine the presence or absence
Physiologically, prothymocytes from bone marrow colonize the of foreign antigen, which is handled by killing or by stimula-
outer cortex of the thymus, where they proliferate and are selected tion of antibody development. T-cell development involves
and trained by the cortical epithelium. In this region, the epi- the rearrangement of the T-cell receptor genes analogous
thelial cells form large membrane-lined cavities called caveo- to the same process by which the B cells gain antibody diver-
lae in which the marrow-derived lymphocytes divide and sity. Whereas B cells recognize antigen on the basis of molecular
undergo phenotypic development. On release from the shape, T-cell recognition is on the basis of peptides. Because
marrow, prothymocytes have the ability to home selectively antigen is presented to the T cell by antigen-processing
to the thymus, but they lack helper, suppressor, or killer func- phages and dendritic cells, denaturation of antigen is of no
tions. In contrast, peripheral T lymphocytes are characterized consequence because it is the amino-acid sequence that is
phenotypically by CD4 (cluster derived, helper) or CD8 (sup- detected as foreign. In nonhematopoietic cells, internal antigen
pressor) expression, functionally by the major histocompati- is displayed within a groove in the MHC I molecule on cell
bility complex (MHC) determinants they recognize, and by membranes so that viral infection or tumor antigen are avail-
their collective inability to react against normal self-antigens. able for recognition by T lymphocytes. This process of cell
The naive T cells arriving in the thymus from the bone marrow recognition is accomplished by intracellular transporter pumps
express CD34 and CD7 and are pluripotent in their ability to that display all of the proteins (self or foreign) produced
become types of T cells as well as dendritic or natural killer within the cell on the cell surface. The diversity of T-cell rec-
(NK) cells. They undergo a sequential pattern of antigen ognition appears to be a function of receptor diversity and
expression as a function of orderly gene rearrangements permits survival of cells with acceptable recognition of self
encoding the T-cell receptor (TCR), which requires the activ- to avoid “holes” in antigen detection. Thus most NK cells
ity of the recombinase genes (RAG-1 and RAG-2). The earli- recognize targets without MHC restriction, whereas the
est T-cell development occurs in the outer cortex with the CD8+ cytotoxic cells with appropriate antibody mediate
144 CHAPTER 2 • Hematopoietic System Thymus
antibody-dependent cytotoxicity (ADCC). Cytotoxic T cells replaced by adipocytes. The only recognizable structures are
and NK cells can induce apoptosis in adjacent cells by releasing the thymic medulla and central Hassall’s corpuscles. In
cytotoxic granules called perforins or granzymes, both of which X-linked SCID, Hassall’s corpuscles are not detectable.
act in a Ca2+-dependent manner. A case of hypotrichosis and concurrent thymic hypoplasia
Cells exiting the thymus have not only managerial recep- has been reported in a single litter of Birman kittens that all
tors but also “homing” receptors to guide them to appropriate died within the first 13 weeks of life. The condition is believed
areas in the peripheral nodes and Peyer’s patches. Only 1-3% to be autosomal recessive inherited.
of thymocytes bear homing receptors, all of which are in the
cortex and all of which are phenotypically mature. Thus it
appears that the homing direction is added last, with most of Further reading
the cortical cells homed to nodes and likely medullary cells homed Casal ML, et al. Congenital hypotrichosis with thymic aplasia in nine
to Peyer’s patches. Birman kittens. J Am Anim Hosp Assoc 1994;30:600-602.
It appears that the thymic epithelium, besides making Philipp U, et al. A rare form of persistent right aorta arch in linkage
trophic hormone for the immune system, also makes the pep- disequilibrium with the DiGeorge critical region on CFA26 in
tides oxytocin and vasopressin in common with the pituitary, German Pinschers. J Hered 2011;102(Suppl. 1):S68-S73.
thus indicating a mechanism for the interaction of the nervous,
endocrine, and immune systems.
In terms of ontogeny, lymphocytes first appear in the Thymic involution and atrophy
thymus of the fetal lamb at day 43, nodes at day 45, spleen The reduction of the size of the thymus is caused by alteration
at day 54, and Peyer’s patches at day 65. These relationships of its cellular density and/or cellular composition. A physio-
are altered by fetal infection (see Vol. 3, Female genital logic, age-associated decrease of cellularity is called thymic
system). In the dog, the thymic epithelial anlage is present by involution, whereas induced shrinkage of thymic lobules
a gestational age of 23 days, lymphopoiesis begins by day 33, caused by inadequate nutrition, intoxications, infectious
and corticomedullary differentiation with formation of Has- agents, lack of antigenic stimuli, medical therapy, and so on,
sall’s corpuscles is first evident at ~38 days. is referred to as thymic atrophy. Thymic involution is part of
the normal process of ageing that is gradual and irreversible. It
normally begins at sexual maturity and may be slowed by
Further reading dietary restriction or gonadectomy or can be accelerated by
Cejalvo T, et al. Ephrin-B-dependent thymic epithelial cell-thymocyte toxic insult. The morphologic change of thymic involution
interactions are necessary for correct differentiation and thymus reflects its functional change from lymphocyte production to
histology organization: relevance for thymic cortex development. J recirculation.
Immunol 2013;190:2670-2681. Atrophy of the thymus is commonly observed in cachectic
Cheng G, et al. IL-2R signaling is essential for functional maturation of animals and has been associated with vitamin B6, fatty acid,
regulatory T-cells during thymic development. J Immunol or zinc deficiencies, all of which cause immunosuppression.
2013;190:1567-1575. The recognition that a number of environmental and dietary
Coquet JM, et al. Thymic epithelial cells use macroautophagy to turn contaminants may accelerate immune deterioration has
inside out for CD4 T cell tolerance. J Exp Med 2013;210: resulted in the development of testing protocols specifically
715-728. designed to assess adverse effects of this nature. In a general
Farley AM, et al. Dynamics of thymus organization and colonization in sense, thymic atrophy can be used as an index of disease severity
early human development. Development 2013;140:2015-2026. and duration in young animals, in which the organ would
normally be much larger.
The thymus is the most sensitive of the lymphoid tissues
Developmental diseases of the thymus to fluctuations in sex hormone levels, and changes in adreno-
Thymic hypoplasia is commonly observed in a number of cortical hormone levels or growth hormone levels. Elevated
immunodeficiencies that affect T cells. Nude mice have a levels of glucocorticosteroids as induced by stress can result in
specific defect that results in developmental arrest of the significantly reduced thymic weight. Apoptosis of cortical thymic
thymus and a defective cell-mediated immune response. In T cells with secondary digestion by macrophages occurs
humans, a condition called DiGeorge syndrome is caused by an within hours of treatment with corticosteroids. However,
embryologic development defect of the third and fourth pha- thymic atrophy secondary to stress-induced glucocorticoste-
ryngeal pouches. The defect is caused by a deletion mutation roid levels is reversible upon removal of the stressor.
of a gene located on chromosome 22q11 and results in low A further form of thymic atrophy occurs as a result of
number of T cells in blood and lymphoid organs. Affected exposure to a variety of environmental contaminants, with the
individuals are predisposed to viral and fungal infections. most serious effects being those caused by exposure to various
Although rare forms of right persistent aortic arch have been forms of dioxin and various congeners of the polychlorinated
associated with mutations in the DiGeorge syndrome critical and polybrominated biphenyls (PCB, PBB). Heavy metal ions
region of the canine chromosome 26, there have been no such as lead or mercury have direct effects on cell membranes,
reports of thymic hypoplasia caused by a DiGeorge-like syn- organelles, or cell enzymes, causing apoptosis of cortical thy-
drome in domestic animals. mocytes. Mycotoxins such as fumonisins B1 and B2 produced
In domestic animals, thymic hypoplasia most commonly by fungi of the genus Fusarium or aflatoxins can cause severe
occurs as part of severe combined immunodeficiencies in foals or lymphocytolysis of the thymic cortex.
certain breeds of dogs. In affected animals, the thymus is small The thymus is also highly sensitive to a wide variety of
and consists of 1-2 mm diameter lobules that are almost immunotoxicants. Many physical, chemical, or other agents,
entirely depleted of lymphocytes, and thymic cortex is including anticancer drugs or radiation treatment, can cause
144.e1
Further reading
Ardavin C, et al. Thymic dendritic cells and T cells develop simultane-
ously in the thymus from a common precursor population. Nature
1993;362:761-763.
Cowan JE, et al. the thymic medulla is required for Foxp3+ regulatory
but not conventional CD4+ thymocyte development. J Exp Med
2013;210:675-681.
LeFrancois L, Puddington L. The role of the thymus in intestinal intraepi-
thelial T-cell development. Ann NY Acad Sci 1996;778:36-46.
Pezzano M, et al. Questionable thymic nurse cell. Microbiol Mol Biol
Rev 2001;65:390-403.
Suster S, Rosai J. Histology of the normal thymus. Am J Surg Pathol
1990;14:284-303.
Wilson CB. The ontogeny of T lymphocyte maturation and function.
J Pediatr 1991;118:S4-S9.
Thymus 145
Figure 2-31 Thymic atrophy in a dog. Infection with canine Figure 2-32 Thymic atrophy in a cat. Infection with feline pan-
distemper virus caused multilobular acute hemorrhage. Histologi- leukopenia virus caused lobular collapse, and only a narrow rim
cally, there was marked depletion of lymphocytes. of lymphocytes remains beneath the capsule. Hassall’s corpuscles
are prominent, and there is condensation of medullary tissue.
A
Figure 2-33 Thymic necrosis in a horse. Equine herpesvirus
caused extensive necrosis of lymphocytes. Pyknotic nuclear debris
persists in the multiple necrotic foci.
Further reading
Day MJ. Review of thymic pathology in 30 cats and 36 dogs. J Small
Anim Pract 1997;38:393-403.
146.e1
Further reading
Chu I, et al. Subchronic toxicity of 3,3′,4,4′,5-pentachlorobiphenyl in
the rat. I. Clinical, biochemical, hematological and histopathological
changes. Fundam Appl Toxicol 1994;22:457-468.
Keenan KP, et al. The effects of overfeeding and moderate dietary
restriction on Sprague-Dawley rat survival, pathology, carcinogenic-
ity and the toxicity of pharmaceutical agents. Exp Toxic Pathol
1996;48:2-3.
Little S, et al. Feline leukemia virus and feline immunodeficiency virus
in Canada: recommendations for testing and management. Can
Vet J 2011;52:849-855.
National Toxicology Program. Mirex. Rep Carcinog 2011;12:273-275.
Orandle MS, et al. Selective thymocyte depletion and immunoglobulin
coating in the thymus of cats infected with feline immunodeficiency
virus. AIDS Res Human Retrovir 1997;13:611-620.
146.e2
A
eFigure 2-5 Thymic hemorrhage, in a dog. Extensive hemor-
rhage expands the thymic capsule and has largely replaced cortex
and medulla.
B
eFigure 2-4 Thymic hematoma in a dog. A. A well-circumscribed
single hematoma in the thymus. B. Idiopathic thymic hemorrhage
resulting in hemothorax in a dog. (Courtesy D.J. Patrick.)
Thymus 147
Figure 2-35 Thymic remnant in a dog. Complete thymic involu- Figure 2-37 Thymic hematoma in a dog. The thymus contains a
tion does not occur, and thymic remnants can usually be found single, large, well-demarcated area of hemorrhage.
embedded in some mediastinal stroma in older animals.
Figure 2-36 Thymic fibrosis in a dog. Focal areas of fibrosis occur Figure 2-38 Idiopathic thymic hemorrhage in a dog. Extensive
most commonly secondary to localized inflammation. hemorrhage expands the thymic capsule and interlobular septa,
and also extends into the thymic cortex and medulla.
Further reading
Coolman BR, et al. Severe idiopathic thymic hemorrhage in two lit-
termate dogs. J Am Vet Med Assoc 1994;205:1152-1153.
Liggett AD, et al. Thymic hematoma in juvenile dogs associated with
anticoagulant rodenticide toxicosis. J Vet Diagn Invest 2002;
14:416-419.
Further reading
Sheafor SE, Couto CG. Anticoagulant rodenticide toxicity in 21 dogs.
J Am Anim Hosp Assoc 1999;35:38-46.
van der Linde-Sipman JS, van Dijk JE. Hematomas in the thymus in
dogs. Vet Pathol 1987;24:59-61.
Thymus 149
vomiting, and diarrhea. Following initial replication of the gram-negative, 0.3-2.0 µm, pleomorphic organisms are located
rickettsiae in villar epithelial cells, the organisms are dissemi- exclusively within macrophages. They appear blue-purple with
nated by histiocytic cells to the lymph nodes, spleen, tonsils, blood stains, and blue with Macchiavello stain. At the time
thymus, liver, lungs, and brain. Dogs succumbing to infection dogs are showing acute signs of salmon poisoning, there are
with salmon poisoning have marked enlargement of spleen usually large numbers of operculated fluke eggs in fecal
and lymph nodes with focal hemorrhages in the thymus smears. Mortality rate is very high, and approaches 100% in
and pale often swollen liver with an exaggeration of the untreated animals. Organisms are present in virtually all
lobular pattern visible through the capsule. In the thymus, lymph nodes.
infection with N. helminthoeca causes depletion of lymphocytes, Salmon poisoning needs to be distinguished from a related
foci of necrosis with neutrophilic infiltrates, and increased numbers disease known as Elokomin fluke fever, named after the river
of histiocytes in the cortex and medulla (Fig. 2-43). Affected in Washington State where the disease was first recognized.
lymph nodes are characterized by massive lympholysis and There are antigenic differences between the agent of salmon
loss of germinal centers and generalized cortical depletion of poisoning and that of Elokomin fever (Neorickettsia elokomi-
cells. In animals that survive 10-12 days, there is prominent nica), which were initially distinguished on the basis of the
node enlargement because of diffuse paracortical hyperplasia specificities of the antibody reaction in surviving animals
with a prominent “starry-sky” appearance, but without the applied in fluorescent antibody staining of the infectious
development of germinal centers (eFig. 2-6). Splenic lesions agents. The lesions in both diseases are similar.
are characterized by follicular lympholysis in the acute phases
of the disease, as well as loss of cells in the periarteriolar
lymphoid sheaths. There is marked congestion of sinus areas Further reading
with numerous macrophages containing ingested debris as Anderson ML, et al. Histochemical and immunohistochemical evidence
well as the neorickettsial organisms. Hepatic lesions consist of of a bacterium associated with lesions of epizootic bovine abortion.
isolated foci of necrosis with macrophage reaction. The J Vet Diagn Invest 2006;18:76-80.
149.e1
B
eFigure 2-6 Neorickettsia helminthoeca (salmon poisoning
disease) in a dog. A. N. helminthoeca causes increased numbers of
histiocytes in the cortex. B. Lower magnification of the lymph
node shows loss of lymphoid follicles and infiltrating histiocytes
in the cortex. (Courtesy R.J. Bildfell.)
150 CHAPTER 2 • Hematopoietic System Thymus
A
Figure 2-44 Diffuse thymic hyperplasia in a horse. Diffuse
enlargement or large thymuses are commonly referred to as
diffuse hyperplasia, but may simply represent a physiologic
variation.
B
Figure 2-43 Neorickettsia helminthoeca (salmon poisoning
disease) in a dog. A. N. helminthoeca causes cortical depletion of
lymphocytes and increased numbers of histiocytes in the cortex
and medulla. (Courtesy R.J. Bildfell.) B. The gram-negative,
0.3-2.0 µm, pleomorphic organisms are located exclusively within
macrophages and appear blue-purple with Wright stain. (Cour-
tesy J.L. Johns.)
Figure 2-45 Thymic follicular hyperplasia in a dog. Thymic fol-
licular hyperplasia indicates chronic inflammation or another
immunologic response, for instance, immune hemolytic anemia
Headley SA, et al. Neorickettsia helminthoeca and salmon poisoning or systemic lupus erythematosus.
disease: a review. Vet J 2011;187:165-173.
Sykes JE, et al. Salmon poisoning disease in dogs: 29 cases. J Vet Intern
Med 2010;24:504-513. normally sized thymus. Thymic enlargement is usually
observed as an incidental finding on autopsy, and no clinical
signs have been reported.
Hyperplastic and neoplastic diseases In most cases, thymic hyperplasia consists of lymphoid hyper-
of the thymus plasia characterized by the development of B-cell germinal centers
Thymic hyperplasia and therefore referred to as follicular lymphoid hyperplasia. A
Hyperplasia of the thymus is an often misleading term because much less common form of lymphoid hyperplasia is called
the size of the thymus varies widely and a larger thymus in a focal lymphoid hyperplasia.
young animal may simply represent physiologic variation. Follicular hyperplasia is the result of typical B-cell germi-
Regardless, diffuse enlargement or large thymuses are com- nal centers forming, usually at the corticomedullary junction
monly referred to as diffuse hyperplasia (Fig. 2-44). This (Fig. 2-45). Follicular hyperplasia most commonly appears in
process may occur in any species, but is most commonly animals >6 months of age. The presence of hyperplastic lym-
observed in calves, rabbits, and birds that have been repeatedly phoid follicles in the thymus is independent of the size of the
immunized. Grossly, the glands may fill the cranial mediasti- actual thymus, and may be concurrent with thymic involution
num and extend up the neck in calves. The capsules remain or atrophy. In most cases, thymic follicular hyperplasia indi-
thin and delicate and the lobulation is distinct. The ratio of cates chronic inflammation or another immunologic response.
cortical and medullary components is similar to that of a Follicular development has been reported in dogs with
Thymus 151
immune hemolytic anemia and systemic lupus erythematosus, lesion does not appear to undergo neoplastic transformation.
but the frequency is not documented. Follicular hyperplasia No clinical signs have been reported, and the lesion is primarily
may also be found in association with thymoma, suggesting important because of its resemblance to thymomas. In thymic
some period of immune dysfunction preceding development hyperplasia, there is always normal separation of cortex and
of the tumor. In humans, thymic follicular hyperplasia is medulla, whereas thymomas have a diffuse architecture and
strongly associated with autoimmune disease, particularly loss of corticomedullary delineation.
myasthenia gravis, and 75% of patients with myasthenia gravis Pseudoepitheliomatous hyperplasia has rarely been
develop thymic follicular hyperplasia. Histologically, germinal reported within thymic cysts in young dogs as a regenerative
centers in the thymus may be surrounded by a thin layer of response to thymic injury or inflammation. The hyperplastic
epithelial cells and physiologically can be considered to be lesions are characterized by 1-8 layers of plump to slightly
outside of the thymus and do not indicate immune attenuated polygonal squamous epithelial cells lining thymic
dysfunction. cysts. Scattered lymphocytes and Hassall’s corpuscles are com-
Focal hyperplasia is an unusual and incidental finding in monly admixed within the squamous epithelial lining. The
older animals, and is most often of the nonimmune type. It is squamous epithelial cells have indistinct cell borders; variable
an appropriate term for lesions characterized by proliferation amounts of wispy, pale eosinophilic cytoplasm; and vesicular
of cortical lymphocytes in one or more lobules of the gland, nuclei with peripheralized chromatin. Mitotic figures are
usually with compression of surrounding, often atrophic, absent. The pleomorphic presentation of thymic pseudoepi-
lobules, suggesting an attempt at regeneration. The lesions are theliomatous hyperplasia is similar to some variants of
usually lightly encapsulated, often with some laminar infiltra- thymoma; however, the association with thymic cysts and the
tion of the perithymic tissues. Single epithelial cells are usually early onset of the lesion help distinguish the 2 entities.
scattered through a relatively diffuse area of lymphoid prolif- Rarely, ectopic thymic tissue has been reported in some
eration. Focal hyperplasia of the thymic cortex is visible on animals.
architectural or low-power examination by the presence of
increased numbers of large tingible body macrophages impart- Thymic cysts
ing a “starry-sky” appearance, similar to that seen in a reactive Thymic cysts can occur in both the developing and mature
germinal center. thymus, or persist during involution in the cranial mediasti-
Epithelial hyperplasia is seen most frequently in the num in all domestic species. Congenital thymic cysts are usually
thymus of rats, especially females, but has rarely been observed thin walled and unilocular, whereas acquired thymic cysts are
in dogs. Treatment with diethylstilbestrol has caused similar often thick walled and multilocular. Cysts are lined by ciliated
lesions in mice. In rats, the hyperplastic change is age associ- columnar to cuboidal epithelial cells, indicating their origin
ated and can be focal or diffuse, and is characterized by loosely from the remnants of the branchial arch epithelium (eFig.
defined aggregates of cells arising at the corticomedullary 2-7). There are commonly histologic differences of the epi-
junction (Fig. 2-46). These aggregates are recognizable on thelium within an individual cyst. Areas of ciliated epithelium
low-power examination by increased density because of a interchange with pseudostratified epithelium (Fig. 2-47).
greater proportion of small cells than the surrounding thymic Some epithelial cells may have elongated ovoid nuclei, whereas
medulla. Epithelial cells are columnar to cuboidal and often others have narrower, indented nuclei. Although most cases
form cords or tubules. Tubular epithelial cells are commonly are incidental findings, if the cysts become large, they may
ciliated and contain secretory material. Hassall’s corpuscles cause dyspnea. In other cases, thymic cysts may be formed
appear not to be present within epithelial hyperplastic foci. secondary to compression and distortion of the normal thymic
The significance of epithelial hyperplasia is unclear, but the parenchyma by a neoplastic process.
Thymic neoplasms
Primary neoplasms of the thymus are uncommon. The most
commonly observed neoplasms include thymic epithelial
tumors (thymomas and thymic carcinomas) and thymic lym-
phomas. Rare neoplasms include thymic germ cell tumors.
The distinction between thymomas with benign cellular fea-
tures from thymic carcinomas is often straightforward;
however, accurate diagnosis and subclassification of thymomas
with benign cellular features can be difficult. Most thymic
epithelial neoplasms have a favorable long-term prognosis follow-
ing surgical removal, but a small subset will recur or metastasize.
Furthermore, like other thymic diseases, thymic epithelial
neoplasms increase the risk of having one or more autoim-
mune disorders, most notably myasthenia gravis. Thymomas
in the cat may be associated with a type of chronic exfoliative
dermatitis. The successful management of autoimmune disease
remains one of the biggest challenges, especially in dogs.
Unfortunately, there is little information available that would
allow predicting the likelihood of occurrence of paraneoplas-
Figure 2-46 Thymic epithelial hyperplasia in a dog. Proliferating tic syndromes, such as myasthenia gravis or erythema multi-
epithelial cells are columnar to cuboidal and often form cords or forme, based on the observed thymic epithelial neoplasm
tubules. subtype.
151.e1
A B
Figure 2-47 Thymic cyst in a dog. A. Cysts are lined by ciliated columnar to cuboidal epithelial
cells indicating their origin from the remnants of the branchial arch epithelium. B. Immunohisto-
chemistry for pancytokeratin is useful for identifying the epithelial lining.
Table • 2-4
The WHO classification of thymic epithelial neoplasms as applied for use in animals
Histologic subtype Histologic criteria
Type A thymoma Neoplastic thymic epithelial cells are spindle/oval shaped, lack nuclear atypia, and are accompanied
by few, if any, non-neoplastic lymphocytes.
Micronodular thymoma Neoplastic spindle-shaped epithelial cells form nodules that are separated by large aggregates of
predominantly B cells. Immunohistochemistry for pancytokeratin highlights the distinct separation
of the 2 cell components. This thymoma is probably a subtype of type A thymoma.
Type AB thymoma Neoplastic epithelial cells have cellular features of type A thymoma and are admixed with foci of
non-neoplastic lymphocytes. The segregation of such foci can be sharp or indistinct, and a wide
range exists in the relative amount of the 2 components.
Type B1 thymoma Neoplastic epithelial cells closely resemble the normal thymus with an appearance almost
indistinguishable from thymic cortex with some areas resembling thymic medulla.
Type B2 thymoma Neoplastic epithelial cells are plump with vesicular nuclei and distinct nucleoli and are scattered
among a heavy population of non-neoplastic lymphocytes. Perivascular spaces are common and
prominent.
Type B3 thymoma Neoplastic epithelial cells are round or polygonal and exhibit no or only mild atypia. They are
admixed with a minor component of non-neoplastic lymphocytes, which results in a sheet-like
growth of neoplastic epithelial cells.
Thymic carcinoma Neoplastic epithelial cells have malignant cellular features and are named based on their
differentiation status. They lack immature lymphocytes, and lymphocytes within the tumor tend
to be mature and are usually admixed with plasma cells.
Combined thymoma Benign thymic tumors that demonstrate a combination of thymoma subtypes.
Thymoma (type X) with anaplasia Subgroup of tumors with morphologic features between a thymoma and thymic carcinoma.
WHO, World Health Organization.
Thymic epithelial tumors are uncommon cranial mediastinal classification has also been shown to be applicable to thymic
neoplasms that are derived from the thymic epithelial components epithelial tumors in dogs (Table 2-4). The morphologic basis for
of ectodermal origin with the potential to differentiate toward this classification is the cell morphology of the neoplastic epithelial
either a cortical or medullary phenotype. They are highly vari- cells and the relative proportion of non-neoplastic lymphocytes. It
able histologically, making their diagnosis and classification is rare for thymic epithelial tumors to be purely epithelial, and
difficult. In human medicine, different histologic classifica- the association of lymphocytes with epithelium, even in meta-
tions have been proposed for thymic epithelial tumors to static sites, suggests that the latter retains some lymphoid
better correlate their histology with clinical behavior, but inductive capacity, notwithstanding the malignant state. The
the 2004 World Health Organization (WHO) classification 2004 WHO classification system for thymic epithelial tumors
scheme for thymic epithelial tumors is most widely used. This identifies encapsulated or invasive thymomas and thymic
Thymus 153
Figure 2-48 Thymoma in a dog. The vast majority of thymomas Figure 2-50 Compressed thymic remnant in a dog. Remnant of
in dogs or cats are heavily encapsulated. normal thymus has been compressed to the periphery of the
thymic capsule by the expanding thymoma.
B
eFigure 2-8 Thymoma in a dog (A) and a sheep (B). A. The
thymoma appears as an expansile mass in the mediastinum.
B. Cross section of a large well-circumscribed thymoma with
multifocal areas of cyst formation.
154 CHAPTER 2 • Hematopoietic System Thymus
A
Figure 2-52 Thymoma in a goat. The thymoma is encapsulated,
cystic, and areas of neoplasm have undergone ischemic infarction.
(Courtesy K.G. Thompson.)
A A
B B
Figure 2-54 Micronodular thymoma in a dog. A. Multiple
nodules composed of neoplastic epithelial spindle cells separated
by an abundance of lymphocytes. B. Immunohistochemistry for
pancytokeratin shows the epithelial character of the proliferating
spindle cells.
A
Figure 2-57 Type B3 thymoma in a dog. Neoplastic epithelial
cells are round to polygonal and admixed with only small numbers
of non-neoplastic lymphocytes.
B
Figure 2-56 Type B2 thymoma in a dog. A. Epithelial cells form
discrete groups surrounded by lymphocytes and are easily recog-
nizable. B. Clear cells can be the dominant neoplastic cell type in
thymomas, and these cells are rich in glycogen.
Figure 2-59 Thymic carcinoma in a dog. Anaplastic malignant Figure 2-60 Thymic lymphoma in a dog. A large, homogeneous,
epithelial cells are arranged in tubulopapillary structures. pale mass expands the cranial mediastinum.
observed thymic carcinoma in dogs. These neoplasms are cells. The autoantibodies diversify in the resulting germinal
lobulated, have ample hyaline stroma, and neoplastic cells centers and recognize native acetylcholine receptors. Myasthe-
have pleomorphic, vesicular nuclei. Mitoses are common, and nia gravis is primarily caused by the attachment of antibodies to
a high mitotic index (>10 mitoses/high-power field [HPF]) skeletal muscle acetylcholine receptors of the postsynaptic mem-
carries a worse prognosis. Islands of neoplastic cells undergo brane, leading to decreased of functional receptors. In addition,
squamous differentiation with various degrees of keratiniza- antibodies against titin and ryanodine receptors have been
tion, and are surrounded by desmoplastic stroma that is com- shown to be associated with more severe disease, an older
monly infiltrated by plasma cells and mature lymphocytes. onset, or the presence of a thymoma in humans and dogs.
Thymic carcinomas are highly invasive and have to be dif- Although the physiologic role of titin is unknown, ryanodine
ferentiated from pulmonary squamous cell carcinomas that receptors act as calcium-release channels in skeletal muscle
invade the mediastinum. Accurate diagnosis is relevant because and are therefore important for excitation/contraction cou-
pulmonary carcinomas carry a worse prognosis. In humans, pling in skeletal muscle. In a thymoma model in mice, even
thymic carcinomas are commonly positive for KIT; a similar in the absence of acetylcholine receptor antibodies, antibodies
expression profile has not been described in domestic animals. against ryanodine receptors caused severe skeletal muscle
Thymoma (type X) with anaplasia is the suggested diag- weakness. Recent studies in humans strongly suggest that
nostic term for a very uncommon group of thymomas that myasthenia gravis may develop after viral infections, leading to
demonstrate morphologic features that do not fit into either interferon I overexpression, together with the activation of
the thymoma or thymic carcinoma categories. innate immunity pathways in thymoma-associated myasthe-
Myasthenia gravis is an autoimmune disorder of humans, nia gravis. This hypothesis is supported by detection of neu-
dogs, and cats, characterized by progressive muscle weakness tralizing antibodies against interferon I in thymoma-associated
and reduced exercise tolerance. Specific areas of involvement myasthenia gravis patients, but not in patients with thymomas
include the facial and extraocular muscles with the develop- without muscular disease or those with normal thymuses.
ment of megaesophagus associated with difficult swallowing, However, no specific viral etiology has been described. Surgi-
regurgitation, and aspiration pneumonia. It can be congenital cal removal of the neoplastic or hyperplastic thymus has been
or acquired. Only acquired myasthenia gravis commonly reported to restore muscle function.
occurs secondary to thymic abnormalities, especially thymoma Thymic lymphomas. In general, lymphoid tumors of the
in dogs and thymic follicular hyperplasia in humans. All of the cranial mediastinum in cats and cattle, and less commonly dogs,
physiologic features of the acquired myasthenia gravis can be are most commonly precursor T-lymphoblastic lymphomas (see
accounted for by the reduction in functional acetylcholine recep- details of the histologic and immunohistochemical features
tors of neuromuscular junctions (see Vol. 1, Muscle and tendon). under lymphomas) that can be easily misdiagnosed as
The disease arises as an immune-mediated phenomenon, lymphocyte-rich thymomas (eFig. 2-9). A less common type
whereby an antibody reaction is developed against the thymic of thymic lymphoma that has rarely been observed in dogs is
myoid cells that express intact acetylcholine receptors. The myoid a large B-cell lymphoma (Fig. 2-60). Because these neoplasms
cells tend to be associated with Hassall’s corpuscles and the have rarely been reported, there is limited data on whether
germinal centers, which resemble those of antigen-activated they truly resemble mediastinal B-cell lymphoma in humans
lymph nodes, and diffuse areas of B-cell proliferation that are or are actually diffuse large B-cell lymphomas arising in the
centered on the medullary areas with sparing of the cortex, mediastinal lymph nodes.
which is often reduced in volume. It has been hypothesized In the cat, mediastinal lymphomas can reach a large size,
that thymic epithelial cells present epitopes from the isolated with dorsocaudal displacement of the lungs before they are
acetylcholine receptor subunits, which they express and auto- presented for clinical examination (Fig. 2-61). There is a wide
immunize helper T cells. These helper T cells induce an early age distribution of feline thymic lymphoma, with 90% occur-
antibody response directed against the rare thymic myoid ring relatively evenly between 1 and 10 years of age.
157.e1
B
eFigure 2-9 Thymic lymphoma in a dog (A) and a pig (B). A. A
large, homogeneous, pale mass has displaced the lungs caudally.
(Courtesy K.G. Thompson.) B. Thymoma and mediastinal lym-
phoma are often difficult to differentiate grossly.
158 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
Further reading
Lara-Garcia A, et al. Cervical thymoma originating in ectopic thymic
tissue in a cat. Vet Clin Pathol 2008;37:397-402.
Pearse G. Histopathology of the thymus. Toxicol Pathol 2006;34:
B 515-547.
Figure 2-61 Thymic lymphoma in a cat. A. The thymic lym- Ponce F, et al. A morphological study of 608 cases of canine malignant
phoma has displaced the lungs caudodorsally. There are mul lymphoma in France with a focus on comparative similarities
tifocal areas of necrosis and petechiae throughout the mass. between canine and human lymphoma morphology. Vet Pathol
B. Precursor T-cell lymphoblastic lymphoma characterized by 2010;47:414-433.
diffuse, dense infiltrates of monomorphic, intermediate-sized lym- Rickman BH, Gurfield N. Thymic cystic degeneration, pseudoepithelio-
phoid cells with oval or folded convoluted nuclei with dispersed matous hyperplasia, and hemorrhage in a dog with brodifacoum
chromatin and indistinct nucleoli. toxicosis. Vet Pathol 2009;46:449-452.
Robat CS, et al. Clinical features, treatment options, and outcome in
dogs with thymoma: 116 cases (1999-2010). J Am Vet Med Assoc
Involvement of the lung, even by direct extension, is unusual, 2013;243:1448-1454.
although there may be infiltration into the atria and through Suster S, Moran CA. Histologic classification of thymoma: the World
the pericardium into the base of the heart and around the Health Organization and beyond. Hematol Oncol Clin North Am
origins of the great vessels. Infiltration beneath the sternal 2008;22:381-392.
pleura is consistently present. Metastases may be widespread, Tepper LC, et al. Diagnosis of erythema multiforme associated with
but they are rare and small compared to the mediastinal neo- thymoma in a dog and treated with thymectomy. J Am Anim Hosp
plasm, suggesting that these lesions spread by local expansion Assoc 2011;47:19-25.
until late in the disease. Tillman H, et al. Application and clinical relevance of the WHO histo-
Thymic lymphoma in cattle characteristically occurs in logical classification system to canine thymomas. Vet Pathol
yearlings of the beef breeds, and is not associated with infec- 2009;46:1043.
tion with bovine leukemia virus (BLV). Typically, there is Zitz JC, et al. Results of excision of thymoma in cats and dogs: 20 cases
swelling, sometimes massive, at the base of the neck, and (1984-2005). J Am Vet Med Assoc 2008;232:1186-1192.
brisket edema. Bloating and dysphagia associated with esopha-
geal compression are common. The animals are seldom leu-
kemic, although in advanced cases there are usually neoplastic
lymphocytes in the peripheral blood without changes in abso- SPLEEN AND HEMOLYMPH NODES
lute numbers of cells, and neoplastic cells may be identified Structure and function of the normal spleen
in sternal marrow aspirates. The thymic lymphoma may The spleen is a peripheral lymphoid organ that, together with
extend from the rami of the mandibles to the base of the the hemal nodes, is also part of the blood circulatory system,
heart, with a constriction at the entrance to the thoracic cavity, and functions as an effective filter of blood through a sinusoidal
and may weigh 20 kg or more. They are lightly encapsulated system.
158.e1
Further reading
Hadlow WJ. High prevalence of thymoma in the dairy goat. Report of
seventeen cases. Vet Pathol 1978;15:153-169.
Oksanen A. Fine structure of epithelial thymus cysts in dogs. Acta
Pathol Microbiol Scand [A] 1977;85:470-480.
Rottenberg S, et al. Thymoma-associated exfoliative dermatitis in cats.
Vet Pathol 2004;41:429-433.
Shelton GD, et al. Titin and ryanodine receptor autoantibodies in dogs
with thymoma and late-onset myasthenia gravis. Vet Immunol
Immunopathol 2001;78:97-105.
Willcox N, et al. Autoimmunizing mechanisms in thymoma and thymus.
Ann N Y Acad Sci 2008;1132:163-173.
Spleen and Hemolymph Nodes 159
The spleen develops between the serosal membranes that blood volume can accumulate in the spleen of horses. Pigs and
are part of the dorsal mesogastrium that connects the stomach ruminants have less capacity. Spleens that have limited storage
to the cranial abdominal wall and from which the greater capacity are classified as defense spleens. Such spleens have
omentum develops. The spleen is a highly elastic organ of fewer elastic fibers and smooth muscles in their trabeculae and
purple-gray color that tends to be darker in herbivores and capsule, and examples include the spleens of humans and
redder in carnivores. There are significant differences in shape, rabbits. The autonomic nervous system regulates the ability of
structure, attachment, and function of the spleen among storage spleens to actively contract through innervation by
domestic animals, but all spleens are flattened, elongated vagal and sympathetic fibers and release of catecholamines.
organs. The spleen is located primarily in the intrathoracic The spleen has no cortex or medulla, but the parenchyma
portion of the abdominal cavity in the left cranial hypogastric is composed of 2 distinct compartments: the white pulp and
region. It is attached to the greater curvature of the stomach red pulp (Fig. 2-62). The white pulp represents macrophages,
by the gastrosplenic ligament, except in ruminants, where it antigen-presenting cells, and B and T lymphocytes in the peri-
closely adheres to the dorsolateral aspect of the rumen. The arteriolar lymphoid sheaths (PALS), the splenic follicles (Mal-
position of the spleen depends in carnivores and, to a lesser pighi bodies), and the marginal zone. The red pulp is composed
degree in horses, on the amount of food in the stomach. Espe- of a meshwork of reticular fibers, reticular cells, and associated
cially in dogs, large amounts of food content can displace the monocytes/macrophages, and surrounds the red pulp vascular
spleen far caudally. Each spleen has a parietal or diaphrag- spaces.
matic surface and a visceral surface, a cranial and a sharp To understand the structure and function of the red pulp
caudal border, as well as a proximal and distal end. In carni- and white pulp, it is necessary to have a detailed understand-
vores, the spleen is dumbbell shaped with a wider distal end, ing of the blood circulation through the spleen. Blood vessels
whereas in pigs it remains uniformly strap-like. In cows, the are an important component of the splenic architecture and,
spleen has the shape of an elongated oval, whereas in sheep whereas arteries and veins are similar in all domestic animals,
or goats it is more triangular or quadrangular, respectively. In the capillary beds of the red pulp differ. In cats and dogs, the
horses, the spleen is falciform with a broad dorsal end and a red pulp is richly supplied with an anastomosing network of
pointed ventral end. On the visceral surface is the splenic hilus, sinusoids, and the spleen is classified as a sinusoidal spleen. All
which is characterized by insertion of the greater omentum other domestic animals have a nonsinusoidal or reticular spleen
and the splenic arteries and veins as well as the beginning of in which the penicillary arterioles empty into the red pulp
the gastrosplenic ligament. In ruminants, the hilus appears as vascular space and only small numbers of venous capillaries
a small grove only while the spleen is fused through connec- can be found in the red pulp. The main anatomic differences
tive tissue with the rumen at a serosa-free region. In rumi- between sinusoidal and nonsinusoidal spleens can be found
nants, the spleen is also anchored through the phrenicosplenic in the arterial vasculature. In dogs, arterial capillaries either
ligament that connects the dorsal portion of the spleen to the continue into the described venous sinusoids, or they termi-
diaphragm. In horses, the gastrophrenic ligament becomes nate into the red pulp vascular spaces. The continuous lining
the phrenicosplenic and splenorenal ligaments and connects by endothelium as observed for the circulation through the
the spleen to the left kidney and the transverse colon. sinusoids is called a closed system, whereas the interruption
On macroscopic examination, 3 components of the splenic of endothelial lining in vascular spaces is referred to as an
structure are recognizable: the splenic capsule and connective open system. Dogs and cats have therefore a closed and an open
tissue trabeculae, the red pulp, and the white pulp. A strong system, whereas all other domestic animals have an open
capsule surrounds the spleen of all domestic animals, and the system.
trabeculae extend from the capsule internally. The chambers The spleen receives its blood from the splenic artery, which
between the trabeculae are filled with the soft splenic paren- comes from the celiac artery, and the blood drains through
chyma, the splenic pulp. This pulp is composed of darker red, the splenic vein into the portal vein. Approximately 2.5% of
blood-rich areas—the red pulp—that surround lighter-colored the cardiac output flows through the spleen. The splenic
areas that are devoid of erythrocytes—the white pulp. artery divides into multiple branches, each of which functions
Except for the serosal-free area in ruminants, the spleen is as an end artery that supplies a specific segment of the spleen.
covered by the peritoneum that continues onto the splenic These arteries enter the spleen through the hilus and continue
ligaments. The internal coat of the capsule, also called the within the capsule or trabeculae as trabecular arteries. Trabecu-
elastic coat, is formed by fibrous connective tissue with a high lar arteries have the typical wall structure of muscular arteries
percentage of elastic fibers, and in contrast to humans, up to and carry the splenic nerves in their adventitia. The returning
80% of this coat is composed of smooth muscle fibers. In trabecular veins have an intima that is directly integrated into
ruminants and pigs, a large percentage of smooth muscle fibers the trabecular tissue. Cats have the most extensive trabecular
can also be found in the red pulp. In carnivores, the internal vascular system of all domestic animals. As the trabecular
capsule is formed by a single layer, whereas in ruminants and arteries branch and enter the white pulp, they become
horses, 2 layers can be identified. The trabeculae extend from ensheathed, with cuffs of T lymphocytes forming the periar-
the capsule into the splenic parenchyma and form, together teriolar lymphoid sheaths (PALS). The arteries surrounded by
with the reticulum, the supporting stroma. The high percent- these PALS are now identified as central arterioles. Irregularly
age of elastic fibers combined with the capsular and trabecular along the length of these sheathed central arterioles, the lym-
musculature allows for tremendous expansion of the spleen phoid tissue widens eccentrically to the arteriole and forms
in domestic animals and enables the spleen to store blood. the B-cell–derived splenic follicles (Malpighian bodies).
Spleens with such storage capacity are classified as storage Although the PALS are not vascularized, and oxygen is
spleens, and horses and carnivores have the highest capacities provided through diffusion from the central artery, the splenic
of domestic animals. Approximately 13 of the blood volume follicles have their own capillary bed that provides both sus-
can be stored in the spleen of dogs, and half of the circulating tenance and antigen exposure. The first branches of the central
160 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
Periarteriolar macrophage
sheath (PAMS)
Splenic
sinusoid
Central
arteriole Marginal
sinus
Penicillar
arterioles
Closed
circulation
Open
circulation
Splenic
follicle
Marginal zone
Red pulp with ending
capillaries
Trabecular Radial
vein arteriole
Nonsinusoidal Sinusoidal
spleen spleen
Figure 2-62 Schematic drawing of normal spleen. The left side depicts a nonsinusoidal spleen as
observed in most domestic animals; the right side shows a sinusoidal spleen characteristic of dogs.
arterioles form a vascular plexus surrounding the splenic fol- side, but an incomplete endothelial layer on the peripheral
licles. The capillaries of this plexus, the follicular capillaries, are side. The blood percolates through the marginal sinuses via
characterized by dense zonulae occludens. Numerous follicu- this incomplete coverage, and enters the meshwork of the
lar capillaries emerge on the surface of the splenic follicles and marginal zone. Although most blood flows directly from the
form anastomoses. These thin-walled vascular spaces separate marginal zone into the adjacent splenic sinusoids (fast
the splenic follicles from the periphery and are known as pathway), some blood enters the red pulp vascular spaces
marginal sinuses. Because the marginal sinuses are supplied by (slow pathway).
the first branches of the central arterioles, the splenic follicles Ultimately, the central arterioles terminate in the arboriz-
are the first to be exposed to antigens transported to the ing penicillar arterioles when entering the red pulp. Penicillar
spleen. arterioles can be divided into 3 segments: pulp arterioles, macro-
The marginal areas surrounding the whole white pulp, phage sheathed portions, and terminal arterial capillaries. Shortly
including the PALS, are called the marginal zone and are char- after branching, the pulp arterioles are ensheathed by macro-
acterized by a very fine reticular meshwork. The marginal phages that form the periarteriolar macrophage sheath (PAMS).
sinuses have uniform endothelial coverage on the follicular These structures have historically been called ellipsoids.
Spleen and Hemolymph Nodes 161
Subsequently, penicillar arterioles lose their media and become also nuclear remnants and red blood cell membranes. Nuclear
capillaries. The sheathed arterioles are lined by elongated remnant–containing erythrocytes are pitted of their inclusions,
endothelial cells that are isoprismatic on cross section and such as Howell-Jolly bodies, as they squeeze through the
contain large numbers of vimentin filaments. Adjacent endo- interendothelial slits of venous sinusoids in their passage out
thelial cells are not joined by junctions, and they therefore of the spleen, and return to the circulation. The observation
form a lattice-work through which blood and plasma cells of excessive amounts of nuclear remnants in erythrocytes
readily permeate. Blood passes from the capillaries into the often indicates a splenic disease. In dogs, ~90% of blood passes
surrounding mantles that form up to 200 µm–long structures through the splenic sinusoids and bypasses the red pulp vas-
sheathing capillaries. Integrated into this reticular network cular space. The remaining blood perfuses the splenic cord
composed of type III collagen reticular fibers are macrophages areas, where sorting and processing by macrophages is carried
that are exposed to the migrating red blood cells. Blood passes out to remove senescent or injured red cells. The flow rate
through the reticular meshwork into the surrounding red pulp through the spleen is relatively large, and even with this low
vascular spaces. In all domestic animals, capillaries emerging sorting fraction, all of the blood passes through the splenic cord
at the distal end of the splenic cords terminate in rounded system once per day. Because the spleen plays a central role in
excavations (ampullae of Thoma) from which blood empties removing senescent erythrocytes, it also has a central role in
into the red pulp vascular space. Actin filaments in the endo- iron metabolism. Iron is scavenged by macrophages when
thelial cells forming these ampullae might indicate the ability removing senescent red blood cells from circulation and ini-
to actively regulate the blood flow. In dogs, some capillaries tially stored as a protein-iron complex ferritin, but ferritin can
enter into the splenic sinusoids as previously described. The be incorporated by phagolysosomes to form hemosiderin
space between the sinusoids is occupied by loose reticular granules.
stroma in which macrophages, lymphocytes, and plasma cells The vascular system of the spleen does not include lym-
are enmeshed, called splenic cords (cords of Bilroth). Splenic phatics. As a consequence, all antigens reach the spleen
cords are irregularly supported by encircling reticular fibers, through the blood, which determines that primary sensitiza-
like the staves and hoops of a barrel. Regardless of the differ- tion and antibody production take place in the spleen only if
ences in blood flow in different animals, erythrocytes are the first contact with antigen occurs by hematogenous sensitiza-
subject to surveillance by macrophages that are located peri- tion (Fig. 2-63). On subsequent challenge, the splenic follicles
vascularly around sinusoids, in the red pulp vascular spaces, of the spleen play an important role in the humoral anamnes-
and splenic cords, depending on the animal species. Blood tic response, both by local production of antibodies and by
from the red pulp vascular spaces collects in the venous capil- the provision of committed B memory cells to the peripheral
laries that have an open connection to the meshwork of the lymphoid organs. The clearance of bacteria from the blood by
pulp reticulum. The venous capillaries and the splenic sinu- the spleen predominates only if systemic opsonization is defi-
soids drain the blood into trabecular veins and ultimately the cient. In other circumstances, the clearing appears to occur
splenic vein. The splenic vein drains blood directly into the mainly in hepatic Kupffer cells. Thus splenectomy increases
portal vein, and therefore any increase in portal pressure susceptibility to a number of blood-borne infections, including
increases the blood volume of the spleen, leading in long- bacterial septicemia and protozoal infections such as malaria,
standing conditions to congestive splenomegaly. anaplasmosis, and hepatotrophic mycoplasmal infection
In domestic animals, the red pulp functions as both storage (hemobartonellosis). All of these hazards can be prevented by
compartment, as described previously, and the red pulp mac- specific immunization that brings the hepatic Kupffer cells to
rophages together with the marginal zone macrophages have an alerted state following splenectomy.
essential functions in phagocytizing foreign material, bacteria, The white pulp is composed of macrophages, antigen-
and senescent or defective erythrocytes. The red pulp is com- presenting cells, and B and T lymphocytes in the periarteriolar
posed of splenic cords and vascular spaces; cylinders of pulp
spaces that are organized in a reticular meshwork, fed by a
peripheral ring of arterial capillaries, and drained by a central
venule. In dogs, it also consists of venous sinusoids. The red
pulp macrophages are derived from bone marrow monocytes
and are CD11d positive. Macrophages are integrated into the
reticular meshwork composed of type III collagen and reticu-
lar fibers. They use a number of different mechanisms to
recognize senescent erythrocytes. Although decreased meta-
bolic activity, morphologic alterations, including decreased cell
volume, and changes in cell shape predispose erythrocytes to
removal, macrophages can also detect senescent cells through
surface receptors. Such receptors can bind to Amadori
products—aminoketoses that are the result of nonenzymatic
browning, the nucleophilic addition of an amine to the car-
bonyl function of a reducing sugar, with formation of glyco-
sylamines that occurs over time on the surface of erythrocytes.
Other surface alterations in aging erythrocytes include
decreased levels of sialic acid and CD47, which result in
binding of autologous immunoglobulins and opsonins that can Figure 2-63 Splenic babesiosis in a dog. Babesia canis can be
be recognized by macrophages. In dogs, macrophages remove detected as single or paired, piriform organism within erythro-
entire erythrocytes, a process called erythrophagocytosis, but cytes of a severely congested spleen. (Courtesy E.P. Lane.)
162 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
Further reading
Dullmann J, et al. Lectin histochemistry of the spleen: a new lectin
visualizes the stromal architecture of white pulp and the sinuses of
red pulp. J Histochem Cytochem 2000;48:923-931.
Schmidt EE, et al. Circulatory pathways in the sinusal spleen of the
dog, studied by scanning electron microscopy of microcorrosion
casts. J Morphol 1983;178:111-123.
Spleen and Hemolymph Nodes 163
Figure 2-65 Accessory spleen in a dog. The smaller spleen on the Figure 2-66 Splenic fissure in a horse. Splenic fissures occur as
gastrosplenic ligament most likely represents an implant of splenic smooth elongated indentations that are covered by normal splenic
parenchyma following trauma to the spleen. capsule. (Courtesy R.L. Amorim.)
rupture of the main organ (see Rupture of the spleen). Acces- ened. Microscopically, there is lymphoid atrophy affecting
sory splenic tissue has rarely been reported in the pancreas of both lymphoid follicles and periarteriolar sheaths. The severity
dogs and cats as an incidental finding, but care should be taken of atrophy is an indication of the duration and severity of the
to not misdiagnose such splenic nodules as neoplasms. Intra- atrophic process. The sinus areas appear fibrous as a result of
pancreatic accessory spleens appear grossly as firm, well- condensation of the sinusoids, and lack of blood and resident
demarcated, dark red nodules. hematopoietic cells. Contraction without atrophy of lym-
Duplication of the spleen is occasionally observed in normal phoid tissue can be observed in storage type spleens, most
swine and as one of multiple visceral defects in nonviable commonly because of catecholamine release or activation of
calves and lambs. Ectopic pancreatic tissue, either exocrine or the autonomic innervation. Common causes include splenic
endocrine, is occasionally observed in spleens that are other- rupture, “fight and flight” situations, heart failure, and hypo-
wise developmentally normal. volemic, cardiogenic, or septic shock.
Splenic hypoplasia occurs most commonly as part of severe In hyperimmune states, there are characteristic changes in
combined immunodeficiencies as the result of lymphoid the germinal centers of animals that are severely stressed.
hypoplasia. Affected spleens are grossly small, firm, and pale Lympholysis occurs, and germinal centers appear epithelioid
red, and histologically lack lymphoid follicles and periarterio- and hypocellular. If the cell loss is acute, there will be promi-
lar lymphoid sheaths. nent tingible body macrophages, as in foals aborted because
Splenic fissure is a congenital abnormality that has been of equid herpesvirus 1 infection. If the reaction has persisted
mainly described in horses and appears as a smooth elongated for more than a day, cellular debris is absent and only dendritic
indentation parallel to the splenic edge that is covered by cells remain. Various vascular changes occur, consisting of
normal splenic capsule (Fig. 2-66). hyaline changes in small arterioles that may proceed to
mineralization.
Old dogs often have yellow encrustations along the splenic
Further reading margins, or even covering most of the capsule (Fig. 2-67, eFig.
2-11). Microscopically, there is condensation and thickening
Knostman KA, et al. Intrahepatic splenosis in a dog. Vet Pathol
of the capsule, trabeculae, and perivascular tissue. The yellow
2003;40:708-710.
or brown encrustations are known as siderotic plaques or
Ramírez GA, et al. Intrapancreatic ectopic splenic tissue in dogs and
Gamna-Gandy bodies, and represent deposits of bilirubin,
cats. J Comp Pathol 2013;148:361-364.
hemosiderin, and/or calcium in connective tissue, usually the
Rossi F, et al. B-mode and contrast-enhanced sonographic assessment
trabeculae (Fig. 2-68, eFig. 2-12). The salts become encrusted
of accessory spleen in the dog. Vet Radiol Ultrasound 2010;51:
on connective tissue and elastic fibers, which are swollen,
173-177.
refractile, and stain with hematoxylin. The encrusted fibers
occasionally are misinterpreted as fungal hyphae. In associa-
tion with ceroid, these nodules likely represent the residual
Degenerative diseases of the spleen effects from areas of hemorrhage. Although siderotic plaques
Senile atrophy affects the spleen, as it does other lymphoid occur primarily in older dogs, they are often interpreted as an
tissues, and is seen particularly in old dogs and old horses. incidental aging change, but their deposition on the capsular
Atrophy also accompanies cachexia and is seen in wasting margins suggests a dystrophic lesion secondary to previous
disease caused by starvation, malignant neoplastic diseases, or trauma.
malabsorption syndromes. Chronic radiation can also cause Amyloidosis of the spleen occurs as part of generalized
severe atrophy of the spleen and red pulp fibrosis. Atrophied amyloidosis and can be either primary (AL) or secondary
spleens are small, and their capsule is contracted and thick- (AA), but the deposits in the spleen may not be detectable
163.e1
Further reading
Movitz D. Accessory spleens and experimental splenosis. Principles of
growth. Chic Med Sch Q 1967;26:183-187.
163.e2
A
eFigure 2-12 Splenic siderotic plaques in a dog. Yellow bilirubin
pigment surrounded by extensive fibrosis.
B
eFigure 2-11 Splenic siderotic plaques in a dog. A. Yellow
encrustation along the splenic margin. B. Multiple siderotic
plaques on the capsular surface.
164 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
A A
B B
C C
Figure 2-67 Splenic siderotic plaques in a dog. A. Yellow encrus- Figure 2-68 Splenic siderotic plaques in a dog. A. Yellow biliru-
tation along the splenic margin. B. Some cases can have extension bin pigment surrounded by extensive fibrosis. B. Extensive fibrosis
of siderotic plaques over the whole capsule. C. Depending on the is highlighted in blue with a trichrome stain. C. Hemosiderin
content of bilirubin, hemosiderin, calcium, and the extent of pigments stain blue, and bilirubin stains orange with Prussian blue
fibrosis, the color of plaques varies from white to yellow or green, staining.
as shown in is this remarkably hypoplastic spleen.
grossly or histologically without appropriate stains (Fig. 2-69). or white, opaque 2-mm spherules) in which the enlarged and
Amyloidosis of an obvious degree is not common, and when waxy follicles protrude from the cut surface. The spleen is not
present it involves the germinal centers and may spare the red enlarged. The deposition of amyloid occurs first in the small
pulp vascular spaces completely (eFig. 2-13). This distribution arteries of the lymphoid nodules, and minor deposits are
of amyloid gives the organ the “sago-spleen” appearance (gray common.
164.e1
B
eFigure 2-13 Splenic amyloidosis in a dog (A) and in a horse (B).
A. Cross section of spleen shows a follicular distribution of
amyloid resulting in a “sago” spleen appearance. B. Eosinophilic
hyalinized germinal center as a result of amyloid deposition.
Spleen and Hemolymph Nodes 165
A A
B B
Figure 2-69 Splenic amyloidosis in a dog (A) and in a horse (B). Figure 2-70 Splenic hemosiderosis in a cow. A. Phagocytosed
A. Uniformly pale orange, slightly swollen spleen, with a waxy hemosiderin appears as aggregates of large coarse granules. B.
consistency. B. Multifocal eosinophilic hyalinized foci of amyloid Pigment can be confirmed as hemosiderin through blue staining
that involve the germinal centers and spare the red pulp vascular with Prussian blue.
spaces.
Most lysosomal storage diseases (see Vol. 1, Nervous system) is increased coarse splenic iron as a result of continued scav-
will ultimately result in accumulation of the undegradable enging of the transferrin system by the acute phase–reacting
substrate in histiocytes that accumulate in the spleen and proteins.
lymph nodes. Such accumulation causes a uniformly enlarged,
firm, often pale red spleen.
Hemosiderin is a storage form of iron and the only splenic Further reading
pigment of importance (Fig. 2-70). The amount and form of Cole PA. Association of canine splenic hemangiosarcomas and hema-
storage iron vary greatly in normal animals with age and tomas with nodular lymphoid hyperplasia or siderotic nodules. J Vet
species. The pigment is usually present only in macrophages, Diagn Invest 2012;24:759-762.
but in long-standing iron accumulation, it may be encrusted Murakami T, et al. Atypical AA amyloid deposits in bovine AA amyloi-
on fibers of connective tissue. The amount of hemosiderin is dosis. Amyloid 2012;19:15-20.
significant only when it is in excess to the point of causing
tissue injury and fibrosis, and justifies the name hemosiderosis.
Iron is absorbed in excess in any anemia where it is sufficiently Rupture of the spleen
available. Increased iron is one of the splenic changes in hemo- A normal spleen can be ruptured by the level of trauma that
lytic anemias. The patterns of iron storage in the spleen and cats and dogs suffer regularly in automobile collisions or
marrow can yield information about the type of anemia. In through blunt trauma, for instance, kicks. The result is more
nonresponsive anemias, the iron is mainly aggregated into or less severe loss of blood into the abdomen often causing
large coarse granules within the phagocytes, which themselves death. Pathologic rupture may occur in any species with only
are inapparent. In responsive hemolytic anemias where there minor trauma if the spleen is enlarged and the capsule thinned.
is rapid iron turnover, there is a spectrum of iron deposition Severe diffuse splenomegaly or focal splenic nodules may
from barely stainable, diffusely or focally distributed ferritin, develop secondary to a variety of causes, including diffuse
to coarse hemosiderin. In the anemias of chronic disease, there passive congestion, hyperemia secondary to septicemia,
165.e1
Further reading
Day MJ, et al. A review of pathological diagnoses made from 87 canine
splenic biopsies. J Small Anim Pract 1995;36:426-433.
166 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
Figure 2-71 Splenic hematoma in a dog. Localized hematoma Figure 2-73 Splenic rupture in a dog. The ruptured spleen is
covered by stretched capsule with focal tear. (Courtesy S. contracted and clotted blood adheres to the tear. (Courtesy R. L.
Kesdangsakonwut.) Amorim.)
Figure 2-72 Splenic scar in a dog. Healing of a focal tear resulted Figure 2-74 Splenosis in a dog. Widespread seeding of splenic
in contracted scar tissue. (Courtesy E.P. Lane.) explants onto the serosal surfaces following rupture. (Courtesy S.
Kesdangsakonwut.)
hyperplastic or neoplastic cell proliferations, infarcts, or hema- Concurrent hepatic lacerations are usually characterized by
tomas. As a result of rupture, the spleen may be fully divided a rise in transaminases, indicating an additional source of
into 2 or more parts, or have a merely focally torn capsule. In abdominal hemorrhage. Following rupture of the splenic
some cases, only the red pulp will be ruptured resulting in a capsule and spilling of the sinus cells into the abdominal
localized hematoma covered by the intact capsule (Fig. 2-71). cavity, there may be widespread seeding of splenic explants
Early hematomas appear as solitary, large, dark red, bulging onto the serosal surfaces, called splenosis (Fig. 2-74). These
masses that are prone to rupture, causing hemoabdomen and accessory spleens are functional, and there may be hundreds
death resulting from hypovolemic shock. Over time, splenic on the omentum with a few on the peritoneum. They appear
hematomas may resolve and develop into soft brown masses grossly like hemal nodes and histologically like normal spleen.
that are histologically characterized by infiltrated macro- Following splenectomy, any splenic implants present will
phages that have phagocytized erythrocytes. Breakdown of increase in size and may give some protection against infec-
hemoglobin into bilirubin and hemosiderin is responsible for tious diseases.
color changes. Complete healing will usually result in con-
tracted scar tissue (Fig. 2-72). In areas of a ruptured capsule, Further reading
the spleen is normally contracted, and clotted blood may Tian J, et al. Evaluation and establishment of a canine model of delayed
adhere to the tear (Fig. 2-73, eFig. 2-14). Small non–life- splenic rupture using contrast-enhanced ultrasound. Mol Med Rep
threatening ruptures will heal, and scarring lines of healing 2012;6:483-487.
can produce notches and fissures.
166.e1
A B
C
eFigure 2-14 Splenic rupture in a dog. A. Contracted spleen with clotted blood adhering to the
tear. B. Ruptured splenic hematoma. (Courtesy R.L. Amorim.) C. Following complete rupture,
the scared splenic fragments are shown as “multiple” spleens.
166.e2
Further reading
Pollock S, et al. Traumatic subcapsular splenic cystic hematoma in the
dog/a case study. Vet Med Small Anim Clin 1978;73:600-606.
Spleen and Hemolymph Nodes 167
A
Figure 2-75 Splenic volvulus in a dog. Volvulus of the spleen and
stomach occurs mainly in deep-chested dogs.
Further reading
Neath PJ, et al. Retrospective analysis of 19 cases of isolated torsion of
the splenic pedicle in dogs. J Small Anim Pract 1997;38:387-392.
Wendt M. Stomach torsion in swine. Tierarztl Prax 1987;15:375-376.
168 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
blood. Noncongested spleens feel firmer, hence the descriptive Dogs and cats
term “meaty,” and do not ooze blood on their cut surface. The Barbiturates
color of such enlarged noncongested spleens varies depending Acquired hemolytic anemias
on the underlying disease process, and hyperplastic follicles Leishmaniasis
may be visible grossly. Volvulus (dogs)
Congested splenomegaly is most commonly the result of Trypanosomiasis
circulatory disturbances (see later) and the process can result
from acute hyperemia, for instance, septicemia, passive con- The absence of splenomegaly does not eliminate any of
gestion; or euthanasia with barbiturates, splenic volvulus, these causes, but makes them unlikely. Multiple focal lesions
acute hemolytic anemia; or infectious disease, for instance, normally do not cause splenomegaly, although hemangiomas
babesiosis or trypanosomiasis. Noncongested splenomegaly can of the canine spleen and metastatic melanomas of the equine
be caused by a number of different disease mechanisms, spleen are exceptions.
including phagocytosis, cell proliferation, or storage material. In contrast to diffuse splenomegaly, single or multiple
Each of these conditions is described in more detail under nodules are also commonly encountered in the spleen. In
inflammatory, neoplastic, or degenerative diseases of the similar fashion as diffuse splenomegaly, splenic nodules can
spleen. Although many acute bacterial septicemias can cause be further divided into “bloody” nodules and “firm” nodules
diffuse splenic congestion, subacute to chronic infections are (Fig. 2-78). The most common types of bloody nodules are
often associated with noncongested splenomegaly, for instance, splenic hematomas or vascular neoplasms, for instance, hem-
salmonellosis (Fig. 2-77). The following is an arbitrary list of angioma, hemangiosarcoma (Fig. 2-79). Hematomas can occur
diseases to be considered when congested splenomegaly is secondary to trauma or can be caused by vascular neoplasms.
present. Splenic hyperplastic nodules can also become engorged
with blood and may closely resemble hematomas grossly (Fig.
Cattle and sheep 2-80, eFig. 2-15). Acute splenic infarcts may also grossly
Anthrax resemble “bloody” nodules, but their marginal distribution and
Salmonellosis shape usually allow differentiation on gross examination.
Babesiosis
Hemolytic disease
Horses
Equine infectious anemia
Isoimmune hemolytic anemia
Salmonellosis
Anthrax
Barbiturates
Pigs
Volvulus
Salmonellosis
Isoimmune hemolytic anemia
Mycoplasma haemosuis
African swine fever
B
Figure 2-77 Congested splenomegaly in a pig. Salmonella
choleraesuis can cause severe diffuse splenic congestion. A Figure 2-78 Splenic nodules in a dog. A. Splenic hematoma
normal spleen is shown below for comparison. (Courtesy S. representing a “bloody” nodule. B. Cross section of splenic nodular
Kesdangsakonwut.) hyperplasia representing a “firm” nodule.
Spleen and Hemolymph Nodes 169
A A
B B
Figure 2-80 Splenic hyperplastic nodule in a dog. A. Hyperplas-
tic nodules can become engorged with blood and appear as
“bloody” nodules. B. A few splenic follicles surrounded by severely
congested splenic parenchyma are indicative of the pathogenesis
of this “bloody” nodule.
Figure 2-81 Diffuse splenic congestion, in a dog. Euthanasia Figure 2-82 Splenic infarct in a pig infected with classical swine
with barbiturates can cause diffuse congested splenomegaly. fever virus, formalin-fixed spleen. Acute infarcts appear as dif-
fusely hemorrhagic, sharply demarcated areas that raise the
splenic capsule (bottom), whereas chronic infarcts (top) change
With acute hyperemia, the spleen becomes moderately in color from dark red to gray-white and become more organized.
enlarged and oozes blood on cut section. Histologically, acute (Courtesy S. Kesdangsakonwut.)
hyperemia is first observed in the marginal zones, followed by
the splenic cords. In acute septicemia, such as anthrax, disten-
tion with blood may represent the only finding. In more
chronic cases, neutrophils and macrophages may accumulate
in marginal zones and splenic cords, and there is a marked
increase in fixed cells in the red pulp and heavy sinus coloniza-
tion with macrophages and hemosiderin. A passively congested
spleen is extremely enlarged, moderately turgid, and cyanotic
with the capsule blue-black. The normal architecture is not
discernible on the cut surface, and the pulp is red-black,
bulges, and progressively exudes blood. Microscopically, the
splenic sinuses are dilated with packed red cells, and the ger-
minal centers are widely separated, and trabeculae are thinned.
The severity of acute hyperemia may make histologic exami- Figure 2-83 Splenic infarct as a result of metastasizing carcinoma
nation difficult in the horse because the tissue, being largely in a dog. Sharply demarcated, wedge-shaped, gray-white chronic
clotted blood, fragments on sectioning. Splenic samples from infarct extending from the capsule into the splenic parenchyma.
horses destroyed with barbiturate should be taken from a thin
marginal area where the parenchyma is supported on 2 sides
by capsule. endothelial damage secondary to septicemic salmonellosis has
Spleens that are enlarged for any reason are prone to been observed to cause splenic infarcts in pigs, and there are
thrombosis and infarction. Thrombosis of the splenic vein has a few reports of Mycoplasma haemosuis also causing splenic
been observed in association with traumatic reticulitis and infarcts. In dogs, infarcts occur most likely with various splenic
portal thrombosis in cattle, arterial thrombosis in cattle with neoplasms, including myeloma, lymphoma, or myeloid leuke-
theileriosis, and with splenic abscesses in horses. Thrombosis mias, as a result of thrombocytopenia, procoagulant content
of both arteries and veins is seen in hypercoagulable states, of hypogranular promyelocytic leukemia, or hyperviscosity
such as immune hemolytic anemias, purpura, and hemor- associated with myelomas (Fig. 2-84). The spleen may suffer
rhagic pancreatitis. Infarcts are most commonly observed in infarction secondary to hyperviscosity syndrome caused by
the subcapsular areas because the red pulp in these areas is massive hyperproteinemia most commonly associated with a
poorly perfused and has a reduced venous return (Fig. 2-82). monoclonal gammopathy, but hyperviscosity can also be
Acute infarcts might be difficult to visualize because they caused by leukemia, polycythemia vera, essential thrombocy-
appear as diffusely hemorrhagic, sharply demarcated areas tosis, or myelodysplastic disorders. Embolism with infarction is
that raise the splenic capsule. In more chronic stages, infarcts uncommon. The outcome has the usual dependence on
appears as wedge-shaped areas, extending from the capsule whether the emboli are septic or bland. Emboli are frequently
into the parenchyma, that are sharply demarcated and change derived from valvular vegetative endocarditis. In dogs, Dirofi-
in color from dark red to gray-white as the lesion becomes laria immitis may cause thromboembolism (Fig. 2-85).
more organized (Fig. 2-83, eFig. 2-16). Ultimately, infarcts will Incompletely contracted splenic areas occur most com-
resolve as fibrous scars. In acute classical swine fever in pigs, monly in dogs secondary to disseminated intravascular coagu-
there is widespread endothelial damage and fibrinoid throm- lation, where small thrombi prevent vascular outflow of
bosis of splenic follicular arterioles, resulting in raised dark segments of spleen. Lesions develop when spleens contract
infarcts 0.2-2.0 cm in diameter in the splenic capsule. Severe during cardiogenic shock or following a parasympathetic
170.e1
B
eFigure 2-16 Splenic infarcts in dogs. A. Hemangiosarcoma
causing multiple wedge-shaped infarcts along the splenic margins.
B. A metastasizing carcinoma causes vascular emboli and multifo-
cal splenic infarcts.
Spleen and Hemolymph Nodes 171
filtering mechanism of each is successively swamped. Bacilli They are large truncate organisms that are easily observed.
that enter the blood are taken up in other parts of the mono- They are differentiated from putrefactive bacteria by their distinct
nuclear phagocyte system, especially the spleen, to establish capsule, which stains pink with old methylene blue, and by having
secondary centers of infection and proliferation. square ends when these are apposed. The free ends of B. anthra-
There is notably little response on the part of a susceptible cis are often rounded as in Clostridium spp. The organism can
animal to the local establishment of anthrax infection. Physi- be cultured readily from putrefied exudates if advantage is
ologic disturbances, clinical signs, and death depend on the devel- taken of its aerobic requirements and the heat resistance of
opment of a massive septicemia. In immune animals, for instance, the anthrax spores, to separate it from nonsporulating organ-
guinea pigs, infection is followed by a period of 2-4 hours in isms and sporulating anaerobes. The organism can also be
which the bacilli proliferate; the area then becomes infiltrated purified in guinea pigs by applying the inoculum to scarified
by leukocytes, and the bacilli fragment with little or no phago- skin. In nonsepticemic anthrax, such as occurs in swine and
cytosis of intact organisms. The lysis of bacilli, of which the dogs, it is best to look for the organism in the local exudates
first sign is loss of capsule and staining properties followed by and affected lymph nodes. For the diagnosis of anthrax, when
fragmentation, is apparently caused by anthracidal substances other methods have failed or the tissues are old and dry, the
in plasma or, more likely, liberated from leukocytes. Anthrax Ascoli agar-gel precipitin test is useful but not completely
has always been regarded as dependent on invasiveness rather specific.
than toxigenicity, but it appears that antitoxic immunity does, Bovine anthrax is usually septicemic, and sudden death is
in some manner, inhibit invasiveness. usually the first indication of its presence in a herd. Even when
Vegetative cells produce a small array of toxins. The organ- cattle are observed closely, they may be dead within 1 hour
isms themselves and the capsular material are virtually non- of showing signs of illness, although some will show general
toxic, although the capsular material may act as a spreading signs of illness for about 24 hours before death. The signs of
factor and inhibit the activity of leukocytes. The activity of illness vary with the route of entry and when, as usually
toxins in septicemic anthrax is well illustrated by the demon- happens, entry is by inhalation or ingestion with no area of
stration that, once the degree of bacteremia passes a certain localization, the animals are depressed and listless. On exami-
threshold, which is ~0.3% of the usual maximum, death will nation, there is high fever, increased heart and respiratory
occur even though all bacilli may have been destroyed by rates, and congested and terminally cyanotic mucosae that
antibiotic therapy. The toxin consists of 3 complementary com- show evidence of bleeding. Animals that survive for a day may
ponents designated factors I, II, and III, or edema factor, protective have dysentery, abortion, edematous swellings of the perineum,
antigen, and lethal factor, respectively. Edema factor is an adenyl- throat and abdominal wall, and blood-stained milk. Although
ate cyclase that increases cyclic AMP after activation by infection may be virtually synonymous with disease and death
calmodulin. Protective antigen is likely a receptor-binding in goats and sheep, it is not necessarily so in cattle, in which
protein that appears to be essential for the biological effects species some infected animals probably recover. This is suggested
of edema and lethal factors. Lethal factor is a central nervous by the recovery of some animals that are experimentally inoc-
system (CNS) depressant, but its major effects may be else- ulated and by the occurrence of transient febrile reactions
where. The toxins have been assessed only in experimental attributable to no other causes, in herds in which fatal anthrax
laboratory animals, between species and strains, of which there is occurring. For most animals, however, treatment to be effec-
are considerable differences in sensitivity. The 3 toxins are tive must be administered early before there is marked septi-
serologically distinct and, because there is autostimulation, it cemia and toxin production.
is not surprising that they do not produce lesions when The carcass of an animal dead of this disease putrefies quickly,
injected separately. The combined effects of the 3 toxins are becomes very rapidly distended with putrefactive gases, and
injury and inactivation of phagocytes, increased capillary per- blood exudes from the natural orifices. These changes are, of
meability, anticomplementary activity, and impairment of course, not diagnostic, but when they are observed in an
coagulation. animal that has died suddenly in an area in which anthrax is
Immunity to anthrax appears to depend on the neutraliza- endemic or has at any time occurred, examination of smears of
tion of toxin. Antibodies against the bacterial cells and cap- blood should always precede autopsy. Anthrax in the fulminat-
sules are useless, as is evident from the experience that ing disease is very largely an intravascular infection, with most
completely avirulent or dead bacilli are not immunogenic; in of the organisms in the blood and the rest in the spleen. Sep-
fact, the most potent vaccines are of bacilli that proliferate ticemia in anthrax is a terminal event, and smears of blood
and cause acute local inflammation but do not invade the may not be helpful when prepared more than a few hours
blood. The antigen that provokes antitoxic immunity is the before death.
protective antigen that is presently regarded as being a non- The morbid picture of the disease in cattle is characterized
toxic degradation product (toxoid) of the very labile toxin by splenomegaly, multiple hemorrhages, and edematous effu-
found in the blood of affected animals. The vaccine of Pasteur sions in connective tissues. A very large soft spleen is the most
apparently resulted from the loss of a temperature-sensitive significant lesion, and very rarely is it absent (Fig. 2-86). Sple-
plasmid that encoded for the protective antigen. nomegaly occurs in other diseases of cattle, but rarely is it as
When an animal is suspected of having died of anthrax, large in association with sudden death. In anthrax, the spleen
organisms should be detected in smears of blood or local is soft, sometimes it ruptures spontaneously, and when it is
exudate. All bacilli in internal organs are likely to be destroyed incised, the pulp exudes very thick black-red blood that
in 48 hours or less by putrefaction. Hence it is best to obtain brightens in color on exposure to air. Smears and sections of
blood for diagnostic purposes from close to the coronet or the tip the spleen reveal very large numbers of bacilli if the carcass
of the tail, places that are likely to be involved last by putrefac- is fresh (eFig. 2-17), but, when decomposition is advanced,
tive processes that destroy the vegetative bacilli. Bacillus they are destroyed by putrefactive changes. In some cases,
anthracis occurs in blood in pairs or in short chains of 3-4 cells. splenomegaly is the only lesion. The histology of the spleen is
172.e1
B
eFigure 2-17 Anthrax, in a cow. A. The red pulp is expanded by
sludged red cells admixed with numerous leukocytes and bacilli
in chains. B. Cytologic smears of sections of spleen stained with
M’Faydean stain reveal very large numbers of bacilli. (Courtesy
R.B. Moeller.)
Spleen and Hemolymph Nodes 173
lymphangitis. Some bacilli no doubt reach the blood, but they Amastigotes proliferate by binary fission and then rupture out
do not establish septicemia. Bacteria may localize in liver, of macrophages and infect new cells. When sandflies ingest
spleen, or kidney to produce a metastatic carbuncle but, blood from infected hosts, they also ingest host cells infected
usually, only individual nodes near the site of entry are with amastigotes. In the midgut of the sandfly, amastigotes are
involved. The lymphadenitis may be diffuse or focal but in released from cells and transform into their flagellated, procy-
both cases it is, in the initial stages, hemorrhagic. An intense clic, promastigote form and replicate. Promastigotes are leaf-
leukocytic infiltration occurs, all cells within the affected por- shaped with a single flagellum arising at the anterior pole.
tions of the node die, and the focus becomes encapsulated. Following sufficient replication and a number cell surface
With necrosis, the affected tissue changes from a brick-red to changes, the promastigotes transition to the infectious meta-
a gray friable mass that can be easily shelled-out when the cyclic form that detaches from the midgut and migrates to the
gland is incised. mouthpart, where it is injected into the host with saliva.
In primary intestinal anthrax in pigs, the initial lesion is focal Leishmaniasis is important as a disease of humans, and
or multifocal hemorrhagic enteritis, with a central zone of wherever it occurs in humans, it may also occur in dogs.
diphtheresis that eventually ulcerates. The adjacent serosa and Although the human population may be the only reservoir for
mesentery are thickened with edema fluid and yellow, with some Leishmania spp., for instance, L. donovani, for other
foci and streaks of hemorrhage; they are the site of focal Leishmania spp., for instance, L. infantum or L. braziliensis,
hemorrhagic necrosis resulting from acute necrotizing vascu- dogs, cats, and other carnivores, including rats, serve as reser-
litis and lymphangitis. These mesenteric lesions extend only voir hosts. Leishmaniasis may occur in 3 clinical forms:
as far as the regional nodes, which show the type of lymph- • Cutaneous leishmaniasis (“oriental sore”) is the most
adenitis characteristic of anthrax in swine. common clinical presentation and caused by different
Dogs are reputedly quite resistant to B. anthracis, but a Leishmania spp. in different parts of the globe. In the
number of outbreaks have been observed in kennels in which Eastern Hemisphere, cutaneous leishmaniasis can be
the dogs have inadvertently been fed meat from an animal caused by L. tropica, L. major, L. aethiopica, L. infantum,
that has died of the disease. Anthrax in dogs may pursue a and L. donovani. In the Western Hemisphere, the disease
peracute course to sudden death, it may be of the pharyngeal is caused by the L. mexicana spp. complex (L. mexicana,
type in which extensive edema develops in the face, head, and L. amazonensis, L. venezuelensis) or the L. braziliensis spp.
neck, or it may be of the intestinal type with signs of acute complex (L. braziliensis, L. guyanensis, L. panamensis, L.
gastroenteritis. Anthrax may occur in mink with high mortal- peruviana).
ity after feeding fresh meat from infected animals. • Mucocutaneous leishmaniasis (“espundia”) represents the
spread of cutaneous infection to the naso-oropharyngeal
mucosa and is caused by the L. braziliensis spp. complex.
Further reading • Visceral leishmaniasis (“kala-azar”) is the most severe form
Biswas PK, et al. Risk factors associated with anthrax in cattle on and can occur with a wide variety of clinical signs. It is
smallholdings. Epidemiol Infect 2012;140:1888-1895. usually caused by the species L. donovani and L. infantum
Epp T, et al. Case-control study investigating an anthrax outbreak in (L. chagasi).
Saskatchewan, Canada - summer 2006. Can Vet J 2010;51: The species of Leishmania are not well distinguished. Spe-
973-978. ciation depends on degrees of cross-immunity, different clini-
Liu S, et al. Anthrax lethal and edema toxins in anthrax pathogenesis. cal manifestations, geographic location, and reservoir hosts.
Trends Microbiol 2014;22:317-325. However, sequence data on kinetoplast DNA on several
Mongoh MN, et al. Risk factors associated with anthrax outbreak in species permits their molecular identification. In situ hybrid-
animals in North Dakota, 2005: a retrospective case-control study. ization is available to identify leishmanial organisms and to
Public Health Rep 2008;123:352-359. speciate these in formalin-fixed tissues.
Sweeney DA, et al. Anthrax lethal and edema toxins produce Infections of animals with Leishmania spp. are common in
different patterns of cardiovascular and renal dysfunction and syn- endemic areas, but many dogs may have subclinical disease.
ergistically decrease survival in canines. J Infect Dis 2010;202: Rate of infection in dog populations is usually based on sero-
1885-1896. logic data combined with immune response and detection of
Twenhafel NA. Pathology of inhalational anthrax animal models. Vet parasitic DNA in tissues. Both cutaneous and visceral forms of
Pathol 2010;47:819-830. the disease have been described in dogs, as well as cases of vis-
ceral disease in which the organisms are diffusely present in
the dermis. Leishmaniasis is a disease of the monocyte-
Leishmaniasis macrophage system, and the visceral disease mimics histoplas-
The genus Leishmania includes protozoal parasites within the mosis. The protozoa are not cytopathogenic in the usual sense,
family Trypanosomatidae. Species of the genus are parasites of and destruction of host macrophages appears to be purely a
humans, dogs, and other mammals. Sandflies of the genus Phle- mechanical consequence of proliferation of the protozoa in
botomus in the Old World and the genus Lutzomia in the New the cytoplasm.
World are the intermediate hosts. The tick Rhipicephalus may Cutaneous leishmaniasis in dogs can occur as generalized
act as mechanical vector. Direct transmission and vertical or focal, exfoliative dermatitis with alopecia that commonly
transmission may occur in kenneled dogs. starts around the limbs or the face and the ears, as ulcerative
In the mammalian host, Leishmania is found in macro- dermatitis, as multinodular dermatitis, as mucocutaneous pro-
phages in the amastigote form. Amastigotes are round to ovoid, liferative dermatitis, and as papular dermatitis. The organisms
2.0-5.0 µm in diameter with a basophilic, vesicular nucleus are inoculated by the biting insect and are soon ingested by
and smaller, rod-shaped, darker-staining kinetoplast, but no histiocytes. Rapid proliferation of the protozoa disrupts the
flagellum. They are best visualized by Giemsa staining. phagocytes, and the released organisms are ingested by other
174.e1
Further reading
Dragon DC, et al. A review of anthrax in Canada and implications for
research on the disease in northern bison. J Appl Microbiol
1999;87:208-213.
Spleen and Hemolymph Nodes 175
Figure 2-87 Leishmaniasis in a dog. Leishmania infantum can Figure 2-88 Leishmaniasis in a dog. Spleens infected with Leish-
cause severe lymphadenomegaly. (Courtesy R.C. Menezes.) mania infantum are symmetrically enlarged 2-3 times or more
normal size. (Courtesy R.C. Menezes.)
phagocytic cells to repeat the process. Lymphocytes and lesions in bone marrow may be focal, but consist of clusters
plasma cells surround the lesion, and neutrophils are attracted of epithelioid macrophages with phagocytosed organisms. In
to the debris. When the inflammation extends to the overlying the dog with a well-developed infection, the bone marrow will
epithelium, ulceration occurs especially over bony prominences have remarkable plasma cell hyperplasia that may approach
and along mucocutaneous junctions. Numerous parasites are 50% of cells present, and there is characteristically hypergam-
present within macrophages, and some are free in the tissue. maglobulinemia. The protein is broadly polyclonal, and the
Many dogs will develop concurrent conjunctivitis, uveitis, and plasma cells lack atypia. Renal changes are variable and may
blepharitis. Lymphadenomegaly of multiple subcutaneous consist of interstitial scarring with some parasitic involvement;
nodes is common (Fig. 2-87, eFig. 2-18). Onychogryphosis and however, the effects of hyperproteinemia and immune com-
epistaxis develop in some affected dogs. plexes appear to injure the kidney indirectly. Animals with
The clinical signs of visceral leishmaniasis in the dog are leishmaniasis and amyloidosis have been described, and there
of chronic debilitation and often recurrent oculonasal dis- may be concurrent changes caused by both processes.
charge, with some crusting of the nose, and recurrent diarrhea. Diagnosis is based on the demonstration of the organism in
Many dogs lose weight despite a ravenous appetite. There are cytologic or in histologic preparations, the former being easily
often focal scurfy skin lesions, but generally, in visceral leish- achieved by aspiration of marrow, node, spleen, or liver. There
maniasis, the presentation is of a mature dog in poor body condi- are now several tests based on immunoglobulin titers by
tion with a rough haircoat. Other clinical signs may include ELISA or PCR, immunohistochemistry, or in situ hybridiza-
locomotion disturbances resulting from neuralgia, footpad tion to detect organisms in tissue.
clefts, interdigital ulcers, or, rarely, paraparesis. There may be
mild enlargement of lymph nodes, and the spleen is always
symmetrically enlarged 2-3 times or more normal size and is Further reading
dark brown to black on the capsular surface (Fig. 2-88, eFig. Barral-Veloso L, et al. A β-mercaptoethanol-modified enzyme linked
2-19). The oral and cervical viscera are normal and the lungs immunosorbent assay for diagnosis of canine visceral leishmaniasis.
generally have mild tan mottling but are otherwise normal, as J Vet Diagn Invest 2013;25:239-242.
is the heart. The liver may contain numerous granulomas and Figueredo LA, et al. Clinical and hematologic findings in Leishmania
is symmetrically enlarged and dark brown. Renal disease is braziliense-infected dogs from Pernambuco, Brazil. Rev Bras Para-
common, and the kidneys are darker than normal, and while sitol Vet 2012;21:418-420.
of normal contour, a severe immune-complex glomerulone- Koutinas AF, Koutinas CK. Pathologic mechanisms underlying the clini-
phritis can lead to chronic renal failure. The bone marrow is cal findings in canine leishmaniasis due to Leishmania infantum/
uniformly reddened in midfemoral shaft in well-developed chagasi. Vet Pathol 2014;51:527-538.
cases, but the fat is generally of normal character. Other less Menezes RC, et al. Sensitivity and specificity of in situ hybridization for
common lesions include non-erosive polyarthritis, polymyosi- diagnosis of cutaneous infection by Leishmania infantum in dogs.
tis, osteolysis and osteoarthritis, proliferative periostitis, pan- J Clin Microbiol 2013;51:206-211.
creatitis, meningitis, or chronic colitis. Nascimento MS, et al. Naturally Leishmania infantum-infected dogs
The microscopic lesions in the spleen initially are of hemic- display impairment of chemokine and chemokine-receptor expres-
lymphatic hypertrophy with macrophage proliferation and sion during visceral leishmaniasis. Vet Immunol Immunopathol
focal granulomas. Splenic follicles are hyperplastic, often with 2013;153:202-208.
follicular hyalinosis. In advanced cases, there is atrophy of Rigo RS, et al. Renal histopathological findings in dogs with
lymphoid follicles, and the sinus areas may be diffusely occu- visceral leishmaniasis. Rev Inst Med Trop São Paulo 2013;55:
pied by large macrophages heavily laden with intracytoplas- 113-116.
mic organisms, and numerous plasma cells (Fig. 2-89). The
175.e1
Figure 2-90 East Coast fever in a cow. Bovine lymphoblasts Figure 2-91 East Coast fever caused by Theileria parva in a cow.
containing numerous intracytoplasmic Theileria parva schizonts. Enlarged, diffusely pale lymph node with multiple petechiae.
(Courtesy Plum Island Animal Disease Center, U.S. Department (Courtesy Plum Island Animal Disease Center, U.S. Department
of Agriculture.) of Agriculture.)
Further reading
Bakheit MA, et al. Serological diagnostic tools for the major tick-borne
protozoan diseases of livestock. Parassitologia 2007;49(Suppl. 1):
53-62.
Mbassa GK, et al. Theileria parva infection in calves causes massive
lymphocyte death in the thymus, spleen and lymph nodes without
initial proliferation. Vet Parasitol 2006;142:260-270.
177.e3
Further reading
Tinkler SH, et al. Premature parturition, edema and ascites in an
alpaca with Anaplasma phagocytophilum. Can Vet J 2012;53:
1199-1202.
178 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
A
Figure 2-96 Classical swine fever in a pig. Multifocal necrosis of
palatine tonsils. (Courtesy J.P. Teifke.)
Further reading
Ji W, et al. Studying classical swine fever virus: making the best of a Figure 2-98 Classical swine fever in a pig. Lymphoid necrosis in
bad virus. Virus Res 2015;197C:35-47. Peyer’s patches.
Lange A, et al. Pathogenesis of classical swine fever—similarities to viral
haemorrhagic fevers: a review. Berl Munch Tierarztl Wochenschr
2011;124:36-47.
180.e1
Further reading
Gómez-Villamandos JC, et al. Morphological and immunohistochemi-
cal changes in splenic macrophages of pigs infected with classical
swine fever. J Comp Pathol 2001;125:98-109.
Gregg D. Update on classical swine fever (hog cholera). J Swine Health
Prod 2002;10:33-37.
Spleen and Hemolymph Nodes 181
A
eFigure 2-21 African swine fever in a pig. Acute splenic hemor-
rhage and necrosis. (Courtesy J. Arzt, Agricultural Research
Service–U.S. Department of Agriculture.)
B
eFigure 2-22 African swine fever in a pig. A. Tonsil with severe
lymphoid necrosis. B. Immunohistochemistry depicting African
swine fever virus (red) in macrophages. (Courtesy J. Arzt, Agri-
cultural Research Service–U.S. Department of Agriculture.)
182 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
A
Figure 2-101 African swine fever in a pig. Severely and diffusely
enlarged, dark black spleen. (Courtesy J. Arzt, Agricultural
Research Service–U.S. Department of Agriculture.)
B
Inflammatory diseases of the spleen
Systemic inflammation causes a regular and fairly predictable
pattern of response in the spleen. The phagocytic function of
the spleen is critical in the immune response to blood-borne
pathogens. Therefore all blood passes at least one time every
day through the spleen. Septicemia and bacteremia result in
microbial deposition in the splenic sinus areas, where the
abundance of phagocytic cells usually leads to their rapid
destruction. In septicemia and following injection of endo-
toxin or gram-negative bacteria, there is rapid accumulation
of neutrophils in the splenic marginal zone and the surround-
ing red pulp vascular spaces become congested and form a
concentric ring. There is bacterial destruction and processing
of antigen in this area followed by a predictable pattern of
migration. This consists of foreign material moving in special-
ized macrophages (metallophils) successively into the marginal C
zone and then to the small-lymphocyte corona, reaching the
germinal center in 10-12 hours. In contrast, immune com- Figure 2-102 African swine fever in a pig. (Courtesy J. Arzt,
plexes appear to move by flow and not by cellular transport. Agricultural Research Service–U.S. Department of Agriculture.)
Overwhelming infections result in acute hyperemia and A. Lymph node with severe lymphoid necrosis. B. Immunohisto-
severe lympholysis of the follicular center cells, characterized chemistry depicting African swine fever virus in macrophages.
by accumulation of nuclear debris. Severe lymphoid necrosis is C. Multichannel indirect immunofluorescence technique detects
also a feature of numerous viral diseases, for instance, rinder- African swine fever virus in macrophages in the tonsil. The virus
pest (Fig. 2-103, eFig. 2-23), canine distemper, equine herpes- (red) co-localizes to CD163-expressing macrophages (aqua)
viral infection (Fig. 2-104), canine parvoviral enteritis, feline within and subjacent to a deep epithelial crypt. Cytokeratin-
panleukopenia, and bovine viral diarrhea. The nuclear frag- expressing (green) cells are spared. Nuclei are labeled blue.
ments are rapidly removed in 1 day so that the follicular
center appears empty, with the nuclei of the dendritic cells
relatively widely spaced and surrounded by their densely pink
cytoplasm, and epithelioid macrophages. These epithelioid
182.e1
B
eFigure 2-23 Rinderpest in a cow. A. Acute hyperemia and
severe lymphocytolysis of the follicular center cells in a splenic
follicle. B. Lymphoid necrosis with intranuclear inclusions.
Spleen and Hemolymph Nodes 183
A
Figure 2-103 Rinderpest, in a cow. Acute hyperemia and severe
lymphocytolysis of the follicular center cells in a splenic follicle.
B
Figure 2-105 Mycobacteriosis in a horse (A) and a beaver (B).
A. Multiple granulomas disseminated over splenic capsule.
B. Multiple granulomas throughout splenic parenchyma. (Cour-
tesy E.P. Lane.)
Figure 2-104 Equid herpesvirus, in a horse. Severe lymphoid
necrosis in the spleen.
germinal centers are seen in a variety of acute toxemic diseases to intracellular bacteria, for instance, Mycobacterium spp. (Fig.
in young animals. In older animals, the changes occurring in 2-105); fungi (Fig. 2-106, eFig. 2-24), for instance, histoplas-
splenic germinal centers are often more severe and long mosis; or in chronic hemolytic conditions. Blood monocytes
lasting, and consist of a depopulation of the follicular center may also accumulate in the red pulp. Such reactions can
cells and transudation of plasma proteins into the germinal appear as focal or diffuse granulomatous inflammation. Some
centers to form a fairly persistent coagulum recognized as blood parasites, for instance, Cytauxzoon felis, infect macro-
intrafollicular hyalinosis. These fibrinous exudates may be phages and can cause severe histiocytosis (Fig. 2-107).
removed, with restitution of the follicular center cells or, if Splenic abscesses may be miliary or large and focal, but both
there is extensive vascular damage, they may become mineral- types are uncommon (Fig. 2-108). Abscessation occurs most
ized and result in involution of the germinal center. In very commonly secondary to septicemia or bacteremia by pyogenic
acute diseases, such as anthrax in cattle, the reaction is almost bacteria, including Trueperella (Arcanobacterium) pyogenes,
solely vascular. In the less severe septicemias, such as erysipelas Fusobacterium necrophorum (Fig. 2-109, eFig. 2-25), Rhodococ-
in swine, there is moderate reactive hyperplasia that may be cus equi, Burkholderia pseudomallei, Corynebacterium pseudo-
more developed than that seen in acute fulminant gram- tuberculosis, and Streptococcus equi. Abscesses are usually
negative septicemias such as salmonellosis. localized in the red pulp, where they develop after failure of
Marked hyperplastic changes of the sinus areas are a feature the monocyte-macrophage system to kill them. They usually
of some diseases, such as malaria, trypanosomiasis, equine bulge over the surface, stretching the splenic capsule and
infectious anemia, and malignant catarrhal fever, although contain white or yellow pus. Purulent splenitis may develop by
involution characterizes some infections. Some pyogenic bac- local extension in cattle from penetrating wounds of the retic-
teria, for instance, Francisella tularensis, Yersinia pestis, and ulum and, in horses, by extension from the stomach as a result
Brucella spp., will cause more widespread liquefactive necro- of penetrating ulcers caused by Habronema spp. Inflammation
sis. Red pulp macrophages proliferate, especially in response of the abdominal serosal membranes may extend to the
183.e1
A
eFigure 2-25 Fusobacterium necrophorum in a cow. Splenic
necrosis with sequestration.
B
eFigure 2-24 Aspergillus terreus in a dog. A. Pyogranulomatous
splenitis with intralesional fungal hyphae. B. Hyphae are difficult
to recognize on routine H&E sections and require special stains,
for instance, periodic acid–Schiff.
184 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
Figure 2-106 Aspergillus terreus in a dog. Pyogranulomatous Figure 2-109 Fusobacterium necrophorum in a cow. Multifocal
splenitis with intralesional fungal hyphae. splenic necrosis with sequestration.
Tularemia
Tularemia (deer fly fever) is caused by Francisella tularensis.
The disease was first described in Tulare county of California
and is still more common in the western United States than
elsewhere. The organism is a small, gram-negative, pleomor-
phic, non–spore forming, facultative intracellular bacillus that
is strictly aerobic and shares many cultural and epidemiologic
features with Yersinia pestis, the cause of bubonic plague.
Francisella tularensis is found worldwide except for Australia
and Antarctica, but the biovar tularensis (type A) is found only
in North America, whereas biovar holarctica (type B) occurs
throughout the Northern Hemisphere. Type A is associated
with the terrestrial tick-rabbit cycle of infection and causes
severe illness in humans, cats, and rabbits. Type B is more
commonly found in aquatic species, including beavers and
muskrats. Although both type A and B have been isolated
from cats, type A generally causes more severe disease.
Figure 2-108 Splenic abscess in a horse. Streptococcus equi is a The organism is abundant in nature as an infection of many
rare cause of splenic abscesses. species of rodents, and it is from these, either directly or by the
Spleen and Hemolymph Nodes 185
A
Figure 2-112 Tularemia in a cat. Francisella tularensis causes
severe liquefactive splenic necrosis.
B
Figure 2-111 Tularemia in a beaver. Francisella tularensis causes
multifocal miliary necrosis in mesenteric lymph nodes (A) and
spleen (B).
Further reading
Larson MA, et al. Francisella tularensis bacteria associated with feline
tularemia in the United States. Emerg Infect Dis 2014;20:
2068-2071.
Sjöstedt A. Tularemia: history, epidemiology, pathogen physiology, and
clinical manifestations. Ann N Y Acad Sci 2007;1105:1-29.
Wobeser G, et al. Tularemia, plague, yersiniosis and Tyzzer’s disease in
wild rodents and lagomorphs in Canada: a review. Can Vet J
2009;50:1251-1256.
Histoplasmosis
Histoplasmosis is caused by Histoplasma capsulatum, a soil- Figure 2-114 Histoplasma capsulatum in a dog. Diffuse severe
borne, facultative intracellular, dimorphic fungus that infects splenomegaly with multiple white foci.
macrophages, and is characterized by diffuse involvement of
the mononuclear phagocyte system. Histoplasmosis has a
worldwide distribution. H. capsulatum var. capsulatum is fre- fatal. Given that intestinal and skin lesions have been observed
quently diagnosed in the Mississippi, Ohio, and St. Lawrence without respiratory tract lesions, the intestinal tract or skin
River valley areas of North America. H. capsulatum var. far- may also represent primary routes of infection. However, in
ciminosum has been reported in Japan, and H. capsulatum var. disseminated disease, the intestine could be secondarily
duboisii causes African histoplasmosis. infected like many other tissues.
Like all dimorphic fungi, H. capsulatum exists in a free- Cats with advanced histoplasmosis show nonspecific clini-
living mycelial form that produces small, smooth, globose cal signs, including weight loss, mental depression, anorexia,
2-3 µm in diameter microconidia, and a large, thick-walled, dyspnea and tachypnea, and pale mucous membranes. Dogs
globose 5-18 µm in diameter macroconidia, and in a yeast may have similar signs; however, most cases of disseminated
form. Infection originates most commonly from soil that is rich histoplasmosis will involve the intestinal tract, causing emacia-
with bird or bat feces, and occurs primarily through inhalation tion, persistent large-bowel diarrhea, or even voluminous
of microconidia. Transmission from dog to dog has been estab- watery diarrhea associated with protein-losing enteropathy,
lished, but it is not known if dogs can transmit the disease to tenesmus, and fresh blood in the stool. Both dogs and cats
humans. Inhaled microconidia convert in the infected animal with disseminated histoplasmosis commonly have an enlarged
to the yeast form, which reproduces through budding. Yeast spleen (Fig. 2-114, eFig. 2-26), lymph nodes, and liver, in
organisms are phagocytosed by the monocyte-macrophage combination with icterus.
system and continue to undergo further intracellular replica- Animals with histoplasmosis most consistently have mild
tion. In most cases, organisms are killed through cytokine- nonresponsive, normochromic normocytic anemia. Leuko-
mediated macrophage killing, and infection is cleared through cytic changes vary with the reserves of the animal and the
T-cell immunity. However, even in immunocompetent hosts, stage of the disease. If the animal is in good body condition,
H. capsulatum may become dormant and is not entirely elimi- the bone marrow is competent, and there is neutrophilic
nated from the phagocytic system. Such dormant infections can leukocytosis with some degree of monocytosis. Later with
persist for many months and years. Yeast organisms are more debilitation, the leukocyte count drops to normal levels or
resistant to host immune defenses because they are more lower with left shift and marked toxic changes, including the
invasive and can impair the immune system by raising the appearance of Döhle bodies. There is usually lymphopenia and
intracellular pH and stimulating IL-4 production. The myce- eosinopenia. The organisms are readily recognized on micro-
lial form is only rarely encountered on valve leaflets from scopic examination, hence fine-needle aspiration of liver, spleen,
animals with endocarditis. enlarged lymph nodes, marrow, or skin provides adequate mate-
Most animals are subclinically infected, and clinical disease rial for diagnosis in appropriate cases. Occasionally, the organ-
occurs most frequently in dogs and cats, but has been reported ism may be diagnosed in fine-needle aspirates of lung or
in other species, including humans, swine, cattle, horses, and bronchoalveolar lavage fluids, or lavage of the turbinates in
birds. Cats are at least as likely as dogs to develop clinical animals with sinusitis. Cytologically, the organisms are present
disease and, in fact, histoplasmosis is the second most common in the cytoplasm of macrophages, unless the cells have been
systemic fungal disease in cats in North America. Persian cats injured, and are somewhat larger than when seen in histologic
as well as Weimaraner, Pointers, Terriers, Brittany Spaniels, and preparations.
sporting or working dogs are at higher risk to develop disease. Grossly, the pulmonary lesions of histoplasmosis may be in
In most cases, infection is limited to the respiratory system the form of gray, rounded nodules 1-2 cm in diameter, and
and associated lymph nodes, but lymphatic and hematogenous with a distinct tendency to become confluent, or there may
dissemination may occur quickly in immune-compromised be a diffuse increase in the consistency of the lungs. Intestinal
hosts or animals infected with a high dose of spores. When lesions are located chiefly in the lower part of the small intes-
histoplasmosis becomes apparent clinically, the infection is tine. The mucosa is the site of nodular thickenings or of cor-
disseminated, and the disease is then progressive and always rugations similar to those seen in Johne’s disease of cattle. The
186.e1
Further reading
Gyuranecz M, et al. Tularemia of European brown hare (Lepus euro-
paeus): a pathological, histopathological, and immunohistochemi-
cal study. Vet Pathol 2010;47:958-963.
Stundick MV, et al. Animal models for Francisella tularensis and Burk-
holderia species: scientific and regulatory gaps toward approval of
antibiotics under the FDA Animal Rule. Vet Pathol 2013;50:
877-892.
186.e2
A
Figure 2-115 Histoplasma capsulatum in a horse. Severe multi-
focal granulomatous lymphadenitis.
Further reading
Bialek R, et al. Comparison of staining methods and a nested PCR assay
to detect Histoplasma capsulatum in tissue sections. Am J Clin
Pathol 2002;117:597-603.
Tyre E, et al. Histoplasmosis in a dog from New Brunswick. Can Vet J
2007;48:734-736.
188 CHAPTER 2 • Hematopoietic System Spleen and Hemolymph Nodes
B
Figure 2-118 Melioidosis in a pig. A. In the bronchial lymph
nodes, Burkholderia pseudomallei causes multiple abscesses that
contain thick, caseous, yellow or white pus. (Courtesy S. Kesdang-
sakonwut.) B. Within the center of an abscess is a small eosino-
Figure 2-117 Melioidosis in a pig. Burkholderia pseudomallei philic, club-shaped aggregate (Splendore-Hoeppli reaction)
causes splenic abscessation. (Courtesy S. Kesdangsakonwut.) surrounded by degenerate neutrophils.
Spleen and Hemolymph Nodes 189
Further reading
Najdenski H, et al. Experimental Burkholderia pseudomallei infection
of pigs. J Vet Med 2004;51:225-230.
Sprague LD, Neubauer H. Melioidosis in animals: a review on epizooti-
ology, diagnosis and clinical presentation. J Vet Med B 2004;51:
305-320.
Further reading
Choy JL, et al. Animal melioidosis in Australia. Acta Trop 2000;74:
153-158.
O’Brien CR, et al. Disseminated melioidosis in two cats. J Feline Med
Surg 2003;5:83-89.
189.e2
Figure 2-120 Splenic nodular hyperplasia in a dog. A hyperplas- Figure 2-122 Ruptured splenic hyperplastic nodule in a dog.
tic nodule projects hemispherically above the capsule. Splenic hyperplastic nodules can become engorged with blood
and are prone to rupture causing hemoabdomen.
Figure 2-121 Splenic nodular hyperplasia in a dog. The varie- Figure 2-123 Splenic fibrohistiocytic nodule in a dog. Grossly,
gated pattern is the result of persistent islands of vascular spaces fibrohistiocytic nodules appear similar to nodular hyperplasia, but
in a field of lymphocytic proliferation. do not undergo differentiation toward hematoma.
rearrangements (PARR) testing (see section on Lymphoma on adjacent vascular sinuses, resulting in vascular pooling and
for more details). Architecturally, benign focal lymphoid hyper- thrombocytopenia.
plasia in the spleen tends to be arranged in large irregular
islands that are loosely facetted in a relatively cohesive mass. Fibrohistiocytic nodules
In contrast, lymphomas of a mantle cell or marginal zone type The term splenic fibrohistiocytic nodule has been used by
can be seen to be related to the arteriolar structure of the veterinary pathologists to prognosticate those lesions in which
spleen in multiple smaller foci, some of which contain rem- it is difficult to differentiate among nodular hyperplasia, follicular
nants of germinal centers. Proliferation immediately surround- type lymphoma, and splenic sarcoma. Although the use of
ing fading germinal centers of small cell type is likely of mantle immunohistochemistry (IHC) and PARR testing allows for
cell lymphoma. If the proliferation can be seen in some foci proper identification of follicular type lymphomas, differenti-
to surround the outside of the mantle cell cuff and is com- ating splenic sarcomas from hyperplastic lesions based on
posed of intermediate-sized cells, then the lesion is likely morphology alone still presents a major challenge. Grossly,
marginal zone lymphoma. It is uncertain whether hyperplastic fibrohistiocytic nodules appear similar to nodular hyperplasia,
nodules may progress to become follicular type lymphomas, but occur as highly cellular masses that do not undergo dif-
but the vast majority has no clinical significance. However, ferentiation toward hematoma (Fig. 2-123). Histologically,
severe expansion with blood may lead to formation of a fibrohistiocytic nodules are composed of mixed populations
hematoma that is prone to rupture causing potential hemoab- of lymphoid cells, histiocytes, and spindle cells, referred to as
domen (Fig. 2-122). Focal lymphoid proliferations in the “fibrohistiocytic” cells, admixed with hematopoietic elements
spleen, either hyperplastic or neoplastic, may also become (Fig. 2-124). They essentially present a morphologic contin-
clinically apparent because of effects of the expanding mass uum between nodular hyperplasia and either follicular
Spleen and Hemolymph Nodes 191
Figure 2-124 Splenic fibrohistiocytic nodule in a dog. Fibrohis- Figure 2-125 Splenic extramedullary hematopoiesis in a dog.
tiocytic nodules are composed of mixed populations of lymphoid Histologically, extramedullary hematopoiesis includes all 3 lin-
cells, histiocytes, and spindle cells referred to as “fibrohistiocytic” eages, but one cell line may predominate.
cells.
lymphoma or histiocytic or splenic sarcoma (eFig. 2-28). The is coincident with increased splenic red cell destruction in
proportion of lymphocytes and fibrohistiocytic cells has been immune hemolytic anemias.
used to grade fibrohistiocytic nodules. Grade 1 nodules are Myeloid metaplasia in spleen and other sites of embryonic
composed of 70% or more lymphocytes, and grade 2 nodules hematopoiesis occurs in myelofibrosis (MF), myelodysplastic
have 40-70% lymphocytes. Both grade 1 and grade 2 fibrohis- syndrome (MDS), myeloproliferative neoplasia (MPN), and
tiocytic nodules most likely represent nodular hyperplasia, but combinations of MF with MDS or MPN. If the animal has
follicular lymphoma should be excluded, especially for grade idiopathic myelofibrosis in bone marrow, myeloid metaplasia
1 nodules by using immunophenotyping and PARR testing. in spleen is benign, and typically consists of all hematopoietic
Grade 3 nodules are composed of <40% lymphocytes and lineages with synchronous maturation. Grossly, the spleen is
most likely represent splenic sarcomas, but histiocytic sarco- uniformly enlarged with turgid capsule and rounded borders.
mas have to be excluded by using IHC for CD18 and CD204. The parenchyma is dry and light pink owing to hematopoietic
When combined with the mitotic index, dogs with grade 1 tissue, rather than dark and cyanotic as in congestion. If the
and 2 fibrohistiocytic nodules with >40% lymphocytes and animal has MDS or MPN, there is predominance of one cell
<10 mitoses/high-power field (HPF) had an 87% survival lineage, most often granulocytes, but other cell lineages may
probability of 12 months or more following splenectomy. In also be present. The predominant cell lineage typically has
contrast, dogs with grade 3 fibrohistiocytic nodules with >10 dysplastic changes, and fills the splenic sinusoids. Dyspoiesis
mitoses/HPF were associated with only 55% survival probabil- may affect only one cell lineage, or more commonly all 3, and
ity at 12 months postsplenectomy. may consist of multinucleated rubricytes, incipient Howell-
Jolly bodies, giant metamyelocytes and band neutrophils,
Hematopoietic alterations donut-shaped nuclei, and hypolobulated megakaryocyte
Extramedullary hematopoiesis (EMH) results when there nuclei. Myeloid metaplasia is often accompanied by lymphoid
is cytokine induction for increased cell production and plu- hyperplasia, hemosiderosis, and splenic fibrosis. With increas-
ripotent hematopoietic stem cells available. These cells nor- ing splenic myeloid metaplasia, there is gradual reduction in
mally circulate in very low numbers and, in preparation for the lymphoid compartment, and eventual lymphoid atrophy.
EMH, they return to embryonic sites of colonization, sparing Small infarcts develop and are likely the result of loss of plas-
the germinal centers and periarteriolar lymphoid sheaths. ticity, and fibrous impairment of vascular structures.
Although EMH is commonly found to some degree within Rarely, the spleen contains a myelolipoma, which appears
the spleen of normal dogs, extensive EMH occurs with chronic grossly as a focal pale nodule on cut surface. Histologically,
anemia, chronic respiratory or cardiovascular disease, various myelolipomas are composed of well-differentiated adipocytes
bacterial septicemias, or with certain neoplastic conditions, for with large fat vacuoles that are sharply demarcated from
instance, hemophagocytic histiocytic sarcoma. Grossly, the the normal splenic parenchyma (Fig. 2-126). Adipocytes are
spleen appears unremarkable or mildly enlarged. Histologi- admixed with hematopoietic and largely erythropoietic cells
cally, EMH is characteristically includes all 3 lineages (Fig. that can be sparse or dominate the neoplastic mass. Myeloli-
2-125), but one cell line may predominate, such as the granu- pomas are usually incidental findings.
locytic system in canine pyometra or the erythroid system in
hemolytic anemia. Megakaryocytes are the most obvious Neoplastic diseases of the spleen
hematopoietic precursor and characteristically lie adjacent to The vascular tumors of the spleen are described in Vol. 3,
the smooth muscle trabeculae when stimulation is mild, but Cardiovascular system, and leukemic diseases involving the
may become diffusely distributed in the sinus areas when spleen are described with the myeloproliferative and lympho-
stimuli are pronounced and prolonged. Splenic erythropoiesis proliferative diseases (this chapter). The spleen is expected to
191.e1
A
Figure 2-126 Splenic myelolipoma in a dog. Myelolipomas are
composed of well-differentiated adipocytes with large fat vacu-
oles admixed with hematopoietic and largely erythropoietic cells,
and sharply demarcated from the normal splenic parenchyma.
eFigure 2-29 Splenic hemangiosarcoma in a horse. Most com- eFigure 2-30 Splenic sarcoma in a dog. A non-angiogenic, non-
monly, hemangiosarcomas appear as dark red, blood-filled cystic hematogenic splenic sarcoma appears as a multinodular, white,
masses. firm, highly destructive mass in the splenic parenchyma.
A B
eFigure 2-31 Splenic sarcoma in a dog. A. A non-angiogenic, nonhematogenic splenic sarcoma
composed of sheets of polygonal neoplastic cells arranged in a storiform pattern that is unencap-
sulated and highly invasive. B. Although necrosis can be extensive, neoplastic cells surrounding
blood vessels tend to be more viable.
192.e2
A
Figure 2-130 Splenic sarcoma in a horse. Well-circumscribed,
firm, gray mass that is raised above the splenic capsule.
B
Figure 2-128 Splenic hemangiosarcoma in a dog. A. Well-
differentiated neoplastic endothelial cells form incomplete vascu-
lar spaces that are supported by a collagenous and fibrous stroma.
B. Thrombosis is commonly observed within hemangiosarcomas.
Jembrana disease
Jembrana disease is a severe acute disease that occurs in Bali
cattle (Bos javanicus) in Indonesia, with a case fatality rate of
20%. Mild or subclinical disease occurs in other cattle species
and buffalo. The cause is species Jembrana disease virus
(JDV), family Retroviridae, genus Lentivirus, which is closely
related to bovine immunodeficiency virus. Virus titers are high
in blood in the acute disease, and virus is present in saliva and
milk; direct transmission may then occur to susceptible cattle
via conjunctival, intranasal, or oral routes. During the height
of viremia, virus may also be transmitted mechanically by B
hematophagous arthropods. Recovered cattle may have per- Figure 2-136 Jembrana disease in a cow. A. Lymph node with
sistent low-level viremia, but are probably an infrequent intense proliferation of large lymphoid cells sparing lymphoid
source of infection. Cattle of European breeds and sheep are follicles. B. The bone marrow is infiltrated by proliferating large
resistant to the disease, although subclinical carrier status may lymphoid cells. (Courtesy M. O’Hara.)
persist for many months.
Clinically, following an incubation period of 5-10 days after
infection, there is transient fever, dullness, and anorexia. Mild The general picture may be complicated by concurrent
oculonasal discharge, pallor of the mucosae, and diarrhea with infections, which have included Pasteurella pneumonia and
blood-stained feces are common. Superficial lymph nodes are helminths of the liver, pancreas, or alimentary tract.
visibly enlarged, whereas examination of the blood during the Histologically, 3 phases can be recognized in the acute
febrile period usually reveals anemia, leukopenia, thrombocy- disease process of ~6 weeks. During the first week, there is a
topenia, and in some cases, which may be fatal, an elevated general response by the lymphoreticular system, but in the
blood urea level. Basophilic cytoplasmic inclusions are occa- second phase, up to the fifth week approximately, there is
sionally seen in circulating mononuclear cells. intense nonfollicular proliferation of reticular and large lym-
At autopsy, lesions may not be remarkable, but several are phoid cells (Fig. 2-136, eFig. 2-33). A similar infiltrative
constant and of diagnostic value. Enlargement of lymph nodes process occurs in the liver, kidneys, adrenal medulla, and
with slight edema and blurred corticomedullary junctions are choroid plexus systems of the brain, although the central
widespread but most marked when regional to other affected nervous tissue shows little change. In the cranial lung lobes,
organs, for instance, lungs and liver. During the acute phase, alveolar cells are enlarged, pleomorphic, and proliferative
there is splenomegaly, and on incision the surface shows small alongside infiltrating mononuclear cells (Fig. 2-137, eFig.
gray-red foci. Scattered petechiae or ecchymoses occur irregu- 2-34). Mid-sized pulmonary veins and arteries may be filled
larly in the serosae of the heart, gastrointestinal tract, kidneys, with large numbers of intravascular macrophages. In the third
and below the endocardium. The myocardium and liver phase, the follicular lymphoid system is reactivated, and
contain gray 1-3 mm foci. Pulmonary lesions are subtle, but plasma cells appear progressively. The sequence is consistent
can be detected in the cranial lobes, which are firmer than with a transient immunosuppressive disease. Indeed, the
normal, blue-red, finely mottled, and slightly edematous. humoral immune response can be suppressed and delayed in
Adjacent lobules show mild overinflation. Shallow erosions JDV-infected cattle. Histologic lesions regress, but traces of
may occur in the gastrointestinal tract and caudal tongue, change can be seen up to 60 days after infection.
where an occasional ulcer is also possible. The kidneys are Pleomorphic basophilic cytoplasmic inclusions are present in
consistently pale and have small numbers of gray foci. all affected tissues. By light microscopy, clumps of minute
195.e1
Further reading
Locke JE, Barber LG. Comparative aspects and clinical outcomes of
canine renal hemangiosarcoma. J Vet Intern Med 2006;20:
962-967.
Spangler WL, et al. Primary mesenchymal (nonangiomatous/
nonlymphomatous) neoplasms occurring in the canine spleen: ana-
tomic classification, immunohistochemistry, and mitotic activity cor-
related with patient survival. Vet Pathol 1994;31:37-47.
Yang TJ, Gawlak L. Lymphoid organ weights and organ:body weight
ratios of growing beagles. Lab Anim 1989;23:143-146.
195.e2
eFigure 2-33 Jembrana disease in a cow. The bone marrow is eFigure 2-34 Jembrana disease in a cow. Pulmonary capillaries,
infiltrated by proliferating large lymphoid cells. (Courtesy M. veins and arteries may be filled with large numbers of intravascu-
O’Hara.) lar mononuclear cells. (Courtesy M. O’Hara.)
196 CHAPTER 2 • Hematopoietic System Lymph Nodes
Lymphoid follicle
in outer cortex
Paracortex
Medullary sinus
Efferent lymphatic
vessel
Vein
Artery
Paratrabecular
sinus
Figure 2-137 Jembrana disease in a cow. Mid-sized pulmonary Subcapsular sinus
veins and arteries may be filled with large numbers of intravascu-
Capsule
lar mononuclear cells. (Courtesy M. O’Hara.)
Afferent lymphatic
vessel
Figure 2-138 Schematic drawing of lymph node. Sectioning at
coccoid bodies about 0.5 µm, and larger, pleomorphic intravac- various levels of lymphoid follicles will results in different histo-
uolar structures occur in reticular and large lymphoid cells, logic appearances.
macrophages including Kupffer cells, pulmonary alveolar cells,
and occasionally in vascular endothelium.
Further reading
Tenaya IW, et al. Flow cytometric analysis of lymphocyte subset kinetics
in Bali cattle experimentally infected with Jembrana disease virus.
Vet Immunol Immunopathol 2012;149:167-176.
196.e2
Further reading
Belisle C, Sainte-Marie G. Blood vascular network of the rat lymph
node: tridimensional studies by light and scanning electron micros-
copy. Am J Anat 1990;189:111-126.
Spalding H, Heath T. Pathways of lymph flow through superficial ingui-
nal lymph nodes in the pig. Anat Rec 1987;217:188-195.
Lymph Nodes 197
provide the functional architecture by which the lymph node differentiate without proliferation into CD14-positive macro-
filters lymph, processes antigen, and returns lymphocytes from phages or CD1A-positive dendritic cells. It is believed that
blood to tissue. this process is repeated in lymph nodes for the maturation of
The microcirculatory arrangement directs antigens enter- Langerhans cells to dendritic cells of the germinal centers, and
ing the cortical area in lymphatics to the germinal centers and monocytes for differentiation into dendritic cells of the paracortical
the outer cortex. The germinal center has a specific polarity areas. The process of B-cell maturation then involves the
directed at the source of antigen, which in those germinal interaction of B lymphocytes that have undergone immuno-
centers near the outer cortex can directly be seen to be ori- globulin chain rearrangement in preparation for antigen-
ented to lymph flow from the peripheral sinus. The germinal driven selection by hypermutation. This process takes place
center is surrounded by an elliptical cuff of small B lympho- with the assistance of T-helper cells and on the basis of antigen
cytes that is thicker at the superficial pole region near the presentation in the context of major histocompatibility
peripheral sinus and thinner on the deep pole region adjacent complex cellular recognition. B lymphocytes bound in this
to the deeper areas of paracortex. Within the germinal center manner are selected for further division, finally to become
itself, the cells in the superficial area nearer to the peripheral plasma cells or memory B cells. Those that fail to be bound
sinus have smaller nuclei with more abundant cytoplasm. This in the T-lymphocyte interaction undergo programmed cell
produces a lighter staining area on low-power examination. In death and are removed by follicular macrophages.
contrast, the cells in the deep pole of the germinal center, In the development of the T and B cells there are 2 major
nearer to the paracortex, have larger nuclei with minimal phases of differentiation that include antigen-independent and
cytoplasm, resulting in this area having a darker appearance. antigen-dependent stages. The antigen-independent differentia-
Within the central area of the germinal center, there are large tion occurs in the primary lymphoid organs of the bone
macrophages that contain ingested apoptotic debris, repre- marrow and the thymus where there is no exposure to foreign
senting lymphocytes that have undergone somatic hypermu- antigen. These early stages are the blast cells of the lymphoid
tation and have not been selected for further development. system that are capable of self-renewal. In the germinal center,
Depending on the plane in which the germinal center is sec- these blast cells on exposure to antigen are able to divide and
tioned, these large macrophages may form a complete field become antigen dependent and become less able to prolifer-
with a “starry-sky” effect across the circumference of the ger- ate, and may become memory cells that can last for years.
minal center. This polarity of germinal centers is a constant Tumors of the undifferentiated B cells are of the aggressive
feature of lymphoid tissue in lymph nodes, tonsil, and Peyer’s type, whereas those of the differentiated type are likely to be
patch, and is always most readily observed in relation to of indolent type.
antigen in those follicles near the peripheral sinus. Recognition The germinal center formation may arise from 3-10 naive
of polarity is an important aspect of differentiating benign follicu- B cells that proliferate to form 10-15,000 B-cells in the more
lar hyperplasia from follicular lymphoma. Germinal centers that than 10 generations of cells required to form a germinal center.
lie deep within the node in cases of follicular hyperplasia do The seed cells for the germinal center are derived from the
not have an obvious orientation to the capsule, but it can be naive cells of the mantle cell cuff. These cells initially express
assumed that the deep and superficial poles are oriented to immunoglobulin M (IgM) or IgD that assists them in recog-
the source of antigen and the fine network of lymphatics that nizing antigen in collaboration with the helper T cells and
drain the peripheral sinus. antigen expressed by the dendritic cells. These antigen-
Paracortical tissue may appear as a solid band encompass- differentiated cells proliferate to fill the dendritic cell mesh-
ing the germinal centers, as is typical of the young. With work in the follicle center in ~3 days after initial antigen
maturity, paracortical areas irregularly recede and regenerate stimulation. These blast cells accumulate in the deep pole or
in loosely defined, but densely aggregated, deep cortical units. dark zone of the germinal center, where they lack surface
These units are also defined by cellular composition and vas- immunoglobulin (sIg) and switch off the gene for BCL-2
cular supply as are the germinal centers, but, in contrast to protein and become susceptible to death through apoptosis.
the latter, the deep cortical units are thymus-dependent areas These blasts undergo the somatic mutation of the Ig gene that
populated by T cells. There are gaps in the inner layer of the alters the affinity for antigen of the antibody they produce.
outer sinus by which the entering lymph can pass directly to They may also at this stage switch from IgM to IgG or IgA in
the medullary sinuses. Presumably, this route is taken by heavy the process of the late primary or secondary immune response.
but nonthreatening flow as occurs when frank blood enters The blast cells then mature to a smaller cell as the clone
the lymph node during biopsy (red cells appear in the medul- reduces from 5-10 at the centroblast stage to a few as 3 as the
lary sinuses within minutes of the initiating surgical trauma). degree of somatic mutation increases. These mutated cells
The processing of antigen occurs at random in lymph node then mature to centrocytes and accumulate in the superficial
cortex but is always associated with a background of dendritic or light pole of the germinal center. This process of Ig muta-
reticular cells that function as antigen-presenting cells of the tion produces a marked intraclonal diversity of antibody-
germinal center. A portion, if not all, of the follicular dendritic combining sites from that of only a few precursors. As well,
cells arise from Langerhans cells that develop contact sensiti- in the germinal center, the BCL-6 gene undergoes mutation
zation with antigen in epidermal areas drained by the particu- of the 5′ noncoding promoter region that permits these cells
lar lymph node. Langerhans cells in epithelial areas bind to be identified as having gone through the germinal center
antigen relatively inefficiently, but within the germinal centers reaction. Those centrocytes that have reduced affinity for
they undergo maturation in the process of forming tight junc- antigen undergo apoptosis and are phagocytized by the ger-
tions with other dendritic cells, thus forming a background minal center macrophages. Those centrocytes that have
network for the lymphoid follicles. Blood monocytes cultured increased affinity for antigen may undergo further differentia-
in the presence of macrophage colony-stimulating factor tion to plasma cells by the action of CD23 on the dendritic
(M-CSF) or granulocyte-macrophage CSF and interleukin-4 cells.
198 CHAPTER 2 • Hematopoietic System Lymph Nodes
The dendritic cells of the germinal centers are long lived and Huang C, et al. Lineage-specific functions of Bcl-6 immunity and
may retain antigen on their surface membranes for weeks or inflammation are mediated by distinct biochemical mechanisms.
months in the process of antigen focusing, by which the speci- Nat Immunol 2013;14:380-388.
ficity of a germinal center for a specific antigen is maintained.
The dendritic cells of the paracortical nodules are also long
lived and, in superficial nodes of humans and cattle, they often Developmental diseases of lymph nodes
contain Birbeck granules characteristic of the Langerhans cells The lesions associated with inherited diseases of the immune
of the skin, consistent with an origin and previous experience system are included in developmental diseases of the thymus.
in that area. There is functional logic in this arrangement In severe combined immunodeficiency, lymph nodes lack both
because the follicular macrophages and dendritic cells (B area) germinal centers and paracortical lymphoid colonization. In
are efficient in the digestion and processing of large particulate severe T-cell deficiency, germinal centers are present, but para-
antigens, whereas those in the paracortex (T area) are more cortical areas are hypoplastic and the spleen lacks periarterio-
efficient in trapping low-molecular-weight substances, such as lar lymphoid sheaths. In severe B-cell deficiency, as occurs in
agents producing contact sensitization in the skin, where the agammaglobulinemic foals, germinal centers are not formed
resident reticular cells likely had their initial training. In in lymph nodes or spleen, and plasma cells are not found. The
general, the lymphocytes in the germinal centers are largely B paracortical areas have normal cellularity, and cell-mediated
cells, whereas those in the paracortex are largely T cells. The immunity is intact.
subsets of T cells are also segregated, but not as cleanly, with
the suppressor and natural killer (NK) cells confined almost Degenerative diseases of lymph nodes
entirely to the paracortex, whereas the helper cells are largely Lymphoid atrophy, with or without architectural alteration,
in the paracortex but also in the germinal centers and their occurs in a variety of circumstances. The lack of antigenic
small cell corona of mantle cells. stimulation will result in smaller lymph nodes, as observed in
The process by which lymphocytes exiting the marrow and animals that have been raised germ free. Histologically, such
thymus are directed to specific tissues is regulated by homing nodes have fewer primary and secondary follicles. Peripheral
receptors on the lymphocytes, called intercellular adhesion mol- lymph nodes of younger animals may appear similar, because
ecules (ICAMs), which bind to tissue-specific addressins on they have not been exposed to the same constant antigenic
high-endothelial or postcapillary venules in the peripheral stimulation as those nodes associated with the alimentary or
lymphoid tissues. The characteristic development and binding respiratory tract. Lymphoid atrophy associated with marked
of hematopoietic progenitor cells is mediated by adhesive dilation of medullary sinuses, termed vascular sinus transfor-
functions of cell surfaces, called integrins and selectins, which mation, results from blockage of the efferent lymphatics, and
are members of the immunoglobulin superfamily and identi- is exacerbated by the development of fibrosis if the venous
fied by the CD44 reagent. There are >30 types of integrins, drainage is also obstructed. These conditions may follow surgi-
which are heterodimeric transmembrane proteins, and 3 cal intervention for lymphatic cannulation or occasionally
major subtypes of selectins, each with an affinity for various develop in animals that have been recumbent for prolonged
ligands of endothelial cells in different areas of the body. By periods and suffered concurrent venous infarction of muscle.
these means, naive B and T cells leaving the bone marrow are High doses of radiation cause rapid destruction of lympho-
guided to specific areas of maturation in the thymus, intestine, cytes, especially B cells, and thereby result in smaller lymph
skin, and lymph nodes, and memory cells are directed to the nodes. Histologically, there is severe lymphocyte apoptosis
endothelium of specific tissues. It is worth mentioning in characterized by cell shrinkage, nuclear pyknosis, and frag-
conclusion that all of the hematopoietic-derived cells resident in mentation with apoptotic bodies and tingible body macro-
lymph nodes are capable of forming malignant tumors, including phages. Prolonged high doses of steroids, cytotoxic cancer
the interdigitating reticular cells. This is in contrast to earlier drugs, hypoxia, or heat can also cause severe apoptosis (Fig.
concepts that the cells of lymphomas of B- and T-cell types 2-139). As long as the bone marrow can supply lymphocytes,
remain relatively confined to the initial site of malignant trans- the normal lymph node size and architecture will be restored
formation until late in tumor progression. It is now under- within a few weeks. However, prolonged radiation will cause
stood that neoplastic lymphocytes from either bone marrow or fibrosis. Many viral infections target lymphocytes and will cause
peripheral lymphoid tissues may circulate at low levels early in lymphocyte necrosis in germinal center. Histologically, there is
the development of disease. Their ability to disseminate is cell swelling with chromatin clumping, karyorrhexis and kary-
dependent upon the development of cell surface proteins, olysis, and ultimately abundant eosinophilic cellular debris.
which mimic those of their benign counterparts, and permit Lymphocyte necrosis is frequently accompanied by inflamma-
them to bind to endothelium and extravasate to new tissue tory cells, for instance, neutrophils and phagocytic macro-
sites. phages with intracytoplasmic cellular debris. Examples of
viruses that cause severe lymphocytolysis include equine her-
pesvirus, canine distemper virus, canine parvovirus, feline pan-
Further reading leukopenia virus, rinderpest virus, and bovine viral diarrhea
Baumjohann D, et al. Persistent antigen and germinal center B-cells virus.
sustain T follicular helper cell responses and phenotype. Immunity Cachectic and senile atrophy lead to moderate reduction in
2013;38:596-605. the overall size of body nodes. Aging changes are largely limited
Brum JS, et al. Eosinophilic sarcoma in a pig. J Vet Diagn Invest to mild thickening of the capsule and medullary trabeculae,
2012;24:807-811. with reduced density of germinal centers. Senile atrophy is
Harris NL, Ferry JA. Classification of non-Hodgkin’s lymphomas. In: seldom of note in large domestic animals, and is only seen with
Knowles DM, editor. Neoplastic Hematopathology. 2nd ed. Lip- frequency in dogs, cats, and primates. Grossly, senile lymph
pincott Williams & Wilkins ed; 2001. p. 691-753. nodes are small with edematous fascia, and characteristically
Lymph Nodes 199
Figure 2-139 Lymphoid atrophy in a dog. Prolonged high doses Figure 2-141 Lymphatic sinus ectasia in a dog. Lymphatic sinus
of steroids can cause severe apoptosis of lymphocytes. ectasia or lymphatic cysts can affect both the medullary and
subcapsular sinuses of lymph nodes.
have dark-brown pigmentation of medullary areas that may (Fig. 2-142). Histologically, dilated or cystic sinuses are lined
extend in decreasing concentration to the subcapsular sinus. by lymphendothelium and filled with pale eosinophilic lymph.
Histologically, there is loss of B and T cells and lymphoid fol- A few lymphocytes, plasma cells, and macrophages may be
licles. Cachectic atrophy is frequently encountered in old admixed with the lymph.
sheep and goats with dental attrition, but can be encountered In emphysema of lymph nodes, gas is confined to the
in any animal with chronic debilitating disease caused by sinuses. It affects the mesenteric nodes of swine in association
systemic cancer, malabsorption, or prolonged starvation with intestinal emphysema. Emphysema of the bronchial
leading to cachexia (Fig. 2-140). Cachexia leads primarily to nodes commonly accompanies interstitial pulmonary emphy-
a loss of T cells and decreased T-cell production with little sema of cattle. The lymph nodes are puffy and light. The
effect on B cells. Histologically, cachectic atrophy is character- sinuses are distended, and their endothelium is lined by large
ized by retention of the overall architecture with marked macrophages and even giant cells, the mobilized cells occur-
reduction in cell density. Germinal centers are small with a ring in small clusters of spotty distribution on the walls of the
hypocellular mantle cell corona, and paracortical areas are sinuses.
sparsely populated. In old animals with cachexia, there are Complete or focal infarction of node is rather uncommon
numerous pigment-bearing macrophages in medullary sinuses, and occurs with obstruction of blood flow. Predisposing condi-
and thin proteinaceous fluid may be present in medullary tions include periarteritis nodosa, but in domestic animals,
cords and sinuses. lymph node infarcts are most commonly observed with large
Lymphatic sinus ectasia or lymphatic cysts can affect both cell lymphoma, and may be the first sign of disease. Throm-
the medullary and subcapsular sinuses (Fig. 2-141). Diffuse bosis is seldom observed.
sinus ectasia usually occurs together with lymphoid atrophy Sinus erythrocytosis, originating from hemorrhages in
and can occur as part of the earlier described senile atrophy tissues drained by the node, may be visible in the cortical or
200 CHAPTER 2 • Hematopoietic System Lymph Nodes
Figure 2-143 Sinus erythrocytosis in a pig. Resulting from hem- Figure 2-145 Anthracosis in a cow. The black pigment detected
orrhage in tissues drained by the node. on cross section of a pulmonary lymph node is an incidental
finding.
B
eFigure 2-35 Sinus erythrocytosis in a cow (A) and in a pig (B).
A. Salmonella choleraesuis causes severe parenchymal hemorrhage
and edema. (Courtesy R.L. Amorim.) B. Hemorrhage in tissues
drained by the node results in a marbled appearance.
200.e2
Further reading
Blanchard JL, et al. Generalized amyloidosis in rhesus monkeys. Vet
Pathol 1986;23:425-430.
Ozcan K, Beytut E. Pathological investigations on anthracosis in cattle.
Vet Rec 2001;149:90-92.
Lymph Nodes 201
Lymphadenosis, although not commonly used, more correctly cells interpreted in terms of the history and clinical signs.
defines generalized lymphoid hypertrophy. Local enlargement Benign lymphoid follicular hyperplasia has a characteristic
usually reflects a pathologic process limited to the drainage morphology because of the antigen-oriented polarity of the
area, particularly inflammatory or neoplastic disease. General- normal germinal center that can be highlighted by immuno-
ized enlargement of lymph nodes is a more serious finding, phenotyping (see Lymphoma). For some cases, additional
because it indicates a systemic disease or a systemic neoplastic PCR for antigen receptor rearrangements may be required
disease. Infectious causes of generalized lymph node enlarge- to accurately differentiate follicular lymphomas from follicu-
ment include tuberculosis, brucellosis, and protozoal infec- lar hyperplasia. If a firm decision cannot be made, it is fully
tions. Generalized lymphadenopathy produced by an justifiable to request a repeat biopsy in 10 days, at which time
extraordinary degree of paracortical blastogenesis is typical of a diffuse benign reaction will have developed a follicular
the early phases of malignant catarrhal fever and theileriosis pattern.
in cattle. There may be mild generalized lymph node enlarge- Many infectious diseases, for instance, brucellosis and
ment in adrenal atrophy. Lymphoid hyperplasia to some trypanosomiasis, present no problem in distinction from lym-
degree is transient in most young animals and in mesenteric phoma, and result in a regular picture of follicular hyperplasia
lymph nodes because of stimulation with intestinal antigens. followed by paracortical atrophy with generalized sclerosis
Endocarditis or abscessation may cause generalized lymphade- and medullary cord hyperplasia. In contrast, an unusual type
nopathy, as will lymphoma. In general, in acute septic inflam- of follicular hyperplasia occurs in old sheep and goats that are
mation the lymph nodes are normally mobile within the in poor condition and may have been destroyed because of
subcutaneous tissues, but may become fixed with chronic debility. There is regular capsular thickening and increased
sepsis. Similarly, lymphadenopathy resulting from lymphoma prominence of medullary trabeculae. The follicles may be
usually does not cause fixation of the nodes in the early stages, very large, angular, and facetted in an irregular fashion.
but there is usually perinodal colonization with loss of mobil- Paracortical atrophy is marked, and there is medullary
ity in advanced stages. cord hyperplasia and empty medullary sinuses. The most
Lymphoid hyperplasia is a benign, non-neoplastic, reactive marked changes affect the follicular vessels, which are large,
response to an immune stimulus. It can involve both B cells tortuous arterioles with hyalinized media and often mineral-
in lymphoid follicles and T cells in the paracortex, suggesting ized endothelium. The follicular centers include large epithe-
either a humoral or cell-mediated response, respectively. lioid macrophages and often a very marked tingible body
The histologic picture in benign lymphoid hyperplasia is vari- reaction. This reaction resembles angiofollicular lymph
able, with small and large lymphocytes, with cleaved and node hyperplasia of the hyaline vascular type as described in
noncleaved nuclei, and macrophages, plasma cells, and neu- humans.
trophils. Unless the stimulation is <10 days old, this mixture A nodular reaction of the paracortical areas occurs in lymph
of cells should be organized architecturally with evidence of nodes draining malignant tumors as well as other conditions,
follicular hyperplasia. Reactive or secondary follicles are and appears to represent an exaggerated thymus-dependent
larger than unstimulated primary follicles, and the detailed response. The nodules may be multiple and coexist with fol-
histologic appearance has been described under lymphoid licular atrophy, raising concern that they represent a multifo-
hyperplasia of the spleen. In the early, marked, immune cal diffuse lymphoma. The nodules represent deep cortical units.
response, there will be diffuse parafollicular hyperplasia They are centered on networks of dendritic reticular cells and
with effacement of pre-existing follicles. The paracortex has are densely cellular, but with the histologic variation in cell
a moth-eaten appearance owing to the mixture of cells type characteristic of the paracortex. These paracortical
present, which includes many large macrophages and pale nodules, unlike germinal centers, are irregularly defined from
dendritic reticular cells. In contrast, in lymphomas, there tends the surrounding paracortex by a lighter staining border of
to be a monomorphic or bimorphic cell population and, larger pale-staining dendritic cells and macrophages and fewer
in animals in which follicular lymphomas are uncommon, small densely stained lymphocytes.
finding a monomorphic cell population with diffuse architecture Plasma cell hyperplasia occurs commonly together with
suggests lymphoma. In some lymphomas, macrophages may be B-cell hyperplasia in animals when the response to antigenic
present, and numerous if there is a high mitotic rate in the stimulation requires antibody production. Affected animals
tumor and a high rate of cell death. In contrast, plasma cells have often enlarged nodes that contain large numbers of
and neutrophils tend to be less numerous than in lymphadeni- plasma cells and their precursors in the medullary cords. There
tis, although the presence of plasma cells in itself is no guar- may be partial effacement of normal nodal architecture, and
antee of a benign reaction. There are no lymphomas with 3 or a plasma cell neoplasm may be considered as a potential dif-
more lymphocyte types regularly present, and this fact tends ferential. However, the lack of cortical and capsular infiltra-
to assist in correctly interpreting the early diffuse lymphoid tion, binucleated, megalokaryocytic, and atypical plasma cells
proliferations. help differentiate hyperplasia from a plasma cell neoplasm.
The most important criteria for distinguishing lymphoma from Chronic ehrlichiosis or leptospirosis has been associated with
hyperplasia are the integrity of normal architecture and the uni- severe lymphoid plasmacytosis.
formity of cell and chromatin type. Architecturally, the periph- Macrophage hyperplasia is primarily the result of resident
eral sinus is preserved, even in reactive states where there is macrophage proliferation in the sinuses, but can be seen as
perinodal colonization by benign lymphocytes. In contrast, the aggregates of macrophages within any region of the lymph
outer sinus is regularly encompassed or destroyed by lym- node that is, cortical, paracortical, and medullary. When
phoma of advanced stage. One of the most difficult distinc- aggregates of macrophages occur within the lymph node
tions is between follicular hyperplasia and follicular parenchyma, other terms such as “granulomatous inflamma-
lymphomas, and in these cases, the decision must be based tion,” “granulomatous lymphadenitis,” “histiocyte aggregates/
upon both the architectural changes and the character of the infiltrates,” and “macrophage aggregates/infiltrates,” have been
202 CHAPTER 2 • Hematopoietic System Lymph Nodes
Further reading
Langenbach A, et al. Sensitivity and specificity of methods of assessing
the regional lymph nodes for evidence of metastasis in dogs
and cats with solid tumors. J Am Vet Med Assoc 2001;218:
1424-1428.
Lymph Nodes 203
25% or more of the cells present. The chromatin pattern of posed of follicular hyperplasia, microabscesses, sinus histiocy-
lymphocytes in acute lymphadenitis differs from lymphoma tosis, and fibrosis. Such chronic mixed lymphadenitis is
in that large chromocenters persist in small lymphocytes, and characteristically present in the supramammary lymph nodes
larger lymphocytes, which are presumed to be the prolifera- of cows with brucellosis of long standing, and to a lesser extent
tive population, maintain larger chromocenters in benign con- in animals with chronic or recurrent bacterial mastitis. In the
ditions, but tend to have a more uniform chromatin pattern latter cases, marked proliferation of the collagenous septa of
characteristic of cells in cycle in lymphomas. Suppurative the medulla may completely displace the medullary cords.
lymphadenitis is commonly encountered with bacterial septi- Examples of chronic suppurative lymphadenitis leading to
cemias, for instance, Streptococcus equi, Brucella spp., or True- abscessation include streptococcal infections in different
perella pyogenes. Although severe pyogenic bacterial infections, animal species, localized Trueperella pyogenes infections, or
for instance, Francisella tularensis or Yersinia pestis, cause foreign bodies in small animals causing severe peritonitis (Fig.
focally extensive to severe liquefactive necrosis, focal areas of 2-150). A specific example of a caseous lymphadenitis is caused
necrosis are common with many infections, including parasitic by Corynebacterium pseudotuberculosis. The classic example of
infections, for instance, toxoplasmosis (Fig. 2-147) or bacterial focal granulomatous lymphadenitis is caused by mycobacterial
infections, for instance, salmonellosis or Tyzzer’s disease. infections. Although Mycobacterium bovis causes caseating
In chronic lymphadenitis, hyperemia and edema are irreg- granulomas in lymph nodes of the digestive or respiratory tract
ularly present, and the infected nodes are large and firm, and in ruminants or humans (Fig. 2-151, eFig. 2-37), Mycobacte-
may be fixed to local tissues if there has been cellulitis. The rium avium complex can cause similar lesions in a wide variety
capsule is thickened as are the internal trabeculae, and with of species. Most commonly, granulomas appear caseous and
prolonged inflammation the node becomes dry and hard. single or multifocal throughout the affected node. Histologi-
Lesions can occur as well-encapsulated abscesses (Fig. 2-148, cally, they are characterized by caseous necrotic centers that
eFig. 2-36), granulomatous inflammation that can be focal or often become mineralized and are surrounded by epithelioid
diffuse (Fig. 2-149), or a mixed inflammatory reaction com- macrophages and multinucleated giant cells of Langhans type
(Fig. 2-152). These granulomas are commonly surrounded by
B
Figure 2-149 Granulomatous lymphadenitis in a cow (A) and a
horse (B). A. Mycobacterium bovis can cause severe granulomatous
Figure 2-148 Lymph node abscess in a dog. Large amounts of inflammation or caseous necrosis. B. Rhodococcus equi causing
yellow green pus surrounded by a thick fibrous capsule. multifocal granulomas.
203.e1
A
eFigure 2-37 Tuberculosis in a cow. Multifocal caseous necrosis
of lymph node caused by Mycobacterium bovis. (Courtesy R.L.
Amorim.)
B
eFigure 2-36 Lymph node abscess in a cat (A) and a deer (B).
A. The lymph node parenchyma has been replaced by yellow pus
surrounded by a thick fibrous capsule. B. Trueperella pyogenes most
commonly causes abscesses in a variety of species.
204 CHAPTER 2 • Hematopoietic System Lymph Nodes
Caseous lymphadenitis
Caseous lymphadenitis (CLA) is a suppurative infection of the
lymph nodes, primarily of sheep and goats, caused by Coryne-
bacterium pseudotuberculosis (ovis). The disease occurs in
A sheep wherever they are raised, but horses, camels, deer,
mules, and rarely cattle and humans may be affected. Cattle
can develop a pathologic syndrome that resembles that in
sheep, but they do so quite rarely, and the infection generally
remains localized to 1-2 regional nodes draining an infected
surface wound or a segment of intestine. C. pseudotuberculosis
is also the cause of ulcerative lymphangitis in cattle and horses,
and of pectoral abscesses in horses.
There are 2 serotypes, with type I in ovine, caprine and
occasionally bovine isolates, and type II in buffalo and most
infections in cattle. An exotoxin that consists of a phospholi-
pase D is an important aspect of virulence, with effects includ-
ing intravascular hemolysis, necrosis, pulmonary edema, and
shock.
C. pseudotuberculosis survives briefly in the environment
and is able to spread indirectly, which is an important means
B of spread in sheep and goats that are routinely corralled on
the same bed ground to avoid predation. Infection also occurs
Figure 2-151 Tuberculosis in a cow. A. Diffuse caseous necrosis in shearing wounds in sheep and butting abrasions in males.
of pulmonary lymph node caused by Mycobacterium bovis. B. M. In horses, the disease occurs as ulcerative lymphangitis on
bovis causing miliary granulomatous inflammation of retropharyn- the fetlocks, which is consistent with the concept that skin
geal lymph node. abrasions are important in spread of the organism. The sea-
sonal incidence of abscesses in the pectoral and other regions
of horses suggests that the organism may also be borne by
arthropods.
The disease in goats can be more severe than in sheep, the
most frequent lesions being in the lymph nodes of the head
204.e1
eFigure 2-38 Johne’s disease in a goat. Mycobacterium avium eFigure 2-39 Rhodococcus equi in a horse. Multifocal granulo-
subsp. paratuberculosis causes noncaseous granulomas in mesen- matous inflammation in mesenteric lymph node.
teric lymph nodes.
Lymph Nodes 205
A A
B B
Figure 2-153 Johne’s disease in a goat. A. Mycobacterium avium
subsp. paratuberculosis causes noncaseous granulomas in mesen-
teric lymph nodes. B. Multifocal granulomatous inflammation
with multinucleated giant cells of Langhans type.
A A
B B
Figure 2-154 Rhodococcus equi in a horse. A. Multifocal granu- Figure 2-155 Feline infectious peritonitis in a cat. A. Multiple
lomatous inflammation in mesenteric lymph node. B. Diffuse pyogranulomas distributed throughout the mesenteric lymph
caseous necrosis of lymph node parenchyma. node and along the peritoneal surface. B. Severe pyogranuloma-
tous lymphadenitis.
A
Figure 2-157 Cryptococcus neoformans in a cat. Granulomatous
lymphadenitis with typical “soap-bubble” appearance caused by
the thick gelatinous capsule of the yeast organisms.
B
Figure 2-159 Corynebacterium pseudotuberculosis in a sheep.
A. Diffuse severe, suppurative lymphadenitis resulting in absces-
sation. B. Microscopic abscesses in the cortex of a lymph node.
A
Figure 2-161 Strangles in a horse. Streptococcus equi var. equi
causing suppurative lymphadenitis of the retropharyngeal lymph
node.
Further reading
Windsor PA. Control of caseous lymphadenitis. Vet Clin North Am Food
Anim Pract 2011;27:193-202.
208.e2
Figure 2-162 Jowl abscess in a pig. Streptococcus porcinus causing Figure 2-163 Yersinia pestis in a cat. Lymph node with focally
cervical lymph node abscesses. (Courtesy S. Kesdangsakonwut.) extensive liquefactive necrosis with intralesional bacterial colo-
nies and fragmented leukocytes surrounded by macrophages.
Further reading
Chalker VJ, et al. Genetic diversity of Streptococcus equi subsp. zooepi-
demicus and doxycycline resistance in kenneled dogs. J Clin Micro-
biol 2012;50:2134-2136.
Jaeger G, et al. Haemorrhagic pneumonia in sled dogs caused by
Streptococcus equi subsp. zooepidemicus—one fatality and two
full recoveries: a case report. Acta Vet Scand 2013;55:67.
Pesavento PA, Murphy BG. Common and emerging infectious diseases
in the animal shelter. Vet Pathol 2014;51:478-491.
210 CHAPTER 2 • Hematopoietic System Lymph Nodes
Figure 2-164 Yersinia pestis in a sheep. Abscessation of mesen- Figure 2-165 Postweaning multisystemic wasting syndrome in a
teric lymph node. pig. Porcine circovirus 2 causes palpable lymphadenopathy affect-
ing the inguinal lymph nodes. (Courtesy S. Kesdangsakonwut.)
Further reading
Backhans A, et al. Occurrence of pathogenic Yersinia enterocolitica and
Yersinia pseudotuberculosis in small wild rodents. Epidemiol Infect
2011;139:1230-1238.
Bush JM, et al. Disease transmission from companion parrots to dogs
and cats: what is the real risk. Vet Clin North Am Small Anim Pract
2011;41:1261-1272.
Lymph Nodes 211
A
Figure 2-166 Postweaning multisystemic wasting syndrome in a
pig. Severe lymphadenopathy affecting sublingual and retropha-
ryngeal lymph nodes.
B
Figure 2-168 Postweaning multisystemic wasting syndrome in a
pig. A. Granulomatous lymphadenitis with multinucleated giant
cells and characteristic botryoid inclusions. B. Amphophilic intra-
cytoplasmic inclusion bodies can vary from botryoid clusters to
fine cytoplasmic dusting.
Figure 2-167 Postweaning multisystemic wasting syndrome in a
pig. Enlarged lymph nodes are pale and homogeneous on cut
surface. (Courtesy S. Kesdangsakonwut.) be mediated by the immune system. The diagnosis of PMWS
requires detection of (1) clinical signs: wasting or ill thrift with
or without the other earlier described clinical signs; (2) histo-
is granulomatous inflammation with or without unique globular logic lesions: depletion of lymphoid organs and/or granuloma-
intracytoplasmic viral inclusion bodies in macrophages (Fig. tous inflammation in any organ; and (3) detection of PCV2
2-168). However, severe lymphoid depletion may be the only infection within characteristic lesions (Fig. 2-169).
lesion in lymphoid organs affecting both lymphoid follicles PMWS has been reproduced with combined PCV-2 and
and parafollicular zones. Granulomatous inflammation in lym- porcine parvovirus inoculation, combined PCV-2 and PRRSV
phoid tissues is characterized by epithelioid macrophages and infection, prenatal PCV-2 infection and postnatal porcine par-
multinucleated giant cells that may contain sharply demar- vovirus infection, and dual infections with torque-teno virus
cated, spherical, basophilic, often botryoid cytoplasmic inclu- (TTV) and PCV-2. PMWS been reproduced in gnotobiotic
sion bodies. Less consistent lesions include interstitial pigs with PCV-2 alone, following administration of keyhole
pneumonia, interstitial nephritis, myocarditis, hepatitis with limpet hemocyanin in incomplete Freund’s adjuvant, and has
hepatic atrophy and/or icterus, and perivasculitis in a number been reproduced with PCV-2 alone in cd/cd pigs. Intramus-
of tissues. Liver lesions have been identified as a frequent cular injection of pigs with a vaccine against Mycoplasma
finding and are the most likely cause of icterus and wasting. hyopneumoniae or a nonspecific immunomodulating drug
Although previous reports indicated that PCV-2 capsid pro- (Baypamun) caused clinical signs, moderate to severe gross
teins localized predominantly in the nuclei of infected cells, and histologic lesions of PMWS. Vaccination with selective
abundant amounts of PCV-2 capsid proteins were observed bacterins increased the severity of lesions in conventional pigs
in the cytoplasm of many cells. Vasculitis has been recently infected with PCV-2. It has been shown that monocyte
described as a hallmark lesion of the severe form of systemic chemoattractant protein-1 (MCP-1) expression, but not
PCVAD, and experimental infections with PCV-2b directly interleukin-8, may play a role in the pathogenesis of granulo-
caused acute vasculitis, whereas chronic vasculitis may in part matous inflammation in pigs with PMWS. There are also
212 CHAPTER 2 • Hematopoietic System Lymph Nodes
A
Figure 2-170 Metastatic squamous cell carcinoma in a cat. Clus-
ters of neoplastic epithelial cells in subcapsular sinus of retropha-
ryngeal lymph node.
Further reading
Madec F, et al. Post-weaning multisystemic wasting syndrome and
other PCV2-related problems in pigs: a 12-year experience. Trans-
bound Emerg Dis 2008;55:273-283.
Segalés J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Lymph Nodes 213
types. Highly secretory adenocarcinomas may induce a stron- most likely because of the failure to histologically detect nodal
ger reaction to their secretory products than to the neoplastic metastases that were present in some nodes, as well as excision
cells themselves. Metastatic mast cells cause the same reaction of nodes based on anatomic location rather than evidence of
in nodes as in primary sites, but tend not to incite a strong drainage. In human medicine, sentinel node detection is com-
cellular and stromal reaction even when highly granulated monly applied to detect those lymph nodes that actually drain
(Fig. 2-171). As noted earlier, the medullary cords of lymph the area where the primary tumor is localized. Lymphatic
nodes form a tissue-vascular boundary similar to marrow, and mapping strategies have been devised using a combination of
extramedullary hematopoiesis will colonize these sites. In leu- radio-labeled and colored colloids to define drainage areas
kemias, the neoplastic cells colonize the medullary cords and from a particular anatomic site. Serial sectioning of draining
benign cells are displaced, in this case to the adjacent medul- lymph nodes and immunohistochemical labeling for neoplas-
lary sinuses. In the acute myeloid leukemias, the primitive tic cells, for instance, cytokeratin for carcinomas, as well as
neoplastic cells have round nuclei and resemble the surround- RT-PCR for detecting mRNA specific for neoplastic cells, for
ing residual lymphocytes, making recognition of the meta- instance, mammaglobin, have been used in human medicine
static disease difficult with H&E stains. Diagnosis is aided by to dramatically improve detection of even single neoplastic
the identification of megakaryocytes in either the cords or cells in draining lymph nodes.
sinuses.
Interestingly, detection of regional lymph node metastasis
has not been found to correlate with remission length or Further reading
survival times of dogs with various malignancies, for instance, Nyman HT, et al. A review of the sonographic assessment of tumor
oral malignant melanomas (Fig. 2-172, eFig. 2-42). This is metastases in liver and superficial lymph nodes. Vet Radiol Ultra-
sound 2004;45:438-448.
Worley DR. Incorporation of sentinel lymph node mapping in dogs with
mast cell tumours: 20 consecutive procedures. Vet Comp Oncol
2014;12:215-226.
Lymphoid neoplasms
Lymphomas are neoplasms of the hematopoietic system and
can arise in lymph nodes or extranodal locations. In human
medicine, they are divided into Hodgkin- and non-Hodgkin
lymphomas. Although a Hodgkin-like lymphoma has been
reported in cats, the vast majority of lymphomas in domestic
animals closely resemble non-Hodgkin lymphomas in humans
and are simply referred to as lymphoma or malignant lym-
phoma. Although the term “lymphosarcoma” has also been
used in veterinary medicine, it should be avoided especially
for comparative reasons. Historically, lymphoid leukemias and
lymphomas have been viewed as separate entities. The World
Health Organization (WHO) classification postulates that pre-
Figure 2-171 Metastatic mast cell tumor in a dog. Diffusely
cursor neoplasms occurring as solid tumors, and those lymphomas
enlarged hepatic lymph node caused by infiltration with neoplas-
with marrow and blood involvement, are biologically the same
tic mast cells.
disease with different clinical presentations. An artificial division
using different names has therefore been avoided by using
lymphoma/leukemia for entities that can occur in either form, for
instance, acute lymphoblastic leukemia/lymphoblastic lym-
phoma. Essentially, the presence of neoplastic cells in the bone
marrow and peripheral blood is principally a prognostic factor
that reflects a stage of disease rather than a difference in clas-
sification. However, the biological basis for the different clini-
cal presentations is not fully understood. Because most
precursor lymphoid neoplasms develop in the bone marrow
and are seen as leukemia, the term acute lymphoid leukemia
is still used for the leukemic phase of precursor neoplasms of
T and B cells. For a detailed review of those lymphomas
appearing primarily as leukemias, see Acute lymphocytic leu-
kemia and Chronic lymphocytic leukemia previously.
More important, the WHO classification recently adapted for
animals characterizes different types of lymphomas as specific
disease entities rather than considering lymphoma as a single
biological entity of various morphologic presentations. Although
Figure 2-172 Metastatic malignant oral melanoma in a dog. The the previous lymphoma classifications used morphologic fea-
lymph node parenchyma has been diffusely replaced by the tures such as cell size to grade lymphomas and to predict their
expansile growth of the pigmented melanocytic neoplasm. behavior, the WHO classification establishes a new paradigm
213.e1
Further reading
Kurosumi M, Takei H. Significance and problems of histopathological
examination and utility of real-time reverse transcriptase-polymerase
chain reaction method for the detection of sentinel lymph node
metastasis in breast cancer. Breast Cancer 2007;14:342-349.
Stroup SP, et al. Preoperative sentinel lymph node mapping of the
prostate using PET/CT fusion imaging and Ga-68-labeled tilmano-
cept in an animal model. Clin Exp Metastasis 2012;29:673-680.
214 CHAPTER 2 • Hematopoietic System Lymph Nodes
that identifies lymphomas according to their unique phenotype histologic evaluation of tissue architecture, immunophenotyp-
and genotype. However, each lymphoma type may appear with ing, and clonality assessment. Clinical pathologists often prefer
a variety of morphologic features and a range of clinical B5 fixative for bone marrow sections because the nuclear
behaviors. morphology will be better preserved; however, standardized
immunohistochemistry (IHC) protocols for B5 fixed, demin-
Clinical features of lymphomas eralized tissues are lacking. A high quality, 2-4 µm thick,
Lymphomas are commonly classified according to their ana- H&E-stained slide is essential for lymphoma evaluation
tomic location. The main types of lymphoma include multi- because thicker sections make it difficult to assess cytologic
centric, thymic/mediastinal, gastrointestinal, cutaneous, detail. Some pathologists prefer Giemsa stains for more
extranodal, and central nervous system (CNS). With the adap- nuclear detail. The integration of flow cytometry will become
tation of the new WHO classification that integrates clinical more commonplace in routine lymphoma diagnostics as will
findings with cell morphology and molecular features, such cytogenetic studies.
gross anatomic classification becomes less important. Common Lymphoid tissue is very fragile, and artifacts are commonly
gross presentations and organ systems involved are described induced through tissue compression, delayed fixation, or
in more detail for each individual species later in this chapter. drying of tissues. Histologically, the center of a formalin-fixed
Clinically, most commonly a diagnosis of lymphoma is lymph node is commonly underfixed or primarily ethanol
based on enlargement of lymph nodes or other organs, for fixed, and immunohistochemical stains appear light, or there
instance, hepatosplenomegaly, or ultrasound findings, for is a lack of labeling. Nuclei may be slightly larger with less
instance, thickening of the intestinal wall with intestinal lym- dense chromatin. These features are in complete contrast to
phoma. Clinical signs are based on the primary organ system the lymph node rim, where overfixation or drying out of the
affected and range from anorexia, lethargy, and weight loss; tissue may result in smaller, more basophilic nuclei, and
to dyspnea, coughing, and caval syndrome with thymic/ intense immunohistochemical labeling. Suboptimal fixation
mediastinal lymphoma; vomiting and diarrhea with gastroin- can be compounded by extensive areas of necrosis caused by
testinal lymphoma; cutaneous nodules and plaques with cuta- infarction or focal cellular lysis. Identifying areas with good-
neous lymphoma; and paralysis, seizures, or paresis with quality cell morphology that are representative for the disease
lymphomas of the CNS. Polyuria and polydipsia are com- process is essential, because determining tissue architecture, cell
monly observed because of paraneoplastic hypercalcemia of size, and mitotic index are all parts of reaching an accurate
malignancy. Clinically, staging has been used to prognosticate diagnosis. After differentiating a diffuse from a follicular
multicentric lymphoma: growth pattern, pathologists should determine cell size. The size
• Stage I: Involvement restricted to a single lymph node or of neoplastic lymphoid cells is based on the size of their nuclei
organ (not bone marrow) compared to erythrocytes. Small lymphoid cells have nuclei
• Stage II: Regional lymph node involvement (restricted to 1-1.25 times the size of erythrocytes, intermediate lymphoid
one side of diaphragm) cells have nuclei ~1.5 times the size of erythrocytes, and large
• Stage III: Generalized lymph node involvement cells have nuclei at least 2 times larger than erythrocytes. The
• Stage IV: Involvement of the liver and/or spleen and gen- mitotic index is determined as the average number of mitotic
eralized lymph node involvement figures in 10 random high-power (40×) fields (HPF) in the
• Stage V: Involvement of blood and bone marrow and/or areas of highest mitotic activity. A low mitotic index is defined
other extranodal sites as 0-5 mitoses/HPF, a medium mitotic index as 6-10 mitoses/
As noted earlier, the more recent classification of lympho- HPF, and a high mitotic index as >10 mitoses/HPF.
mas according to the WHO provides more accurate prognos- Immunophenotyping is an essential part of an accurate
tic information and therapeutic guidance because it recognizes diagnosis of lymphomas. In domestic animals, CD3 is used to
lymphomas as a heterogeneous group of distinct diseases that detect T cells and CD79a for B cells. In dogs and cats, CD20
are unrelated to one another, and not grades of a single disease and Pax-5 are commonly used instead of CD79a because
entity. The WHO classification predicts the biological behav- CD79a commonly causes artifactual nuclear binding. Immu-
ior of different types of lymphoma by pathologic features (cell nophenotyping is required to reach a conclusive diagnosis
size, proliferation) or clinical features, and thereby fosters because a number of lymphoma entities are morphologically
establishment of entity-specific therapeutic approaches. homogeneous, but are phenotypically heterogeneous, for
Laboratory findings are highly variable. Nonregenerative instance, small lymphocytic lymphoma, lymphoblastic lym-
anemia of various severities is commonly observed. Both lym- phoma, marginal zone lymphoma versus T-zone lymphoma,
phopenia and lymphocytosis may occur with different types or diffuse large B-cell lymphoma versus peripheral T-cell lym-
of lymphomas, and hypercalcemia of malignancy owing to phoma. Additional antibodies used for lymphoma diagnosis
secretion of parathyroid hormone-related peptide (PTHrP) or include CD45, CD45RO, CD18, CD204, CD34, CD30,
bone lysis has been commonly observed with some lymphoma CD90, BCL-2, Ki-67, granzyme B, perforin, CD10, BCL-6,
entities. More detailed descriptions are provided with each GCET1, FOXP1, CD204, MUM-1, immunoglobulin and
lymphoma entity. light-chain antibodies, and, in frozen sections, CD4 and CD8.
Details on their application are listed later under the indi-
Diagnosis of lymphomas vidual lymphoma entities. Although the list appears long,
The accurate diagnosis of malignant lymphoma requires compared to human medicine, veterinary pathology stills lacks
proper selection and handling of tissues, and ancillary tests are a number of essential, species-specific antibodies to more
essential. Ideally, a combination of cytology and histology is accurately diagnose lymphomas. It is also important to recog-
desired. Touch preparations are important for cytologic assess- nize that antibodies targeting epitopes in a particular species
ment; submission of surgical biopsies fixed in 10% neutral may not react with another species at all and either do not
buffered formalin is a good all-purpose approach to allow label target cells or, often even more dangerous, label epitopes
Lymph Nodes 215
expressed on other cell types. A good example is Bla.36, which by IHC or flow cytometry not PARR testing, as neoplastic
labels B cells in a variety of species, but will also detect den- lymphocytes may show cross-lineage clonal rearrangement.
dritic cells in most domestic animals, for instance, histiocytic The incidence of cross lineage rearrangement in different lym-
sarcomas in dogs. Regardless, immunohistochemical labeling phomas has been reported between 7-10%. Even exclusive
can only be interpreted in association with the cell morphol- amplification of the cross-lineage receptor can be observed
ogy and has to be correlated to the morphologic diagnosis. either because of failure of the PARR assay primers to recog-
Having a reactive cell background or diffuse infiltration with nize the specific rearrangement within receptor matching the
T cells or dendritic cells is common, and the pathologists need lymphoma phenotype, or because of chromosomal alterations
to carefully determine immunohistochemical labeling of the within the neoplastic lymphocytes that distorted the sequence
neoplastic cell population. This also includes assessment of the of the primer binding site and resulted in binding failure.
proper type of labeling, for instance, membranous versus intra- Unfortunately, it is not uncommon practice to aspirate
cytoplasmic versus nuclear. As an example, nuclear labeling enlarged lymph nodes and to diagnose a B- or T-cell lym-
for CD79a is a common artifact and has to be disregarded phoma based on single-run PARR testing. Failure to properly
when evaluating tissues microscopically. diagnose the aspirate based on cell morphology and to deter-
Numerous lymphoid neoplasms are difficult to differenti- mine the immunophenotype by antibody reaction as well as
ate from inflammatory conditions. In particular, enteropathy- not performing PARR testing in duplicate and for both recep-
associated T-cell lymphomas of small cell type, or cutaneous tors will result in a risk of at least 20% false-positive results.
lymphocytosis in cats, and lymphohistiocytic proliferations in Alternatively, if the histologic features and immunopheno-
the skin or lymphofollicular proliferations in lymph nodes or typical results are consistent with a diagnosis of lymphoma
spleen of dogs pose a morphologic challenge to the patholo- despite a polyclonal PCR result, a diagnosis of a suspected
gist. Detection of clonality using the PCR for antigen receptor lymphoma should still be made and additional biopsy sample
rearrangements (PARR) assay of the T-cell receptor γ and/or from a later date should be tested with PARR.
immunoglobulin heavy chains has become the gold standard
for differentiating neoplastic (monoclonal) from reactive Classification of lymphomas
(polyclonal) lymphocytes in dogs and cats (Fig. 2-173). Throughout the last century, veterinary pathologists have used
However, PARR testing should never be used independently of classifications that were developed for non-Hodgkin lympho-
the histologic features, immunophenotype, and clinical findings. mas in humans to classify malignant lymphomas in domestic
PARR should only be applied after preliminary differential animals, especially dogs. Whereas early classification systems
diagnoses have been established. Testing should be done using were based entirely on the morphologic characteristics of
capillary gel electrophoresis to achieve sufficient resolution for malignant lymphocytes, the ability to further differentiate
properly differentiating monoclonal from polyclonal popula- cells immunohistochemically led to a revision of the historical
tions. False-negative results can occur because of the limits of classification systems.
the qualitative sensitivity (the ability of the assay to detect The Rappaport classification from 1966 is one of the earli-
clonal rearrangement) or quantitative sensitivity (the ability of est classification systems applied to canine malignant lympho-
the assay to detect a clonal rearrangement in a background of mas and according to this classification, a large number of
non-neoplastic lymphocytes). Qualitative sensitivity is espe- canine malignant lymphomas were classified as histiocytic.
cially affected by the use of species-specific primers and early With increasing knowledge of the immunologic aspects of
primer sets that had been developed based on limited sequence malignant lymphomas, a better understanding of maturation
data. Even the most recently published multiplex PCRs do and differentiation of lymphoid cells, and the advance of
not detect all potential gene rearrangements, and aiming for chemotherapy, new classification systems were developed.
100% sensitivity may be simply cost prohibitive with the Almost simultaneously, the Lukes-Collins classification in
current methodology. The qualitative sensitivity is most com- North America and the Kiel classification in Europe were
monly reduced by either having a large population of inflam- published. Both systems were based on immunologic concepts
matory lymphocytes infiltrating the tissue to be tested or by and only differed significantly in the identification of 2 of 13
having numerous other tissue samples included with the test entities. This difference was mainly because of the different
material, for instance, numerous endoscopic biopsy samples position of centrocytes within the line of maturation in each
of small intestine in a single tissue block with only a few classification. Despite these differences, a translation from one
samples being suspect for lymphoma. In general, PARR testing to the other classification was still possible. In particular, the
has a higher sensitivity in nonlymphoid tissues compared to Kiel classification was easily adapted for canine malignant
lymphoid tissues because the rearranged sequences from lymphomas.
normal lymphocytes compete with amplification of the neo- To avoid further confusion and in attempt to unify the
plastic DNA. Although PARR assays have been shown to be European and North American classifications, the National
highly specific, false-positive results can also occur. Very small Cancer Institute initiated a multi-institutional study. As a
number of inflammatory lymphocytes within a sample or result, the Working Formulation was published in 1982. In
certain inflammatory conditions, for instance, infection with contrast to the previously described classifications, the working
Ehrlichia canis, may result in a clonal PCR result. The most formulation represents a form of lymphoma “Esperanto,” a
common false-positive results are cause by a procedural error translational system for the existing human non-Hodgkin lym-
that causes pseudoclones that occur in up to 10% of per- phoma classifications. The Working Formulation was strictly
formed tests. To avoid pseudoclones, all PARR testing should oriented on the clinical outcome and not based on a morpho-
be run in duplicate, along with both native and denatured logic principle. The various lymphoma entities in this classifi-
forms. Furthermore, it is essential not to mistake clonality results cation were based on groups of human patients with similar
for immunophenotype. The phenotype of a lymphoma should survival curves, and the morphologic features for each group
always be based on expression of CD molecules as determined were described following a classification according to survival.
[bp] A1 A2 A3 A4 A5 A6 [bp]
300 300
250 250
200 200
150 150
Peak size
Peak size
100 100
75 75
50 50
25 25
15 15
1.400
1.300
15 bp
1.200 105 bp
1.100
Relative fluorescence
1.000
units [RFU x 180]
0.900
0.800 3,000 bp
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0.000
[bp]
15
50
100
150
200
250
300
400
500
3,000
Size
1.500
1.400
15 bp
1.300
1.200
1.100
Relative fluorescence
3,000 bp
units [RFU x 180]
1.000
0.900
0.800
0.700
0.600
0.500
0.400
0.300 109 bp
0.200
0.100
0.000
[bp]
15
50
100
150
200
250
300
400
500
3,000
Size
Figure 2-173 PCR for antigen receptor rearrangement for T-cell receptor γ in a cat. A. Duplicate
runs with capillary gel electrophoresis result in single strong bands for monoclonal (neoplastic)
cell populations (lanes A1 and A2) or smear for polyclonal (inflammatory) cell populations (lanes
A3 and A4). Negative control (lane A5), positive control (lane A6). B. In the electrophoretogram,
monoclonal (neoplastic) cell populations are characterized by a single dominant narrow peak
(105 bp). C. Polyclonal (inflammatory) cell populations produce a curve or broader peak that is
at least 2 3 shorter (109 bp).
Lymph Nodes 217
Benign follicular hyperplasia Follicular lymphoma (B-cell) Marginal zone lymphoma (B-cell) Mantle cell lymphoma (B-cell)
Retention of mantle: cuff of No mantle cell cuff, with Primary in spleen or node. Primarily spleen, rare in node.
small dark-staining cells. vessels compressed between Splenic are locally extensive intermediate-sized nuclei,
Cells have antigen-related follicles. arising on end arterioles and smaller than MZL: round,
polarity: deep dark zone and Uniform proportion of large to coalescing. Node/spleen follicles dense chromatin, small or
light superficial zone, best intermediate cells arise on fading GCs. Round inapparent nucleoli, little
seen in follicles near capsule. (centroblasts to centrocytes) intermediate-sized nuclei with cytoplasm, no mitoses in early
in all follicles. peripheralized chromatin, very cases. Larger nuclei with
Follicular tingible body nucleoli in blastoid cases.
macrophages numerous. Follicular tingible body large prominent single central
macrophages absent. nucleoli, abundant lightly stained Resemble large fading GCs.
cytoplasm, distinct cell boundaries. Surrounded by variable
Grade based on centroblasts numbers of MZL cells and
per 400: FL1 0-5; Mitoses absent in early cases.
(hyperplasia mixed with mantle plasma cells.
FL2 6-15; FL3 15.
cells)
Diffuse large B-cell lymphoma (B cell) Lymphoblastic lymphoma Anaplastic large cell Peripheral T-cell lymphoma
Uniform, round or cleft nuclei. intermediate-sized nuclei, lymphoma anisokaryosis and poikilokaryosis
Centroblastic Uniformly shaped nuclei, round to oval, moderate Uncommon.
multiple nucleoli impinging on nuclear anisokaryosis. Chromatin Always some
dense and dispersed, Lymphoplasmacytic
membrane, scant cytoplasm. multinucleated cells, very
multiple obscured small lymphoma rare. Nodal, small
Immunoblastic 90% of cells have irregularly shaped nuclei
nucleoli, scant basophilic nuclei, deeply red cytoplasm,
uniform round or oval nuclei with single (horseshoe, elongated);
cytoplasm. Consistently few mitoses.
central nucleolus. often vacuolated cytoplasm.
high mitotic rate with Mostly T cell, can be B cell.
T-cell–rich large B-cell lymphoma. chromosomes not sharply
R/O histiocytic sarcoma. CLL & small lymphocytic
Few large B cells amid many small defined.
lymphoma rare. Small nuclei,
non-neoplastic T cells. Abundant stroma B cell or T cell (most few mitotic figures.
with focal ischemic necrosis. T cell).
Figure 2-174 Schematic flowchart for the diagnosis of the most common canine malignant lym-
phoma entities. (Based on concept created by J.L. Caswell.) Follicular versus diffuse lymphomas
are divided based on their yellow and blue background color, nuclear sizes are divided based on
the purple, green, and red colors outlining the text boxes, and the mitotic rate is divided based
the red, green, and blue font color. CLL, chronic lymphocytic leukemia; DC, dendritic cell; FL,
follicular lymphoma; GC, germinal center; HPF, high-power field; MΦ, macrophages; MZL, mar-
ginal zone lymphoma; RBC, red blood cell; R/O, rule out.
location of the lesion, its clinical course, and tissue architec- the biologically more aggressive diseases. It is of the utmost
ture. This understanding was largely driven by the advent of importance that veterinarians do not simply extrapolate survival
IHC, which demonstrated that cells with similar morphology and therapeutic response data from human medicine to the spe-
might have a differing phenotype and markedly different cific lymphoma entities that are now recognized in domestic
biology in both normal and neoplastic presentations. animals according to WHO criteria. In human medicine, an
The WHO classification of human non-Hodgkin lympho- International Prognostic Index (IPI) has been established that
mas has been tested clinically and for each lymphoma entity is used concurrently with the WHO classification to accu-
its frequency of occurrence, median age of affected patients, rately prognosticate the various lymphoma entities. This index
ratio of males to females, stage distribution, survival, and includes stage, patient age, number of extranodal sites, perfor-
therapeutic response are well known. Basically, the WHO mance status, and serum lactate dehydrogenase (LDH) levels.
classification identifies 3 major categories of lymphoma based Such index has not been established for domestic animals.
on their biological behavior: the indolent, the aggressive, and the The WHO classification is not a rigid classification, and a
highly aggressive entities. This classification does not necessarily number of disease entities, for instance, cutaneous anaplastic
reflect survival of human patients because current therapeutic lymphomas and Burkitt-like lymphomas, still pose difficulties
approaches result in a better outcome/curability for regarding their prognosis or reproducibility of their diagnosis,
Lymph Nodes 219
respectively. Advances in genetics and IHC have helped to nodular-sclerosis feline cases, and lacunar cells were noted in
further categorize diffuse large B-cell lymphomas into cases small numbers in feline LPHD. Whether such cases truly
that respond well or poorly to classic CHOP (cyclophospha- represent a unique type of HLL in cats or a type of T-cell–rich
mide, hydroxydaunorubicin [also known as doxorubicin or B-cell lymphoma requires further studies. Regardless, cats
adriamycin], Oncovin [vincristine], and prednisone) therapy. with solitary lymph node enlargement and a diagnosis of
In a similar manner, the original study of canine lymphomas suspected HLL or T-cell–rich B-cell lymphoma should be
focused mainly on nodal lymphomas, because they are the treated differently than cats with diffuse large B-cell lym-
most common entities in dogs, and ignored other lymphoma phoma. This entity has been suggested to represents a less
types. Individual studies later reviewed other entities in aggressive neoplasm that may not require chemotherapy.
domestic animals, for instance, gastrointestinal lymphomas in Additional studies are needed to more accurately establish the
dogs and cats, and showed efficacy of the WHO classification behavior and therapeutic response of these neoplasms.
for these entities as well. As a pathologist or oncologist diag- Precursor lymphoblastic leukemia/lymphoma. Lympho-
nosing or treating lymphomas, the most current publications blastic lymphomas (LBL) are highly aggressive lymphomas of
should be reviewed pertaining to the current understanding B, T, or rarely natural killer (NK) cell lineage that can occur
of classification and associated behavior and therapeutic in the lymph nodes, spleen, and most commonly thymus/
response of any particular lymphoma entity in any animal mediastinum in all domestic animals. In dogs, they are most
species. frequently of T-cell origin (Fig. 2-175). Neoplastic lymphoid
The following text characterizes each lymphoma entity cells form diffuse, dense infiltrates of monomorphic,
according to the WHO criteria as far as they have been estab- intermediate-sized cells that are characterized by oval or folded
lished for animal species (see Table 2-5). convoluted nuclei with a thin nucleolemma, dispersed chromatin,
Hodgkin-like lymphoma. Hodgkin-like lymphoma (HLL) and indistinct nucleoli. The absence of any parachromatin clear-
that meets acceptable criteria as described for Hodgkin lym- ing makes these tumors appear darker when viewed histologi-
phoma in humans does not occur in animals. Hodgkin-like cally at low magnification. The volume of the deeply stained
lymphoma has been suggested to occur in cats and less com- cytoplasm is minimal. They have a high mitotic rate of usually
monly in dogs. The diagnosis of Hodgkin lymphoma (HL) >10 mitoses/HPF, but the mitotic figures are not as distinct as
rests on the demonstration of one of the types of Reed- in other types of lymphoma. When neoplastic lymphoid cells
Sternberg cell in a background appropriate for the specific sub- infiltrate outside lymphoid tissues, they often appear in a
types of Hodgkin disease, lymphocyte-predominant (LPHL) or single-file pattern. Immunophenotyping may be difficult,
classic, with the subtypes lymphocyte-rich, mixed-cellularity, because CD20 and CD3 may be negative in B- or T-cell lym-
nodular-sclerosis, and lymphocyte-depleted HL. These criteria phoblastic lymphomas, respectively, and a small subset will be
have not been met in suspected cases of HLL in domestic animals. bi-phenotypic, expressing both CD20 and CD3.
The Reed-Sternberg cell has been shown to be of B-cell type With lymphomas of LBL type, it is very important to make
by analysis of single cells derived from human cases, and is the identification of cell type near the edge of the tissue,
Pax-5 positive. Most cases reported as Hodgkin lymphoma in where fixation is rapid for the chromatin to display the dis-
dogs and cats most likely represent T-cell–rich B-cell lym- persed quality. One of the values of the Tru-cut biopsy is its
phoma, a form of diffuse large B-cell lymphoma. Differentiat- small size, permitting rapid fixation of the whole biopsy. Lym-
ing T-cell–rich B-cell lymphoma from HLL is extremely phoblastic lymphoma and lymphoblastic leukemia most likely
difficult even when using IHC. Although Reed-Sternberg cells represent different ends of a spectrum of a single disease
tend to be CD20 and CD79a negative and Pax-5, CD30, and entity. Although the T-cell lymphoblastic lymphoma occurs
CD15 positive in classic forms of Hodgkin disease, in LPHL, commonly in the thymus, the vast majority of B-cell lympho-
CD30 negative, CD20-, and CD79a-positive Reed-Sternberg blastic neoplasms occur as acute leukemia originating in bone
cells have been reported. Uniformly strong positive labeling marrow (see section on Hematopoietic neoplasia). Clinically,
of the large cell population for CD20 confirms a diagnosis of animals with T-LBL frequently have hypercalcemia (Fig.
T-cell–rich B-cell lymphoma. 2-176). Often animals in good body condition suddenly lose
HLL has been best described in cats with unilateral man- appetite and appear depressed and may show signs of labored
dibular or cervical lymphadenopathy. In this study, 9 of 20 breathing on physical examination.
cats were classified as having LPHL-type disease and the Mature (peripheral) B-cell neoplasms
remaining 11 cats as classic forms of Hodgkin disease. All cases B-cell chronic lymphocytic leukemia/small lymphocytic
had labeling of small- to intermediate-sized lymphocytes for lymphoma. B-cell chronic lymphocytic leukemia/small lym-
CD79a, and the different types of Reed-Sternberg cells were phocytic lymphoma (B-CLL/SLL) is characterized by prolif-
negative for CD79a, CD3, Bla.36, and Mac387. Unfortu- eration of mature-looking, small lymphoid cells, and only rare
nately, IHC was not performed for Pax-5, CD20, CD30, and cases occur as lymphomas, whereas the majority occur as
CD15. Although lesions in these cats were classified according leukemias. A detailed description is therefore provided under
to the different subtypes of Hodgkin lymphoma in humans, leukemia. Nodal forms of B-SLL efface the lymph node archi-
there were a number of differences. The reported immuno- tecture and are originally localized in the interfollicular zones.
histochemical labeling is in contrast to human LPHL where The dark-staining, small lymphoid cells surround lighter-
detection of CD20- or CD79a-positive large cells in a nodule staining foci that represent proliferation centers. Neoplastic
of CD20- or CD79a-positive small cells is a characteristic cells commonly infiltrate the perinodal tissue. Nuclei of neo-
histologic feature. Furthermore, diagnostic Reed-Sternberg plastic lymphoid cells are small, round, have condensed chro-
cells were rare in cases of feline mixed cellularity and nodular matin, and inconspicuous nuclei. The cytoplasm is scant and
sclerosis HLL compared to human Hodgkin disease. In addi- the mitotic index is low. Slightly larger, prolymphocytic cells
tion, lymphohistiocytic cells were found in conjunction are dispersed throughout the sheets of neoplastic cells. Immu-
with classic Reed-Sternberg cells in mixed-cellularity and nophenotyping with CD79a will identify B-cell lineage, but
220 CHAPTER 2 • Hematopoietic System Lymph Nodes
A
Figure 2-176 Hypercalcemia of malignancy in a dog. Metastatic
mineralization of the kidney in a dog with precursor T-cell lym-
phoblastic lymphoma. (Courtesy K.G. Thompson.)
A B
C D
Figure 2-177 Diffuse large B-cell lymphoma in a dog. A. The neoplasm expands diffusely and
quickly, destroying the tonsillar architecture. B. Sheets of large centroblastic or immunoblastic B
cells that are interspersed with tingible body macrophages resembling a “starry-sky.” C. Neoplastic
B cells are diffusely positive for CD20 by immunohistochemistry (IHC). D. Rare CD3-positive
non-neoplastic T cells can be detected by IHC.
testing and no immunophenotyping. This practice is very antibodies against CD10, GCET1, BCL-6, MUM-1, and
unfortunate because it carries a risk of misdiagnosis. Peripheral FOXP1. Differentiating these 2 entities is clinically important
T-cell lymphomas can appear histologically similar to DLBCL because ABC DLBCLs have significantly reduced survival
and account for up to 30% of nodal lymphomas. Fine-needle time despite CHOP therapy, but survival improves when
aspirates also do not allow for evaluation of the tissue archi- treated with bortezomib. A similar algorithm has recently
tecture, and differentiating high-grade follicular lymphomas been established for dogs, and preliminary data indicate that
or even hyperplastic lesions from DLBCL may present a chal- labeling, especially with GCET1 and CD10, predicts CHOP
lenge. Considering that the sensitivity of PARR testing for IgH response in canine DLBCL.
receptor has only a sensitivity of ~65% and that cross-lineage Anaplastic DLBCLs are uncommon lymphoid neoplasms
rearrangement occurs in ~10% of cases, making a diagnosis of in dogs that are characterized by neoplastic B cells that have
DLBCL based on cytology and PARR testing alone without large, often bizarre nuclei, and abundant amounts of cyto-
immunophenotyping is not acceptable for diagnostic purposes. plasm. These lymphomas are indistinguishable from the more
DLBCL also pose a therapeutic challenge. Chemotherapy common anaplastic large T-cell lymphomas, and also need to
most commonly consists of CHOP treatment and large number be differentiated from histiocytic sarcomas by IHC. In human
of cases respond to therapy. However, a subset of DLBCL will medicine, the diagnosis of anaplastic T-cell lymphomas is
fail therapy during initiation. There are currently no morpho- based on positive labeling with anaplastic lymphoma kinase
logic features that correlate the neoplastic phenotype to thera- (ALK), which is usually negative in anaplastic B-cell lympho-
peutic response. In human medicine, DLBCL have been mas, thereby justifying their classification as DLBCL.
subclassified into activated B-cell–like (ABC DLBCL) and ger- TCRBCL is a variant of DLBCL that represents the
minal center B-cell–like (GCB DLBCL) based on gene expres- most common lymphoma in horses and the most common
sion profiling. Currently, an immunohistochemical algorithm nodal lymphoma in cats, but has been reported in dogs (Fig.
published by Choi and colleagues (see Further reading, this 2-178). In contrast to DLBCL, TCRBL are primarily com-
section) is used to identify these 2 subtypes by using posed of sheets of small, reactive T cells admixed with
222 CHAPTER 2 • Hematopoietic System Lymph Nodes
Marginal zone
Marginal zone
Marginal zone lymphoma
Intermediate cell:
Mantle cell
Marginal zone lymphocyte
Mantle zone
Mantle cell lymphoma
Intermediate cell:
Mantle cell lymphocyte
Germinal cell–light zone
Figure 2-179 Schematic drawing of origin of B-cell lymphomas based on normal follicle architec-
ture. (Based on concept created by P.F. Moore.)
A B
Figure 2-180 Follicular hyperplasia in a dog. A. Follicular polarity reflected by an eccentric cuff
of small mantle cells that are thicker over the peripherally oriented lighter zone of the germinal
center. B. Immunohistochemistry for BCL-2 highlights polarity by labeling mantle cells, but not
follicular center cells.
follicular hyperplasia. Polarity and the eccentric mantle cell the dendritic bed of fading germinal centers. This feature has
cuff are even more easily recognizable when labeling tissues been described as fading follicular hyperplasia (FFH). Regard-
with CD20. The follicles are discrete and separated by at least less, clonality testing may be required to differentiate neoplas-
some interfollicular lymphoid tissue. Involution and “fading” tic from hyperplastic follicular proliferations.
of follicles are commonly observed with follicular-derived Follicular lymphoma (FL) is an uncommon follicle-derived
lymphomas. The involution of germinal centers results in for- lymphoma that has been reported in lymph nodes, spleen,
mation of aggregates of mantle cells that have collapsed into and extranodal tissues of dogs (Fig. 2-181). As with all
224 CHAPTER 2 • Hematopoietic System Lymph Nodes
A B
C D
Figure 2-181 Follicular lymphoma in a dog. A. Follicles are usually large, uniform in size, lack a
mantle cell cuff, and show no polarity. B. Absence of tingible body macrophages and uniform
proportions of centrocytes and centroblast through follicle, with an absence of a dark zone.
C. Neoplastic B cells in individual and confluent follicles are diffusely and uniformly positive for
CD20 by immunohistochemistry. D. Small rims of immunohistochemically CD3-positive T cells
surround follicles.
follicular-derived lymphomas, FL must be differentiated from percentage of centrocytes and centroblasts, with larger
follicular hyperplasia. Low-magnification examination is numbers of centroblasts indicating more aggressive biological
essential when differentiating follicular-derived lymphoma behavior. There are no data available for domestic animals and
from follicular hyperplasia. A pattern of densely packed fol- grading of FL is not performed routinely. Whether high-grade
licles throughout the whole parenchyma of a lymph node is FLs require more aggressive CHOP-based therapy is unknown.
characteristic for follicular lymphoma. The follicles are usually Marginal zone lymphoma (MZL) is a follicular-derived
large, uniform in size, lack a mantle cell cuff (“bare”) and show B-cell lymphoma that has been described in dogs in the lymph
no polarity. Paracortical high-endothelial venules are com- nodes, spleen, and bronchus-associated lymphoid tissue and
pressed between opposing follicles and cannot be found mucosa-associated lymphoid tissue of the respiratory and
within them. Other important features include an absence of intestinal tracts (Fig. 2-182), respectively. In the spleen, MZL
tingible body macrophages and uniform proportions of cen- often develops as a nodular mass. It is one of the 6 most
trocytes and centroblasts through all follicles, with an absence common types of nodal lymphomas in dogs, accounting for
of a dark zone. The cellular features of centrocytes and cen- ~15% of canine lymphomas. Dogs with MZL usually are in
troblasts have been described previously. Both centroblasts apparent good health and with an enlarged node or single
and centrocytes are positive for CD79a and CD20 and nega- nodule in spleen, intestine, or lungs at the early stage of the
tive with CD3. The Ki67 index is low. Immunohistochemical disease, progressing to multiple nodes, spleen, and tonsils
labeling with BCL-2 is used in human FL because normal being involved in late-stage disease. MZL are considered indo-
follicular center cells are negative for BCL-2. Although similar lent, slowly progressive lymphomas that should not be treated
BCL-2 labeling has been confirmed in hyperplastic lesions in with regular CHOP therapy.
dogs, data on canine FL are missing. Vascular invasion, extra- MZL originate from the marginal zone of the splenic fol-
nodal invasion, and loss of tissue architecture are more obvious licles or from the marginal zone that appears in lymph nodes
features of FL. In humans, FLs are graded based on the in chronic hyperplasia (Fig. 2-183). MZL must be differentiated
Lymph Nodes 225
A B
Figure 2-182 Mucosa-associated lymphoid tissue (MALT)oma in a cat. A. Intermediate-sized
lymphoid cells forming clusters within crypt epithelium of the small intestine. B. Neoplastic B
cells are positive for CD20 by immunohistochemistry.
A B
C D
Figure 2-183 Marginal zone lymphoma in a dog. A. Homogeneous cuffs of neoplastic marginal
zone lymphocytes surround faded and hemorrhagic germinal centers. B. Cuff of intermediate-sized
marginal zone lymphocytes with mildly vesiculated nuclei with peripheralized chromatin and
a large single central nucleolus. C. Neoplastic marginal zone lymphocytes surround regressing
germinal center. D. Rim of marginal zone lymphocytes is strongly positive for CD20 by
immunohistochemistry.
226 CHAPTER 2 • Hematopoietic System Lymph Nodes
from marginal zone hyperplasia (MZH). Both entities are char- not detected in blood of seropositive animals. Neither have
acterized by proliferation of marginal zone lymphocytes in mutations in c-Myc been detected in BKL in dogs.
lymphoid follicles with their germinal centers in regression. Histologically, canine BKL are diffuse neoplasms that give,
Some degree of MZH may also be observed with prominent on low-power examination, the impression of a “starry sky”
follicular hyperplasia. Usually MZH appears often as discon- because of the large number of tingible body macrophages. Neo-
tinuous cuffs of marginal zone lymphocytes admixed with plastic lymphoid cells are of intermediate size with round
smaller mantle cells and centroblasts. Cellular features of mar- nuclei that have a vesicular appearance. Aggregated chromatin
ginal zone lymphocytes have been described previously. In is clumped on the small, but prominent nucleoli and the
MZL, the proliferating neoplastic cells form more homogeneous nucleolemma with irregular parachromatin clearing. Although
cuffs of marginal zone lymphocytes surrounding a fading germinal 3-5 nucleoli have been reported in human Burkitt lymphoma,
center (eFig. 2-43). During tumor progression, perifollicular there are usually fewer nucleoli in canine BKL. There is mild
proliferating areas coalesce and commonly cause paracortical anisokaryosis. The cytoplasm is of moderate volume and stain-
atrophy and marked sinus dilation in the spleen. Cavities are ing density. The mitotic rate is 10 or greater/HPF. During a
filled with erythrocytes and neoplastic cells. MZL have been blinded review of canine nodal lymphomas, participating
classified as “early,” “mid,” or “late” MZL according to their pathologists failed to consistently differentiate BKL from
stage of development, which is reflected by the degree of DLBCL, leading to exclusion of the BKL as an entity from the
coalescence of marginal zones, the amount of tissue affected, review process.
and the number of mitoses, which are absent in early cases. Extramedullary plasmacytoma. Extramedullary plasma-
However, the overall mitotic index remains low even in late cytomas (EMP) occur most commonly in the skin (digits and
cases. Neoplastic lymphoid cells are strongly positive for ears) of dogs (Fig. 2-185), but are also common in the oral
CD20 or CD79a and negative for CD3. MZL should be easily and colorectal mucosa. Rare cases have been reported in
differentiated from DLBCL by its follicular architecture, cats. Overall, EMPs are benign neoplasms with a low Ki67
except in late cases, and size and amount of cytoplasm of index, and complete surgical removal of cutaneous masses is
neoplastic cells. Cellular morphology and the orientation around curative. Plasmacytomas occurring in the facial skin have a
fading germinal centers are the main features to differentiate MZL higher risk to invade into the underlying parenchyma, includ-
from FL. ing bone, but aggressive surgical removal is curative and
Mantle cell lymphoma (MCL) is a rare follicular-derived metastasis rarely occurs. Regardless, malignant variants occur
lymphoma that has been described in the spleen of dogs. MCL and may metastasize widely, but the incidence is <10%.
present as solitary masses and are far less common than other Colorectal plasmacytomas often pose a greater surgical chal-
follicular-derived B-cell lymphomas (Fig. 2-184). The appear- lenge, and local recurrence has been reported. Some cases
ance of MCL in the spleen is determined by the splenic end occur as multiple plasmacytomas throughout the digestive
arterioles that dictate the regular periodicity of neoplastic tract mucosa. Clinically, canine colorectal plasma cell tumors
nodules. The neoplasm arises from the inner mantle cuff and have been reported to cause hematochezia, tenesmus, and
differentiation from splenic follicular hyperplasia is difficult rectal prolapse. Macroscopically, cutaneous plasmacytomas
because both lesions consist predominantly of mantle cells. As are solitary, broad-based, spherical or dome-shaped, hairless
with other follicle-derived B-cell lymphomas, in contrast to neoplasms up to 3 cm in diameter. Some cutaneous EMPs may
hyperplastic lesions, neoplastic cells surround fading germinal be pedunculated, and ulceration is common. Intestinal EMPs
centers that are commonly hyalinized. The cell morphology form solitary, red, raised and smooth, rapidly growing nodules
of mantle cells has been described previously. Mitoses are rare. up to 5 cm in size. EMPs occur in middle-aged to older dogs,
The MCL cells are B cells and label positive with CD79a and and there is no sex or breed predilection. Urinary Bence-Jones
CD20 and are negative with CD3. protein has not been detected in dogs with cutaneous or
Clinically, MCL has been considered to be an indolent intestinal EMPs, and hypergammaglobulinemia, which is com-
lymphoma and is grouped with MZL, but small case numbers monly observed with multiple myeloma, is not a typical
are probably the main reason that published evidence is feature of canine EMPs.
missing. Classification of MCL as indolent lymphomas is also Most EMPs are circumscribed but not encapsulated, and
based on data from human medicine, where MCLs occur as primarily located in the superficial dermis or the intestinal
an incurable disease with a median survival time of 3-5 years. submucosa, but may extend into the mucosa. Cutaneous neo-
Older age, a high Ki67 index, a high mitotic rate (1-3/HPF), plasms typically create a Grenz zone, and do not involve the
blastoid cell morphology, and mutations in p53 have been overlying epithelium. EMPs are densely cellular tumors com-
associated with poor prognosis in humans. None of these posed of densely packed, round to oval neoplastic cells that
factors has been studied in dogs. are commonly arranged in cords and single files. A fine reticu-
Burkitt-like lymphoma (BKL). Although Burkitt lympho- lar stromal network of capillaries separates the cellular neo-
mas represent a well characterized entity in humans, Burkitt- plastic cells. Neoplastic cells have indistinct cell borders and
like lymphoma (BKL) is a highly controversial entity that has round nuclei that are commonly eccentrically placed, and
been reported in dogs. Burkitt lymphomas in humans are highly have coarsely clumped chromatin arranged in a “clockface”
aggressive lymphomas that exist as an endemic form in Africa, pattern and small solitary nucleoli. Megalokaryosis as well as
and are strongly associated with Epstein-Barr virus (EBV). In binucleate and rare multinucleate cells are a characteristic
the sporadic form, the association with EBV is highly variable, feature (eFig. 2-44). Anisocytosis and anisokaryosis are moder-
and in acquired immunodeficiency syndrome (AIDS)-associ- ate and the mitotic index is usually low (0-1 mitoses/HPF).
ated Burkitt lymphomas, there is only an association with EBV There are variable amounts of often deeply amphophilic cyto-
in 30% of cases. In addition, the vast majority of Burkitt lym- plasm with perinuclear pallor. Some cells contain large eosino-
phomas have c-Myc translocations. Although seroconversion philic, intracytoplasmic aggregates of immunoglobulin (Russell
to EBV has been reported in dogs and cats, viral DNA was bodies). Cells toward the periphery of the neoplasm often
226.e1
A A
B B
eFigure 2-43 Marginal zone lymphoma in a dog. A. Homoge- eFigure 2-44 Cutaneous plasmacytoma in a dog. A. Rows of
neous cuffs of neoplastic marginal zone lymphocytes surround neoplastic plasma cells surround aggregates of extracellular
faded and hemorrhagic germinal centers. B. Cuff of intermediate- amyloid. B. Megalokaryosis is a common feature of cutaneous
sized marginal zone lymphocytes with mildly vesiculated nuclei plasmacytomas.
with peripheralized chromatin and a large single central
nucleolus.
Lymph Nodes 227
A B
C D
E
Figure 2-184 Mantle cell lymphoma in a dog. A. Homogeneous cuffs of neoplastic mantle cuff
lymphocytes surround fading germinal centers. B. Splenic end arterioles dictate the regular peri-
odicity of neoplastic nodules. C. Intermediate-sized mantle cuff lymphocytes, which are slightly
larger than small lymphocytes and have chromatin-dense nuclei and inconspicuous nucleoli, form
cuffs around regressed germinal centers. D. Mantle cuff lymphocytes are strongly positive for
CD20 by immunohistochemistry (IHC). E. No CD3-positive T-cells are detected within neoplastic
nodules by IHC.
closely resemble non-neoplastic plasma cells. Different mor- amyloid may be demonstrated with thioflavine T or Congo
phologic types have been reported for cutaneous EMPs in red stains, and it is most commonly of λlight-chain origin.
both dogs and cats, including lymphoid, histiocytic, and pleo- Macrophages and foreign-body giant cells usually surround
morphic subtypes, this classification has not been applied to amyloid deposits. A few cases with metaplastic cartilage and
intestinal EMPs. Submucosal, perivascular, and intracellular bone within the amyloid have been reported. Ultrastructural
228 CHAPTER 2 • Hematopoietic System Lymph Nodes
A B
C D
Figure 2-185 Cutaneous plasmacytoma in a dog. A. Neoplastic plasma cells have indistinct cell
borders and round nuclei that are commonly eccentrically placed; megalokaryosis as well as
binucleate cells are characteristic features. B. Extracellular and intracellular amyloid of λ light-
chain origin can be found in extramedullary plasmacytomas. C. Approximately 80% of cutaneous
plasmacytomas are positive for CD79a by immunohistochemistry (IHC). D. Nuclear labeling
for multiple myeloma oncogene-1 (MUM-1) can be detected by IHC in most cutaneous
plasmacytomas.
A B
C D
Figure 2-188 T-zone lymphoma in a dog. A. Paracortical proliferation of neoplastic T cells causes
compression and fading of germinal centers, which are peripheralized against the capsule.
B. Uniform, small neoplastic T cells with moderate amounts of water-clear cytoplasm and densely
stained nuclei that have shallow, sharp indentations and inapparent nucleoli. C. T cells that
are CD3 positive by immunohistochemistry (IHC) compress and peripheralize germinal centers.
D. Subcapsular remnants of germinal centers are positive for CD20 by IHC.
fading and peripheralized germinal centers that label with ALTCL also have to be differentiated from histiocytic
CD79a and CD20. The neoplastic paracortical areas are sarcomas.
eccentric to fading germinal centers and are composed of Angioimmunoblastic T-cell lymphoma is another nodal
solidly CD3-positive neoplastic cells. lymphoma rarely reported in dogs. It is characterized by poly-
Anaplastic large T-cell lymphoma (ALTCL) is a rare morph lymphoid infiltrates of affected nodes and associated
nodal lymphoma that has been reported in dogs and cats, and systemic disease. Although the node parenchyma is commonly
carries a poor prognosis. Neoplastic cells have abundant cyto- destroyed by the neoplastic cell proliferation, subcapsular
plasm and large, irregular, often bizarre, nuclei that are respon- sinuses often remain open. Prominent high-endothelial capil-
sible for the name of this entity. Affected nodes are partially laries spread through the node. Few fading germinal centers
or completely involved, and predominantly sinusoidal growth may be observed. The neoplastic cells are of intermediate size
is a common feature. Fibrosis of the capsule and parenchyma and have round nuclei and often clear cytoplasm. A charac-
is common. Secondary infiltrates of small lymphocytes, plasma teristic feature of this entity is clusters of immunoblastic cells
cells, and eosinophils may occur. Histologically, ALTCLs are around vessels that also migrate into the vessels. Although the
indistinguishable from the anaplastic variant of DLBCLs. neoplastic cells are consistently positive with CD3, infiltration
However, as discussed previously, in humans, only ALTCLs are of B cells and eosinophils is common. Dendritic cells may
consistently positive for anaplastic lymphoma kinase (ALK). form perivascular, spindyloid proliferations. There are limited
Neoplastic cells are commonly negative for CD3 and clonal data regarding the prognosis of these cases, and an aggressive
rearrangements in T-cell-receptor γ may help in the diagnosis. behavior has been suggested.
Neoplastic cells consistently express CD30 and contain cyto- Enteropathy-associated T-cell lymphoma (EATL).
toxic granule–associated proteins, such as perforin and gran- Enteropathy-associated T-cell lymphomas (EATL) are intesti-
zyme B, suggesting a cytotoxic T-cell phenotype. Unfortunately, nal tumors of intraepithelial lymphocytes. They are further
expression of ALK and CD30 has not been studied in animals. subdivided into EATL type 1 (large cell neoplasms) that are
Lymph Nodes 231
Figure 2-189 Enteropathy-associated T-cell lymphoma type 1 in Figure 2-190 Large granular lymphocyte lymphoma in a cat.
a dog. Neoplastic T cells infiltrating the jejunal mucosa have large Neoplastic T cells in many enteropathy-associated T-cell lym-
round or irregularly folded nuclei with parachromatin clearing phoma type 1 in cats have intracytoplasmic eosinophilic
and prominent central nucleoli of centroblastic nuclear type. granules.
lamina propria. Early cases often show only infiltration of the both cases, whereas involvement of spleen and lung was
lamina propria of individual villi by large number of lympho- minimal. In contrast to HS-TCL, neoplastic lymphocytes in
cytes, and adjacent villi may be uninvolved. In other cases, HC-TCL are not confined to hepatic sinusoids, but invade
lymphocytic infiltration may occur as a band that spans the hepatic cords individually or in clusters. Neoplastic T cells are
crypt-villus junction. In advanced cases, the infiltrating neo- morphologically similar to those described with HS-TCL, but
plastic lymphocytes obliterate both the villus and crypt lamina are CD11d negative. Bile duct epithelium is also infiltrated by
propria and form a band beneath the crypt epithelium, but lymphocytes. However, no degenerative changes are apparent
above the muscularis mucosae (eFig. 2-45). Such cases are in hepatocytes. Erythrophagocytosis is not an important
commonly associated with villous blunting and fusion as well feature, and extramedullary hematopoiesis and fibrin thrombi
as crypt effacement. are absent. Further studies are needed to confirm HC-TCL as
Epitheliotropism is an important feature for diagnosing a specific entity.
EATL type 2, and the presence of intraepithelial nests (clusters Cutaneous T-cell lymphoma. Cutaneous T-cell lympho-
of more than 5 intraepithelial lymphocytes) or plaques (5 mas (CTCL) are a heterogeneous group of lymphomas
adjacent epithelial cells overrun by lymphocytes) of lympho- that include epitheliotropic and non-epitheliotropic lymphomas.
cytes is highly suggestive of lymphoma. IHC for CD3 greatly Epitheliotropic CTCLs appear as mycosis fungoides (MF),
enhances the ability of the pathologist to evaluate epitheliot- Pagetoid reticulosis (PR), or Sézary syndrome (SS). Non-
ropism. Although most epitheliotropic lymphocytes are epitheliotropic CTCLs appear as a subcutaneous “panniculitis-
observed in villi, infiltration of crypt epithelium is an even stron- like” T-cell lymphoma or anaplastic large T-cell lymphoma; all
ger indication of lymphoma. However, intraepithelial lympho- other non-epitheliotropic CTCLs are currently classified as
cytes are a common immunologic response in the intestine, unspecified peripheral T-cell lymphomas, which have been
and individual intraepithelial lymphocytes are commonly described earlier.
found in inflammatory conditions, for instance, cats with Mycosis fungoides (MF) is a disease of older cats, dogs, and
inflammatory bowel disease (IBD). The prognosis of cats with horses. MF may exist originally as patches or plaques in the
EATL type 2 is still somewhat controversial, and large-scale skin that commonly progress rapidly to larger neoplastic
prospective studies using a standardized therapeutic approach masses that invade the deeper dermis and potentially cause
are lacking. Data from many studies are also hampered by the local and distant metastases. In dogs and cats, MF occurs most
lack of an accurate diagnosis of EATL type 2 versus IBD commonly around mucocutaneous junctions and feet or other
because of the lack of TCRG clonality testing. Regardless, skin sites. Many affected dogs have a history of chronic der-
EATL type 2 is considered a slowly progressing, smoldering matitis, and erythema is the most common clinical sign. Pru-
disease that may not require aggressive therapy. Overexpression ritus is sometimes associated with erythema and scaling;
of Bcl-2 has recently been documented in EATL in cats, which ulcerations, hypopigmentation and alopecia can occur. In
may prove useful as a therapeutic target. horses, the skin may not be affected, but the mucous mem-
Extranodal T-cell lymphoma. Although the majority of branes are the primary sites. In advanced cases, MF extends to
extranodal T-cell lymphomas in most animal species are cur- lymph nodes causing them to become enlarged and firm.
rently classified as unspecified peripheral T-cell lymphomas, Histologically, in contrast to humans, MF in animals is char-
hepatosplenic T-cell lymphomas rarely occur in dogs and horses. acterized by a strong tropism of neoplastic T cells for the epider-
Furthermore, hepatocytotropic T-cell lymphoma has recently mis and adnexal structures, including hair follicles, apocrine
been described as an even more rare disease in dogs. sweat, and sebaceous glands (Fig. 2-192). T cells invading the
Hepatosplenic T-cell lymphoma (HS-TCL) causes a rapidly epidermis commonly form cavities filled with lymphocytes
progressive disease in dogs that clinically have lethargy, called Pautrier’s microabscesses. Early lesions typically appear
anorexia, weight loss, diarrhea, and vomiting. Hepatomegaly as small numbers of T cells infiltrating along the basal level of
and splenomegaly, regenerative anemia, thrombocytopenia, the epidermis. As disease progresses, the neoplastic cells
and hypoproteinemia are commonly observed. Dogs have invade the deeper dermis and panniculus, causing larger
mild icterus and mild toxic changes in neutrophils. Horses nodular masses. Neoplastic T cells are intermediate-sized cells
have only been diagnosed after autopsy, and their clinical signs with a round, hyperchromatic and convoluted nuclei that
are not known. Neoplastic T cells are found primarily within occasionally have sharp shallow indentations and large nucle-
hepatic and splenic sinusoids, ranging from small clusters to oli that are difficult to visualize. The amount of cytoplasm is
large aggregates that expand sinusoids and in the liver com- minimal and generally water clear. Mitoses are rare.
press hepatic cords. Periportal and centrilobular neoplastic cell Pagetoid reticulosis (PR) is considered a more epitheliotro-
infiltrates are also common in the liver. Erythrophagocytic pic variant of MF in which the neoplastic T cells form large
macrophages, extramedullary hematopoiesis, and fibrin plaques that are almost entirely confined to the epidermis (Fig.
thrombi with associated ischemic necrosis are all features 2-193). Morphologically, neoplastic cells are similar to those
commonly observed. Neoplastic lymphocytes have mild to described with MF. Sézary syndrome is the generalized stage of
moderate amounts of eosinophilic to clear cytoplasm, inter- MF with secondary lymphadenopathy and leukemia. The immu-
mediate to large size, round to oval nuclei with indistinct nophenotype of canine epitheliotropic CTCL is markedly dif-
nucleoli, and variably distinct cell borders. Anisocytosis and ferent from its human counterpart. In canine epitheliotropic
anisokaryosis are mild, and the mitotic index is low with 0-2 CTCL, T cells are consistently positive for CD3. In MF, neo-
mitoses/HPF. Bone marrow and lungs are also consistently plastic T cells express CD8, and a smaller percentage of cases
affected. Immunohistochemically, neoplastic T cells are posi- are CD4 and CD8 negative, but CD4 expression has not been
tive for CD3, T-cell-receptor γδ (TCRγδ), CD11d, and gran- reported. TCRαβ and TCRγδ are expressed in approximately
zyme B and negative for TCRαβ. equal numbers of cases. This is in contrast to human MF,
Only 2 cases of hepatocytotropic T-cell lymphoma (HC- which is primarily a disease of CD4- and TCRαβ-positive T
TCL) have been described in dogs. The liver was affected in cells. Interestingly, T cells in canine PR have a slightly different
232.e1
B
eFigure 2-45 Enteropathy-associated T-cell lymphoma type 2 in
a cat. A. Epitheliotropism characterized by intraepithelial nests
and/or plaques of lymphocytes is highly suggestive of enteropathy-
associated T-cell lymphoma type 2. B. Immunohistochemistry for
CD3 highlights the marked epitheliotropism of neoplastic T cells.
Lymph Nodes 233
A B
C D
Figure 2-192 Mycosis fungoides in a dog. A. Epitheliotropic cutaneous T-cell lymphoma that
often infiltrates along the basal level of the epidermis. B. Strong tropism of neoplastic T cells for
the epidermis and adnexal structures, including hair follicles. C. Neoplastic T cells in the dermis
and epidermis are CD3 positive by immunohistochemistry. D. Epitheliotropism of immunohisto-
chemically CD3-positive T cells affecting adnexal structures.
A B
Figure 2-193 Pagetoid disease in a dog. A. A more epitheliotropic variant of mycosis fungoides
in which the neoplastic T cells form large plaques that are almost entirely confined to the epider-
mis. B. Intraepidermal T cells are strongly positive for CD3 by immunohistochemistry.
234 CHAPTER 2 • Hematopoietic System Lymph Nodes
immunophenotype characterized also by expression of CD8 to be curative. Lesions usually occur as multiple nodules on
in most cases or being negative for CD4 and CD8, but in the trunk or limbs that are localized in the panniculus and
contrast to canine MF, all cases of PR are TCRγδ positive. almost completely spare the dermis. Histologically, neoplastic
Subcutaneous “panniculitis-like” T-cell lymphoma is rarely T cells infiltrate the panniculus in a lace-like pattern, often
seen in animals and has only been recognized in the dog (Fig. rimming large vacuolated adipocytes. Neoplastic T cells are
2-194). Most cases take an indolent course, and removal seems usually small- to intermediate-sized cells, but large cells may
dominate. Karyorrhexis is a prominent feature, and some cases
have extensive necrosis. This often leads to heavy infiltration
with histiocytic cells, and there is prominent phagocytic activ-
ity. The histiocytic infiltrates may mask the lesion as a histio-
cytic panniculitis, and IHC and clonality testing are helpful in
reaching an accurate diagnosis. Neoplastic cells are CD3 and
CD8 positive. A CD4-negative cytotoxic phenotype has been
described in humans, but has not been investigated in dogs.
Cutaneous anaplastic large T-cell lymphoma has been
described in middle-aged to older dogs as a highly aggressive
form of non-epitheliotropic CTCL with a poor prognosis (Fig.
2-195). Originally, lesions occur as single or multiple nodules
in the skin that progress remarkably rapidly and cause general-
ized lymphadenopathy. A disseminated form has also been
observed, and the nodal form has been described previously.
The neoplasm occurs as a solid mass of neoplastic T cells extend-
A ing from the epithelial basement membrane and irregularly invad-
ing the subcutaneous fat. The neoplastic cells grow in solid
C
Figure 2-194 Subcutaneous “panniculitis-like” T-cell lymphoma B
in a dog. A. Neoplastic T cells infiltrate the panniculus in a lace-
like pattern often rimming large vacuolated adipocytes. B. Karyor- Figure 2-195 Cutaneous anaplastic large T-cell lymphoma in a
rhexis and heavy infiltration with histiocytic cells are prominent dog. A. Neoplastic T cells have large, often bizarre nuclei, and
features. C. Neoplastic T cells rimming adipocytes are strongly abundant amounts of cytoplasm. B. Neoplastic T cells are strongly
positive for CD3 by immunohistochemistry. positive for CD3 by immunohistochemistry.
Lymph Nodes 235
sheets displacing hair follicles and collagen fibers. In deeper contrast to simple retroviruses, deltaretroviruses carry addi-
areas, neoplastic T cells surround vessels and infiltrate between tional genes that encode for several regulatory and accessory
fat cells, forming solid areas of tumor. The morphologic and proteins. One of these proteins, Tax, plays a major role in BLV
immunohistochemical features of the cutaneous form are lymphomagenesis. Tax is an activator of viral gene transcrip-
identical to the earlier described nodal form. Histiocytic sarco- tion from the LTR and modulates the expression of several
mas are the primary differential, and IHC is required for an cellular genes. It also induces immortalization of infected cells.
accurate diagnosis. This may be the first step in the BLV-mediated neoplastic
T-cell large granular lymphocytic leukemia. Large granu- transformation. In contrast to cats, in which FeLV virus pri-
lar lymphocytic lymphomas (LGL) have already been marily causes thymic T-cell lymphomas, BLV infects B lym-
described as a special form of EATL type 1, but they can also phocytes that express surface immunoglobulin M and causes
occur as a leukemia in dogs. For a detailed description of the B-cell lymphomas. IgG heavy chains are frequently found on
leukemic disease, please see the paragraph on LGL leukemias. neoplastic mature B cells. Tax immortalizes CD5-positive
For intestinal LGLs, please see description of EATL type 1. IgM-positive B cells and causes their polyclonal expansion.
Viral etiology and lymphomagenesis. The etiology of most Missense mutations at codons 206, 207, 241, or 242 of p53
lymphomas in domestic animal species is unknown, and there have been identified in more than 50% of BLV-induced lym-
are limited genetic studies. However, feline and bovine retro- phomas, and suppression of p53 most likely represents the
viruses have been shown to cause different types of lympho- crucial step in neoplastic transformation in many cases.
mas in cats and cattle, respectively. However, other genes are most likely involved. Bovine leuko-
Feline lymphoma may be caused by the horizontally trans- cyte antigen (BoLA) significantly contributes to the progres-
mitted species Feline leukemia virus (FeLV), genus Gamma- sion of BLV infection and the host’s immune response.
retrovirus in the oncovirus subfamily of family Retroviridae. Polymorphisms of BoLA influence resistance and susceptibil-
The virus has several subgroups of which FeLV-A, FeLV-B, ity to a wide variety of infectious diseases, including BLV, and
and FeLV-C are the most important. Only FeLV-A is conta- the monoclonal expansion of BLV-infected B cells is associated
gious and spreads horizontally among cats. The other sub- with specific alleles of BoLA. Furthermore, a polymorphism
groups result from recombination or mutation of FeLV-A in in the promoter region of the tumor necrosis factor-α gene
infected cats and can only replicate under natural conditions has been associated with the development of bovine
with the help of FeLV-A. The pathogenicity is higher for lymphoma.
multiple subgroup infections, and the envelop proteins of the Species differences. The general pathology and classifica-
different subgroups determine lesion development. FeLV-B tion of lymphomas are discussed in the preceding sections.
is primarily responsible for development of thymic lympho- The following sections deal with the clinical and topographic
mas in cats. aspects of lymphoma in the various domestic animal species.
Neoplastic transformation is caused by insertional mutagen- Bovine lymphoma. In cattle, bovine leukemia virus (BLV)-
esis. Although some retroviruses insert a viral oncogene into associated lymphomas are predominantly diffuse large B-cell
the host genome, causing rapid neoplastic transformation, lymphomas. Sporadic cases of precursor T-cell lymphoblastic
FeLV is a slowly transforming oncovirus. When FeLV becomes lymphomas occur multicentrically or in the thymus, and epi-
integrated near a cellular proto-oncogene, transcription of this theliotropic T-cell lymphomas occur in the skin.
gene can be upregulated by the promoter and enhancer func- Lymphoma in adult cattle is mainly the enzootic bovine
tion of viral long-term repeats (LTR). In cats, insertion occurs leukosis form caused by an infection with BLV. The viral onco-
most commonly near c-myc, which leads to uncontrolled genesis has been described earlier. Because almost any organ
clonal proliferation of the affected cell without inducing an system may be involved with leukemia-associated lymphoma,
immune response. Because insertion is random at one of hun- it is usually referred to as multicentric. BLV is transmitted
dreds of proviral common integration sites, not all cats will horizontally by direct contact. Small numbers of BLV-infected
develop lymphoma, and neoplastic transformation may only lymphocytes can be transmitted through natural breeding,
occur after long-standing infection. In addition to c-myc, other blood-sucking arthropods, or iatrogenic by contaminated
common insertion loci associated with oncogenesis include needles, ear-tagging, and dehorning equipment, and the use of
flvi-1, flvi-2 (contains bmi-1), fit-1, pim-1, and flit-1. Although whole-blood vaccines. Disease is much less common in beef
most insertion sites have been associated with formation of compared to dairy cattle, where husbandry practices favor
thymic T-cell lymphoblastic lymphomas, insertion at flvi-1 transmission, but shorter life-span may also contribute to a
results in B-cell lymphomas. Although c-myc is an oncogene, lower incidence. BLV does not persist outside the animal, so
bmi-1, and pim-1 are c-myc collaborators, and fit-1 has been contact or environmental contamination is not a source of
closely linked to myb. Flit-1 is associated with overexpression infection. Infection, once established, is lifelong and character-
of activin-A receptor type II–like 1 (ACVRL1). Flvi-2 contains ized by the development of circulating antibodies, which are
a gene that encodes feline homologs to bmi-1 and pmi-1. A also present throughout life. Antibody levels tend to increase
feline oncovirus cell membrane antigen (FOCMA) has been with the number of viral antigens recognized, as the animal
detected on the surface of many transformed neoplastic cells, passes from an asymptomatic carrier stage to lymphocytosis
and many FeLV infected cats will develop antibodies against and to the tumorous state. Almost all infected cows will
FOCMA. The role of FOCMA in protective immunity and its develop detectable serum antiviral antibodies ~5 weeks after
function are still largely unknown. infection. Although lymphocytosis develops in ~30% of
Species Bovine leukemia virus (BLV) is an oncogenic del- infected cows, lymphoma occurs in <5%. Cows develop neo-
taretrovirus. Similar to cats, BLV is a slowly transforming plastic masses usually between 4 to 8 years of age. The low
retrovirus, but does not causes bovine lymphomas through incidence of neoplastic disease, and even lymphocytosis, has
insertional mutagenesis. It lacks a known oncogene and does hindered eradication of the disease. With the development of
not integrate into preferred sites in the bovine genome. In an agarose gel immunodiffusion test that can detect antibodies
236 CHAPTER 2 • Hematopoietic System Lymph Nodes
Figure 2-196 Enzootic bovine leukosis in a cow. Malignant lym- Figure 2-197 Enzootic bovine leukosis in a cow. Diffuse thicken-
phoma in the wall of the uterus. ing of the abomasal submucosa by an infiltrating malignant
lymphoma.
A A
B B
eFigure 2-46 Enzootic bovine leukosis in a cow. A. Malignant
lymphoma in the wall of the uterus. B. Multifocal infiltrates of
malignant lymphoma throughout the liver. (Courtesy K.G.
Thompson.)
C
eFigure 2-47 Enzootic bovine leukosis in a cow. A. Diffuse thick-
ening of the abomasal wall by malignant lymphoma. B. The
kidneys have multifocal infiltrates of neoplastic lymphocytes
extending through the whole thickness of the cortex. C. Cross
section of spleen with multiple white nodules consistent with
malignant lymphoma.
236.e2
eFigure 2-48 Enzootic bovine leukosis in a cow. Malignant lym- eFigure 2-49 Enzootic bovine leukosis in a cow. Malignant ret-
phoma in the myocardium extending into papillary muscles. robulbar lymphoma. (Courtesy D.G. Sledge.)
Lymph Nodes 237
Figure 2-200 Cutaneous lymphoma in a cow. Plaque-like, round, Figure 2-201 Renal lymphoma in a sheep. The cortex is diffusely
raised lesions in the skin. (Courtesy K.G. Thompson.) infiltrated by neoplastic lymphocytes.
The liver and spleen may be massively involved, or relatively in cattle. Generalized lymphadenopathy is most commonly
spared. Calves may be born with lymphoma with the liver so encountered in sheep, and exophthalmos secondary to retro-
enlarged at parturition as to cause dystocia. bulbar lymphadenopathy has especially been reported in
Thymic lymphoma occurs in cattle <2 years of age. Clini- goats. Lymphoma can also be commonly found in the aboma-
cally, it commonly causes presternal swelling, jugular disten- sum, heart, and uterus. Small neoplastic masses are also not
tion, and local edema, as well as compression of the esophagus uncommon in the spleen, whereas kidney and liver are rarely
and respiratory distress owing to displacements of the lungs involved. Thymic and cutaneous lymphoma also occur in
by a very large mediastinal mass. Often large areas of the sheep and goats, and in goats, thymic lymphoma has to be
tumor may be infarcted. differentiated from thymoma because goats have a high preva-
The skin form is the least common type of bovine lym- lence of thymoma B1 as previously described. Furthermore,
phoma, and occurs most often in 2- to 3-year-old cattle (Fig. lymphomas of the central nervous system (CNS) and synovial
2-200). It is characterized by plaque-like, round, raised lesions lymphomas have been described in goats.
that appear on the head, sides, and perineum (eFig. 2-50). The Equine lymphoma. Lymphoma in the horse occurs primarily
lesions become depilated, and are frequently ulcerated. The as a subentity of diffuse large B-cell lymphoma, the T-cell–rich
lesions wax and wane over a period of months with some large B-cell lymphoma (TCRLBCL). Peripheral T-cell lym-
regressing entirely and new lesions appearing. Ultimately, phoma and other diffuse large B-cell lymphomas are also
there is deep organ involvement, and the visceral lesions are commonly encountered. Lymphomas of the large intestine are
then grossly indistinguishable from those of the enzootic type most commonly enteropathy-associated T-cell lymphomas of
of bovine lymphoma. This form of mycosis fungoides often small cell type (EATL type 2) and cutaneous lymphomas are
occurs in the advanced state with leukemia (Sézary epitheliotropic T-cell lymphomas. Individual cases of other
syndrome). entities have been reported. The cases reviewed covered 24
Ovine and caprine lymphoma. Ovine lymphomas most breeds, with Thoroughbreds the most prevalent, and the ages
commonly occur as multicentric disease without leukemia and ranged from 2 months to 31 years.
bone marrow involvement (Fig. 2-201). A retrovirus indigenous Equine lymphomas do not label well with CD79a, and B
to sheep shares major proteins with BLV; however, most spon- cells in the horse are more efficiently marked with CD20.
taneous lymphomas of sheep, and virtually all of those pro- Numerous studies used Bla.36 to label horse B cells, but the
duced experimentally, are caused by BLV. Experimentally antibody has been shown to also label macrophages and den-
infection with BLV causes lymphoma in 30-60% of sheep 2-3 dritic cells. The large number of T cells in TCRLBCL and
years after infection. In sheep, as in cattle, infection with BLV difficulties in detecting neoplastic B cells in the horse may
once established is lifelong, and the virus persists in the face have led to misdiagnosis of some cases of multicentric lym-
of a strong and persistent antibody response that can be phoma. Similarly, the large number of Bla.36-positive non-
detected with the bovine agarose gel immunodiffusion test. lymphoid cells in sections of large intestine with EATL type
BLV produces a moderate persistent lymphocytosis in 50% of 2 and the small size of neoplastic T cells and their close resem-
sheep at 10-13 months postinfection, and causes neoplastic blance to inflammatory T cells may have caused an over-
masses in ~40% of sheep within 6 years postinfection. reporting of intestinal B cell lymphomas in the older
In goats, sporadic forms of lymphoma occur more fre- literature.
quently, and multicentric disease is much less common com- Lymphoma is the most common malignant neoplasm in the
pared to sheep. Disease presentation can be highly variable, horse. Regardless of the anatomic location, lymphomas in
and lymphoma should be considered as a differential in any horses cause a general wasting disease with anorexia and
goat >2 years of age with a fast progressing debilitating disease. depression and ventral edema with or without reported hypo-
The gross and microscopic presentation of BLV-associated proteinemia. Pyrexia and anemia are common, and diarrhea
lymphoma in sheep and goats is very similar to that described and colic can occur with any form of lymphoma. Multicentric
237.e1
A
Figure 2-203 Intestinal lymphoma in a horse. Multiple white
raised nodules protrude over a uniformly thickened intestinal
mucosa.
B
Figure 2-202 Abdominal lymphoma in a horse. A. Large, multi-
nodular intestinal masses. B. Neoplastic masses are white, firm,
and homogeneous on cross section.
B
eFigure 2-51 Malignant lymphoma in a horse. A. Mesenteric
lymph node and mesentery are diffusely infiltrated by a homoge-
neous neoplastic mass. B. The malignant lymphoma in the spleen
is white, firm, and has central areas of ischemic necrosis.
238.e2
lymphomas are clinically silent during the early stages of representing specific types of follicular lymphomas (Fig.
disease. 2-206). Recently, hepatosplenic and hepatocytotropic types
Intestinal lymphomas are not as common in dogs as in cats, have been characterized. Other primary locations include the
and account for ~6% of all lymphomas. They are most com- eye (Fig. 2-207, eFig. 2-54), the spinal cord (Fig. 2-208), or
monly enteropathy-associated T-cell lymphomas of the large the kidney (Fig. 2-209, eFig. 2-55), and clinical signs depend
cell type (type 1). Clinical signs include weight loss and leth- on the organ system affected.
argy, vomiting, and diarrhea, and blood may be present in Feline lymphoma. Lymphomas are one of the most common
vomitus or stool. Boxers and Shar Peis are over-represented. malignant neoplasms in cats. Historically, ~30% of feline neo-
Cutaneous lymphomas account for ~6% of canine lympho- plasms were lymphomas, and an incidence of 0.2% was
mas, and are most commonly epitheliotropic T-cell lympho- reported. Up to 80% of lymphomas were reported to be asso-
mas (mycosis fungoides). The disease is usually seen in dogs ciated with species Feline leukemia virus (FeLV). However,
>10 years of age, but the clinical presentation can vary from there has been a dramatic decrease of the prevalence of
single to diffuse disease and from flat plaques to cutaneous FeLV in cats after cats became routinely vaccinated against
nodules (Fig. 2-205, eFig. 2-53). Half of the affected dogs will FeLV, and testing and elimination programs have been estab-
have pruritus. lished. The majority of FeLV-associated lymphomas were lym-
Mediastinal and extranodal lymphomas are the least phoblastic T-cell lymphomas occurring in the thymus/
common canine lymphomas, accounting together for ~4% of mediastinum, especially in cats <3 years of age. FeLV does not
canine lymphomas. Mediastinal lymphomas are most com- represent a single genomic species, but a family of closely
monly lymphoblastic T-cell lymphomas arising from the related viruses, and the genetic variation among these viruses
thymus, and clinically cause respiratory signs and effusions as causes a highly variable disease outcome, including thymic
well as precaval syndrome. Polyuria and polydipsia occur in
~40% of dogs because of paraneoplastic hypercalcemia of
malignancy. In the spleen, marginal zone lymphomas, and
rarely mantle cell lymphomas, can be encountered,
B
Figure 2-205 Cutaneous lymphoma in a dog. (Courtesy M. Figure 2-207 Ocular lymphoma in a dog. Malignant lymphoma
Umstead.) A. Erythematous, exfoliative dermatitis of the foot- arising from and largely obliterating the anterior uveal tract and
pads. B. Similar lesions in the nasal planum with mucocutaneous filling the anterior and posterior chambers. (Courtesy D.G.
depigmentation. Sledge.)
239.e1
A
eFigure 2-54 Ocular lymphoma in a dog. Malignant lymphoma
arising from and largely obliterating the anterior uveal tract and
filling the anterior and posterior chambers. (Courtesy D.G.
Sledge.)
C
eFigure 2-53 Cutaneous lymphoma in a dog. A. Multinodular
white, homogeneous masses along the lip fold margin. (Courtesy
M. Umstead.) B. Erythematous, exfoliative dermatitis suggestive
of mycosis fungoides. (Courtesy K. Loft.) C. Similar lesions on
the nasal planum and periocular area with mucocutaneous depig-
mentation. (Courtesy M. Umstead.)
239.e2
C
eFigure 2-55 Malignant lymphoma in a dog. A. Multiple white
nodules randomly distributed throughout the myocardium.
(Courtesy S. Kesdangsakonwut). B. Malignant lymphoma in the
urinary bladder occurring as numerous ulcerated intraluminal
nodules. C. Disseminated malignant lymphoma in liver, spleen,
lymph nodes, and kidney.
240 CHAPTER 2 • Hematopoietic System Lymph Nodes
Figure 2-208 Spinal cord lymphoma in a dog. Malignant lym- Figure 2-210 Thymic lymphoma in a cat. Thymic lymphomas
phoma encompassing the nerve roots of the caudal spinal cord. expand the cranial mediastinum causing caudodorsal displace-
ment of the lungs.
Figure 2-209 Renal lymphoma in a dog. A single sharply demar- Figure 2-211 Intestinal lymphoma in a cat. Diffuse circumferen-
cated, white, firm homogeneous mass protrudes from the renal tial thickening of the intestinal wall causing luminal obstruction.
cortex. (Courtesy J.S. Munday.)
lymphoma of T-cell origin, non–T-cell multicentric lymphoma, the reported higher incidence of intestinal lymphoma may
myeloproliferative disorder, or anemia. In one study, a particu- partially result from the shift of the proportion of lymphomas
lar isolate of FeLV caused exclusively multicentric B-cell lym- in cats because of a decrease of FeLV, it more likely reflects
phoma affecting liver, kidney, and lungs, but not thymus. our ability to better diagnose intestinal lymphomas in cats.
About 15% of cats infected with FeLV are also infected The majority of intestinal lymphomas in cats are enteropathy-
with feline immunodeficiency virus (FIV); however, the latter associated T-cell (EATL) lymphomas of small cell type (type
agent is not nearly as infectious as FeLV or as likely to cause 2) that histologically resemble inflammatory bowel disease
disease. FIV plays an indirect role in lymphomagenesis and and often require IHC and clonality testing for an accurate
increases the risk of cats to develop lymphoma. FIV-associated diagnosis. Historically, most intestinal lymphomas have been
lymphomas are typically of B-cell phenotype and occur most reported as B-cell lymphomas. With the establishment of diag-
commonly in the intestine, but the overall incidence of FIV- nostic algorithms to accurately diagnose EATL type 2 based
associated lymphoma is low. on molecular techniques even in endoscopic biopsies, it is now
Up to 90% of cats with thymic/mediastinal lymphomas were certain that EATL type 2 is by far the most common form of
found to be FeLV antigen positive (Fig. 2-210). Most cats with intestinal lymphoma in cats. Another intestinal lymphoma in
thymic lymphoma develop pleural effusions, and clinical signs cats is EATL of large cell subtype (type 1), which, like EATL
include dyspnea and regurgitation because of pressure of the type 2, occurs most frequently in the jejunum. EATL type 1
neoplasm on lung and esophagus, respectively. Horner syn- is often characterized by intracytoplasmic eosinophilic gran-
drome is caused by pressure on sympathetic nerves. ules that express the cytotoxic granule protein, granzyme B,
Since the 1990s, the incidence of thymic lymphoma has consistent with a diagnosis of large granular lymphocyte
decreased, and the most common type of lymphoma in cats (LGL) lymphoma. In contrast, gastric lymphomas are most
is now intestinal lymphoma (Fig. 2-211, eFig. 2-56). Although commonly diffuse large B-cell lymphomas (Fig. 2-212,
240.e1
B
eFigure 2-56 Intestinal lymphoma in a cat. A. Multifocal circum-
ferential thickening of the intestinal wall and enlargement of the
mesenteric lymph node. B. Thickening of the intestinal mucosa
with linear ulceration over Peyer’s patches.
Lymph Nodes 241
A
Figure 2-212 Gastric lymphoma in a cat. Submucosal thickening
by a diffuse, white, homogeneous infiltrate.
B
Figure 2-214 Nasal and nasopharyngeal lymphoma in a cat.
A. Expansile, white firm homogeneous mass that protrudes from
the frontal sinus causing destruction of bone. (Courtesy S. Kes-
dangsakonwut.) B. Plaque-like tonsillar lymphoma. (Courtesy
K.G. Thompson.)
Figure 2-213 Renal lymphoma in a cat. Numerous, sharply
demarcated, white, firm homogeneous masses distributed
throughout the renal cortex. Other extranodal lymphomas in cats include primarily lym-
phomas of the CNS, peripheral nerves (neurolymphomatosis),
cutaneous lymphomas (eFig. 2-59), and ocular lymphomas
eFig. 2-57), and this type of lymphoma can also occur at the (see eFig. 2-58), and account for ~20% of all feline lympho-
ileo-ceco-colic junction or synchronous at both locations. mas. None of these types of lymphoma has been associated
Multicentric lymphoma is another common type of lym- with FeLV or FIV infections. The clinical signs vary based on
phoma in cats, and historically, 70% of cases were positive for the organ system affected, for instance, paraplegia with
FeLV. The vast majority of cases affect internal organs such as neurolymphomatosis.
kidney (Fig. 2-213, eFig. 2-58) or liver, and generalized lymph- Porcine lymphoma. Lymphoma is the most common neo-
adenopathy is uncommon. Clinical signs vary depending on plasm in pigs. There are no published data that apply the
the organ system affected. A specific type of nodal lymphoma, WHO classification to a large series of porcine lymphomas.
Hodgkin-like lymphoma, is seen most commonly as unilateral All ages and both sexes are affected, but there is a higher
mandibular or cervical lymphadenopathy, but other lymph incidence in female pigs. The multicentric form is most com-
nodes may also be the primary sites. monly characterized by generalized lymphadenopathy affect-
Lymphoma is the most common feline upper respiratory ing visceral lymph nodes rather than peripheral lymph nodes.
tract neoplasm. Nasal and nasopharyngeal lymphomas can Multicentric lymphoma may also primarily affect internal
occur individually at each location or synchronous at both organs, such as kidney (eFig. 2-60), spleen, and liver (Fig.
sites (Fig. 2-214). The majority of cases are diffuse large B-cell 2-215). Leukemia occurs commonly at the terminal stage. The
lymphomas, but epitheliotropic T-cell lymphomas and small thymic form most commonly occurs as lymphoblastic T-cell
lymphocytic B-cell lymphomas have also been observed. lymphoma and is the most common form of lymphoma in
Interestingly, epitheliotropism has also been described for piglets as young as 3 weeks of age. An autosomal recessive
some B-cell lymphomas, and FeLV p27 or gp70 antigens have trait has been reported to have caused B-cell lymphomas in
been detected in ~50% of cases regardless of phenotype. 25% of animals from herds of Large White pigs bearing this
241.e1
A
eFigure 2-57 Gastric lymphoma in a cat. Cross section of severely
thickened gastric wall by a diffuse white homogeneous
infiltrate.
B
eFigure 2-58 Malignant lymphoma in a cat. A. Ocular lym-
phoma. (Courtesy D.G. Sledge.) B. Renal lymphoma character-
ized by diffuse infiltration of the cortex by neoplastic
lymphocytes.
241.e2
eFigure 2-59 Lymphocytosis in a cat. Solitary area of alopecia eFigure 2-60 Malignant lymphoma in a pig. White, raised nodules
with scaling, erythema, and ulceration. (Courtesy M. Umstead.) randomly distributed throughout the kidney.
242 CHAPTER 2 • Hematopoietic System Lymph Nodes
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A Durham AC, et al. Two hundred three cases of equine lymphoma clas-
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Fournel-Fleury C, et al. Canine T-cell lymphomas: a morphological,
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Fujino Y, et al. Molecular pathogenesis of feline leukemia virus-induced
malignancies: insertional mutagenesis. Vet Immunol Immunopathol
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Kiupel M, et al. Diagnostic algorithm to differentiate lymphoma from
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Little L, et al. Nasal and nasopharyngeal lymphoma in cats: 50 cases
(1989-2005). Vet Pathol 2007;44:885-892.
B Mazoub M, et al. Histopathologic and immunophenotypic character-
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242.e1
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Histiocytic Proliferative Diseases 243
Valli VE, et al. Canine lymphomas: association of classification type, interdigitating dendritic cells or lymphocytes. Furthermore,
disease stage, tumor subtype, mitotic rate, and treatment with epithelial dendritic cells and interstitial dendritic cells can be
survival. Vet Pathol 2013;50:738-748. differentiated by the expression of CD90 (Thy-1) in intersti-
tial dendritic cells and E-cadherin in epithelial dendritic cells.
Activated dendritic cells express CD4.
HISTIOCYTIC PROLIFERATIVE DISEASES Numerous well-defined histiocytic proliferative diseases
have been characterized in dogs and cats. Canine cutaneous
Proliferative histiocytic diseases in domestic animals occur histiocytomas and canine Langerhans cell histiocytosis (LCH)
largely in dogs and to a lesser extent in cats. They are likely are both diseases of Langerhans cells with different biological
present in other species, but have not been adequately behavior. A pulmonary form of LCH has rarely been reported
described. It is important to recognize that usage of the term in cats; reports of feline cutaneous histiocytomas are only
“histiocyte” has changed over time and that the term “histiocytic anecdotal. Diseases of interstitial dendritic cells include the
diseases” now encompass all proliferative disease processes of cutaneous or systemic forms of reactive histiocytosis, an
dendritic cells or macrophages. Gross or histopathology is often inflammatory disorder, and the various entities of histiocytic
insufficient to properly diagnose these disease processes, and sarcoma complex in dogs, as well as histiocytic sarcomas and
a basic understanding of the cell biology of histiocytes is feline progressive histiocytosis in cats. Canine hemophago-
required to use immunohistochemistry (IHC) as a means to cytic histiocytic sarcoma is the only macrophage-derived entity,
reach an accurate diagnosis. and a feline counterpart has recently been suggested. A con-
Histiocytes are derived from hematopoietic CD34+ stem cells genital histiocytosis of non–Langerhans cell origin has rarely
and differentiate into macrophage, nonlymphoid dendritic cell, been reported in pigs, and the condition most closely resem-
and lymphoid dendritic cell lineages. Nonlymphoid dendritic bles juvenile xanthogranuloma in humans, a generally skin-
cells include interstitial and epithelial (Langerhans) dendritic limited non-Langerhans histiocytic disorder.
cells, whereas lymphoid dendritic cells of the T-cell domains A combination of gross presentation, histopathology, and
in lymphoid organs, such as spleen or lymph nodes, are called IHC is sufficient to accurately differentiate most canine his-
interdigitating dendritic cells. Langerhans cells initially reside in tiocytic diseases. In rare cases, additional frozen sections will
the epithelia of the skin, digestive, respiratory, and reproduc- be required to confirm the diagnosis. A summary of the immu-
tive tract as intraepithelial dendritic antigen-presenting cells. nohistochemical differences of the canine histiocytic diseases
Interstitial dendritic cells can be found in most organs around can be found in Figure 2-216.
vessels, with the exception of the brain. The dendritic cells in
lymph nodes comprise both resident interdigitating dendritic Canine cutaneous histiocytoma
cells as well as migratory epithelial and interstitial dendritic Cutaneous histiocytoma is a benign common skin disease of
cells that have been drained via the lymphatics from their young dogs that usually appears as a single, focal, bulging mass
tributary area. All dendritic cells are part of the adaptive frequently on the head, ears, and limbs. Although most
immune response and act as potent antigen-presenting cells. common in dogs <3 years of age, histiocytomas can occur in
By presenting antigens to naive T-cells in the paracortex of dogs of all ages. All breeds are affected, but there is a predis-
lymph nodes, dendritic cells initiate an immune response. position in brachycephalic breeds, such as Boxers; Dachs-
Most histiocytic diseases in domestic animals originate from hunds, Doberman Pinschers, and Cocker Spaniels are also
interstitial dendritic cells or Langerhans cells. Only hemophago- more commonly affected. The proliferation is of epidermal
cytic histiocytic sarcomas in dogs have been demonstrated to Langerhans cells and usually ulcerates and regresses
originate from macrophages, in particular red pulp macro- spontaneously.
phages from the spleen. The characterization of histiocytic Grossly, canine cutaneous histiocytomas appear as round
cells in formalin-fixed tissues is limited by the availability of 1-2 cm dome-shaped skin protrusions that are usually hairless
species-specific antibodies that will detect the appropriate and may be irritating to the dog, because they are frequently
epitopes. A number of such antibodies have been developed abraded and ulcerated (Fig. 2-217, eFig. 2-61). Much less
for canine and feline tissues and can be used in routinely frequently, the lesion may be a flat thickened plaque. If lesions
formalin-fixed tissues, whereas others are currently only avail- are left unattended, they usually involute spontaneously, with
able for use in frozen sections. Antibodies that can be used to complete healing in young dogs, but in older dogs, they are
characterize histiocytic proliferative diseases and function in more persistent. Surgical excision tends to be curative and
formalin-fixed tissues include CD18, CD11d, CD204, CD90, recurrence or development of additional masses is rare. Mul-
major histocompatibility complex II (MHC II), and E-cadherin. tiple histiocytomas are also uncommon, but Shar Peis are
Additional antibodies of importance that only work in frozen more prone to develop multiple lesions. If dogs develop
sections include CD1a, CD11c (dog only), and CD4. All numerous histiocytomas, such lesions should be better con-
dendritic cells express CD1a that, together with MHC I and sidered as a form of LCH (see later). Rare spread to lymph
MHC II molecules, presents antigens to T cells. Another mol- nodes followed by regression has been reported in individual
ecule that is useful in the diagnosis of histiocytic proliferative cases, but may represent a Langerhans cell histiocytosis. Spon-
diseases is CD18. CD18 is part of the heterodimeric β-2 taneous regression is a major characteristic of canine cutaneous
integrin adhesion molecule that is composed of 1 of 4 differ- histiocytomas, but the mechanisms are poorly understood.
ent CD11 (a-d) subunits and the CD18 subunit. Therefore all Lysis of the histiocytic cells mediated by infiltrating lympho-
histiocytic cells express CD18. CD11c is found in all epithe- cytes, especially CD8+ lymphocytes, has been postulated as
lial and interstitial dendritic cells; CD11d can be detected in the primary mechanism of regression. Some authors speculate
macrophages. Macrophage scavenger receptor 1 (CD204) is that tumor cells could facilitate their own destruction by
expressed on macrophages and interstitial dendritic cells, functioning as antigen-presenting cells, but infiltrating dermal
where it mediates endocytosis, but not in epithelial or dendritic cells may also play a major role.
243.e1
Histiocytic sarcoma
Cutaneous Hemophagocytic
histiocytoma histiocytic sarcoma
Reactive histiocytosis
Langerhans
histiocytosis
Figure 2-216 Classification of canine histiocytic diseases based on cell morphology and immu-
nohistochemical phenotype.
B
eFigure 2-62 Cutaneous histiocytoma in a dog. A. Histiocytic
cells have highly variable morphology, and nuclei tend to be round
to oval, but reniform or convoluted shapes are also common.
B. Epitheliotropism occurs in 30% of cases.
Histiocytic Proliferative Diseases 245
Dermal
vessels
Histiocytic
infiltrate
Subcutis
A B
C D
Figure 2-218 Cutaneous histiocytoma in a dog. A. Cutaneous histiocytomas are located in the
superficial dermis and extend to the basement membrane, resulting in a typical dome-shaped
appearance. B. Schematic drawing of the dermal location of cutaneous histiocytomas that surround
dermal vessels and cause epitheliotropism in 30% of cases. (Adapted from a graphic by P.F. Moore.)
C. Histiocytic cells are more loosely arranged and in rows near the epidermis. D. Immunohisto-
chemistry for E-cadherin labels both epidermal epithelial cells and neoplastic Langerhans cells.
Commonly, expression of E-cadherin is limited to histiocytes commonly leads to extensive ulceration, and euthanasia of
in the superficial portion of the lesion just below the epider- 50% of affected dogs has been reported because of secondary
mis. It may be impossible to detect E-cadherin in severely complications. Dogs with systemic spread of LCH have a poor
ulcerated and regressing tumors, and a panel of antibodies will prognosis, and the reported mortality is 100%, including
be required to accurately diagnose such lesions. euthanasia. Systemic LCH tends to spread to the lymph nodes
first, followed by the lungs, and variably other organs. A peri-
Canine cutaneous Langerhans cell histiocytosis bronchial pattern is most commonly observed in the lungs
Although most histiocytomas occur as solitary lesions, some (Fig. 2-220).
dogs may develop multiple tumors over time. In dogs with Histologically, the individual cutaneous masses resemble
numerous cutaneous neoplasms that histologically and immu- cutaneous histiocytomas. Although cutaneous lesions of LCH
nohistochemically resemble cutaneous histiocytomas, a canine tend to be larger and may extend into the subcutis and under-
cutaneous LCH should be considered as the primary differen- lying muscle, the occurrence of multiple nodules and delayed
tial (Fig. 2-219). LCH always starts as a cutaneous disease regression are the primary indicators of a LCH versus a cuta-
process, but it can also extend to draining lymph nodes and neous histiocytoma. Some cases have a higher degree of aniso-
rarely involve other internal organs. The cutaneous and sys- karyosis, and multinucleated cells may be observed, but the
temic forms of LCH closely resemble their human counter- cellular morphology most closely resembles those of Langer-
parts. Affected dogs may have hundreds of cutaneous masses, hans cells in cutaneous histiocytomas rather than the highly
and secondary self-inflicted trauma commonly leads to severe anaplastic features of neoplastic interstitial dendritic cells in
inflammation and ulceration. Shar Peis are over-represented, histiocytic sarcomas. Lymphatic invasion indicates lymphatic
but other breeds can be affected. The prognosis of LCH is less spread and carries a worse prognosis.
favorable than for solitary cutaneous histiocytomas. Delayed Immunohistochemically, proliferating histiocytic cells in
regression of the cutaneous lesions for up to 10 months LCH have features similar to Langerhans cells in cutaneous
246 CHAPTER 2 • Hematopoietic System Histiocytic Proliferative Diseases
A
Figure 2-221 Pulmonary Langerhans cell histiocytosis in a cat.
Nodular proliferations throughout the pulmonary parenchyma
that coalesce and extend to the pleural surface. (Courtesy F.
Taylor.)
B
eFigure 2-63 Pulmonary Langerhans cell histiocytosis in a cat.
A. Histiocytic aggregates are cohesive, and proliferating cells oblit-
erate the lumen of a respiratory bronchiole and extend into the
surrounding alveoli and alveolar septa. B. Immunohistochemistry
for CD18 detects the infiltrating Langerhans cells.
Histiocytic Proliferative Diseases 247
A B
C D
eFigure 2-64 Reactive histiocytosis in a dog. A. Cutaneous reactive histiocytosis characterized by
large numbers of cutaneous nodules widely disseminated throughout the skin. (Courtesy K. Loft.)
B. Systemic reactive histiocytosis with sharply demarcated nodule on the epiglottis. C. Enlarge-
ment of lymph nodes can be observed in either cutaneous or systemic reactive histiocytosis.
D. Large numbers of nodules in the oral cavity of a dog with systemic reactive histiocytosis.
248 CHAPTER 2 • Hematopoietic System Histiocytic Proliferative Diseases
A B
Figure 2-223 Cutaneous reactive histiocytosis in a dog. (Courtesy K. Loft.) A. Large numbers of
cutaneous nodules widely disseminated throughout the skin. B. Similar sharply demarcated
nodules in the skin of the lower extremities.
A B
Dermal
vessels
Histiocytic
Subcutis infiltrate
C D
Figure 2-224 Cutaneous reactive histiocytosis in a dog. A. Deep dermal and angioinvasive cellular
infiltrates that are dominated by lymphocytes and dermal dendritic cells extend into the subcutis
where they may coalesce. B. Immunohistochemistry for Thy-1 labels activated dermal interstitial
dendritic cells. C. Schematic drawing depicting the “bottom-heavy” topography of reactive histio-
cytosis in contrast to of the superficial, “top-heavy” topography of cutaneous histiocytomas.
(Adapted from a graphic by P.F. Moore.) D. Proliferating histiocytic cells have abundant cytoplasm,
indistinct cell boundaries, and monomorphic round to oval nuclei that can be twisted, indented,
or folded, but features of anaplasia characteristic for histiocytic sarcoma are absent.
Histiocytic Proliferative Diseases 249
and small but prominent central nucleoli. Multinucleated or both entities. Clusters of atypical T cell will aid a diagnosis of
highly anaplastic cells as observed in histiocytic sarcomas are lymphoma, but in many cases, a definite diagnosis has to rely
not a feature of reactive histiocytosis. Mitotic figures are on detection of a clonal T-cell expansion in lymphoma cases
absent or rare, and bizarre forms are lacking. Proliferating by T-cell receptor γ gene rearrangement.
histiocytic cells may be found in draining lymph nodes, where
they selectively invade the sinuses and paracortex. Systemic reactive histiocytosis
Cutaneous reactive histiocytosis must be differentiated Systemic reactive histiocytosis is a much less common disease
from Langerhans cell proliferation (cutaneous histiocytoma of dogs than cutaneous reactive histiocytosis, and essentially
and LCH) and from more aggressive types of histiocytic pro- represents a progression of the cutaneous disease to involve inter-
liferations (histiocytic sarcomas). The clinical presentation nal organs. Like its cutaneous counterpart, systemic reactive
(multiple vs. solitary lesions), the distinct morphologic pattern histiocytosis is also characterized by cutaneous nodules with
(vasocentric “bottom-heavy” vs. commonly epitheliotropic the earlier-described histologic features of a “bottom-heavy”
“top-heavy”), the cellular morphology (well-differentiated his- histiocytic proliferation. Although no breed association has
tiocytic cells vs. marked anaplasia), and the immunohisto- been established for the cutaneous form, the systemic form
chemical features (positive for CD4 [frozen only] CD90, and has a familial association in Bernese Mountain dogs. It is
CD204 (eFig. 2-65), but negative for E-cadherin) allow for an important not to misdiagnose systemic reactive histiocytosis
accurate differentiation among these 3 entities (Fig. 2-225). as a disease process in the histiocytic sarcoma complex, and
Another major differential diagnosis for cutaneous reactive there is no evidence of progression of this inflammatory condi-
histiocytosis is an inflamed cutaneous non-epitheliotropic tion into a malignant neoplasm. Systemic reactive histiocytosis
T-cell lymphoma. The large component of CD3+ T-cells in also has a familial component in Irish Wolfhounds and has
cutaneous reactive histiocytosis may lead to confusion between been reported to occur in other large breeds, for instance,
Rottweilers and Labrador Retrievers. Young to middle-aged
dogs are most commonly affected. Skin nodules occur most
frequently around the nose (planum, apex), scrotum, and
eyelids, similar to what has been described for the cutaneous
form. This distribution makes distinction between the cutane-
ous and systemic form very difficult during the early stages of
a systemic reactive histiocytosis. As with the cutaneous form,
ulceration of skin masses is very common and occurs most
likely secondary to vascular lesions that cause infarction, as
described earlier. Besides the skin, nodular masses are often
observed in the ocular and nasal mucous membranes, and
lymph nodes are typically enlarged (Fig. 2-226). Involvement
of internal organs is quite variable, and lesions in the lungs,
liver, spleen, bone marrow, kidney, and testis have been
reported. The wide range of internal organs that can be
affected drives the variation of clinical signs and the degree of
their severity. Weight loss, anorexia, respiratory distress, ocular,
A and renal disease have all been reported. As with the cutane-
ous form, remission and relapse are also features of systemic
reactive histiocytosis.
B
Figure 2-225 Cutaneous reactive histiocytosis in a dog.
A. Lesions are frequently vasocentric and composed of dense
infiltrates of interstitial dendritic cells admixed with focal small
lymphocytic aggregates. B. Immunohistochemistry demonstrates Figure 2-226 Systemic reactive histiocytosis in a dog. The
expression of CD4 in interstitial dendritic cells, a marker of lymph node is infiltrated by large numbers of activated dermal
dendritic cell activation that is not expressed in histiocytic sarco- interstitial dendritic cells that are positive for CD90 by
mas or Langerhans cell proliferations. immunohistochemistry.
249.e1
B
eFigure 2-65 Cutaneous reactive histiocytosis in a dog.
A. Immunohistochemistry for CD204 labels activated dermal
interstitial dendritic cells. B. These cells are negative for E-
cadherin by immunohistochemistry, thus excluding a cutaneous
histiocytoma.
250 CHAPTER 2 • Hematopoietic System Histiocytic Proliferative Diseases
Histiocytic sarcoma
Histiocytic sarcomas are principally neoplasms of interstitial den-
dritic cells. However, one distinct entity, hemophagocytic his-
tiocytic sarcoma, is an aggressive malignant neoplasm of
macrophage origin in dogs. This neoplastic entity causes a
distinct disease syndrome that differs in many aspects from
other histiocytic sarcomas of dendritic cell origin and will
therefore be discussed as a separate entity.
Histiocytic sarcoma is a relatively frequently occurring
aggressive malignant neoplasm primarily of dogs and much
less commonly cats. The disease presentation is essentially the
same in both species. Lesions may be localized arising at a
single site or organ or disseminated after metastasis to distant
sites (eFig. 2-66). It is uncertain whether multiple simultane-
ously occurring neoplasms in different organs represent a mul- B
ticentric disease process or distant metastases of a primary Figure 2-227 Histiocytic sarcoma in a dog. A. Small white
mass. The term “malignant histiocytosis” has historically been nodules, which in some areas almost become confluent, randomly
applied to disseminated histiocytic sarcomas, but should be distributed throughout the spleen. (Courtesy K.G. Thompson.)
avoided to prevent confusion of histiocytic sarcomas with the B. Discrete neoplastic masses that protrude above the splenic
earlier described inflammatory disease processes of reactive capsule (Courtesy R.L. Amorim.)
histiocytosis.
Histiocytic sarcomas may develop at various locations, but
primary masses are commonly observed in the spleen (Fig.
2-227), lymph nodes (Fig. 2-228), lung, bone marrow, skin
(Fig. 2-229), the periarticular tissue of the extremities (eFig.
2-67), and even the central nervous system (CNS) (Fig.
2-230). Periarticular histiocytic sarcomas occur most com-
monly around the stifle and elbow joints, but carpus and
coxofemoral joints can also be affected. Masses in the brain
most commonly occur as focal, solitary, subdural masses, and
occasionally as diffuse meningeal infiltrates (Fig. 2-231, eFig.
2-68). Histiocytic sarcomas typically appear as white/cream
to tan, homogeneous masses with a smooth cut surface, but
diffuse organ enlargement by infiltrating neoplastic histiocytic
cells can also occur. Nodules can be solitary or multiple at the
primary site and tend to be highly destructive. Metastatic sites
can include any organ system, but liver (eFig. 2-69), kidneys
(eFig. 2-70), lungs (Fig. 2-232, eFig. 2-71), and draining lymph
nodes are most commonly affected.
Numerous dog breeds have a familial predisposition,
including Bernese Mountain dogs, Golden Retrievers, Labra-
dor Retrievers, Flat-coated Retrievers, and Rottweilers. Periar-
ticular histiocytic sarcomas have been most commonly Figure 2-228 Histiocytic sarcoma in a dog. Cross section of a
reported in Rottweilers and Flat-coated Retrievers. A poly- white, firm, and homogeneous splenic nodule. (Courtesy S.
genic mode of inheritance has been postulated for Bernese Kesdangsakonwut.)
250.e1
B
eFigure 2-66 Histiocytic sarcoma in a dog. A. Small white
nodules randomly distributed throughout the spleen. B. Discrete
neoplastic masses that protrude above the splenic capsule, but
their color resembles the splenic parenchyma.
A B
eFigure 2-68 Histiocytic sarcoma in a dog. A. Submeningeal infiltrates of distinct large, highly
anaplastic histiocytic cells with abundant eosinophilic cytoplasm. B. Neoplastic cells expand
Virchow-Robin spaces and invade the cerebral cortex.
250.e2
A B
eFigure 2-69 Histiocytic sarcoma in a dog. A. Multifocal, sharply demarcated neoplastic nodules
randomly distributed throughout the liver. B. A discrete neoplastic nodule with less well-defined
borders in the liver. (Courtesy S. Kesdangsakonwut.)
eFigure 2-70 Histiocytic sarcoma in a dog. Well-circumscribed eFigure 2-71 Histiocytic sarcoma in a dog. Numerous pulmonary
neoplastic masses in the renal cortex. vessels are obstructed by large numbers of neoplastic histiocytic
cells that are highly pleomorphic.
Histiocytic Proliferative Diseases 251
A
Figure 2-229 Histiocytic sarcoma in a dog. Severely ulcerated
discrete and coalescing cutaneous nodules. (Courtesy S.
Kesdangsakonwut.)
C
Figure 2-232 Histiocytic sarcoma in a dog. A. Numerous peri-
bronchial vessels are obstructed by large numbers of neoplastic
histiocytic cells that are highly pleomorphic. B. Multinucleated
giant cells and neoplastic cells with megalokaryosis infiltrating the
hepatic sinusoids. C. Neoplastic histiocytic cells are positive for
CD18 by immunohistochemistry.
A
Figure 2-233 Histiocytic sarcoma in a dog. Lymph node with
diffuse infiltrate of highly anaplastic, large, pleomorphic histio-
cytic cells with abundant eosinophilic, often vacuolated cyto-
plasm. Multinucleated cells, megalokaryosis, and bizarre nuclei are
common.
eFigure 2-72 Feline progressive histiocytosis. Alopecic nodules eFigure 2-73 Feline progressive histiocytosis. Deep histiocytic
with focal ulcerations on the face of a cat. infiltrates into the underlying muscle occur during disease
progression.
254 CHAPTER 2 • Hematopoietic System Histiocytic Proliferative Diseases
Figure 2-237 Feline progressive histiocytosis. As lesions progress, Figure 2-238 Hemophagocytic histiocytic sarcoma in a dog.
cellular pleomorphism, nuclear anisokaryosis, and mitotic activity Diffuse splenomegaly with ill-demarcated neoplastic nodules pro-
increase. truding over the splenic capsule.
have a characteristic interstitial dendritic cell phenotype, and are masses, a neoplasm is often considered less likely as the
positive for CD1a, CD18, and MHC II. Interestingly, some of primary cause than an immune-mediated disease, and the
the cases express E-cadherin at an earlier disease stage, which ultimate diagnosis is often made through autopsy and histo-
would indicate a Langerhans cell differentiation. About half logic examination of the spleen and liver. Adding the poor
the cases in one study expressed CD5. Antibodies specific for response of hemophagocytic histiocytic sarcomas to standard
feline CD molecules are limited, and only an antibody specific chemotherapy to the difficulties in reaching an accurate diag-
for feline CD18 is available for formalin-fixed tissue. The nosis may help to explain reported median survival times of
canine-specific CD18 will not cross react with feline dendritic <30 days.
cells. The infiltrating lymphocytes are CD3 and CD8 positive. Hemophagocytic histiocytic sarcomas are caused by prolif-
The location of the lesions, the progression of the disease eration of neoplastic macrophages that are avidly erythrophago-
process and the cell morphology at the different stage of FPH cytic (Fig. 2-239). Primary sites are the spleen and the bone
in combination with positive IHC for CD18 are used to reach marrow with secondary spread to lung and liver and rarely
an accurate diagnosis. Although inflammatory lesions must be kidneys (eFig. 2-75). Grossly, the spleen is markedly diffusely
excluded at an early stage of the disease, an atypical large cell enlarged with few to many, discolored green-tan to white
lymphoma should be excluded at late stage by using IHC for splenic infarcts that are visible through the splenic capsule. In
CD3, CD79a, CD20, and Pax-5. cats, the involvement of the liver may be of solid foci of neo-
plastic cells.
Hemophagocytic histiocytic sarcoma Microscopically, in the spleen, neoplastic cells differentiate
Hemophagocytic histiocytic sarcoma is the only malignancy of toward red pulp macrophages and cause locally extensive to
macrophage origin and occurs primarily in dogs; a few cases have diffuse expansion of the red pulp sinuses and frequently oblit-
been reported in cats. There is no known breed or age predis- erate the adjacent white pulp. Focal areas of ischemic necrosis
position, but commonly affected breeds are similar to those secondary to vascular thrombosis are common in the splenic
affected by histiocytic sarcoma of dendritic cell origin. It is sinuses. Most cases are accompanied paradoxically by inter-
therefore important to recognize that hemophagocytic histio- spersed foci of extramedullary hematopoiesis. The neoplastic
cytic sarcoma may occur simultaneously to histiocytic sarcoma, histiocytes migrate to the lung and liver, where they insidi-
especially in breeds with a predisposition for the latter disease. ously invade hepatic sinusoids. In the lungs, hemophagocytic
Hemophagocytic histiocytic sarcoma has a unique clinical neoplastic cells are found primarily in the vasculature. The
picture that differs from that caused by other histiocytic sar- bone marrow is also infiltrated by neoplastic hemophagocytic
comas and most closely resembles an immune-mediated hemo- histiocytes. Most neoplastic cells are severely hemophagocytic
lytic anemia, or, more specifically, Evans syndrome because or contain hemosiderin, but it is common to find areas in the
there is concurrent thrombocytopenia. Affected dogs have spleen where cells exhibit less erythrophagocytosis. Some neo-
splenomegaly and hepatomegaly (Fig. 2-238, eFig. 2-74) and plastic cells may also phagocytose red cell precursors and
rapidly progressive, regenerative hemolytic anemia and throm- granulocytes. Although some atypia of the neoplastic cells is
bocytopenia, but are Coombs test negative (no erythrocyte- common, especially in the spleen, in contrast to the highly
bound IgG). The pathogenesis of the disease is the result of pleomorphic cells in histiocytic sarcomas of interstitial den-
the massive level of erythrophagocytosis by the neoplastic histio- dritic cell origin, neoplastic cells of macrophage origin in hemo-
cytes that are primarily located in the spleen, liver, and bone phagocytic histiocytic sarcomas are surprisingly well differentiated.
marrow. Many dogs are icteric at initial presentation and have Especially within the bone marrow, but also liver and lung,
marked hyperbilirubinemia. Hypoalbuminemia and hypocho- neoplastic cells closely resemble their normal counterpart
lesterolemia are also commonly observed. Because dogs with except for erythrophagocytosis. In the spleen, occasional
hemophagocytic histiocytic sarcomas lack grossly visible anisocytosis, anisokaryosis, and hyperchromatic nuclei are
254.e1
eFigure 2-74 Hemophagocytic histiocytic sarcoma in a dog. eFigure 2-75 Hemophagocytic histiocytic sarcoma in a dog. In
Diffuse splenomegaly with ill-demarcated neoplastic nodules pro- the spleen, there is proliferation of neoplastic macrophages that
truding over the splenic capsule. are avidly erythrophagocytic.
Disorders of Hemostasis 255
DISORDERS OF HEMOSTASIS
R. Darren Wood
Hemostasis is the process by which interactions between a
series of plasma proteins and cells, including platelets, endo-
thelial, and white blood cells, combine to provide a balance
between anticoagulant and procoagulant functions. It is essen-
tially a host defense mechanism that protects the integrity of
the vascular system after injury. In recent years, the impor-
tance of activated cell membranes to the hemostatic process
has become well understood, and the entire process is now
frequently referred to as the cell-based model of hemostasis.
During health, anticoagulant mechanisms, which are
B designed to ensure that blood clotting is tightly regulated,
Figure 2-239 Hemophagocytic histiocytic sarcoma in a dog. predominate. When injury to, or activation of, endothelium
A. In the spleen, there is proliferation of neoplastic macrophages occurs, procoagulant proteins are released from these cells,
that are avidly erythrophagocytic. B. Neoplastic splenic macro- and circulating platelets and plasma proteins become exposed
phages are CD11d positive by immunohistochemistry. to subendothelial tissues, including collagen and fibroblasts.
This promotes a tipping of the balance toward procoagulation,
where platelet-mediated hemostasis initially stems the loss of
observed, as well as a few multinucleated giant cells. The blood at the site of the vascular injury via formation of a
abundant cytoplasm is eosinophilic and often vacuolated. platelet plug. Once sufficient platelet activation occurs, initial
Nuclei are most frequently ovoid or cleaved, and bizarre forms thrombin production activates additional platelets, promotes
are rare. The mitotic index is low. Because neoplastic cells the conversion of fibrinogen to fibrin, provides positive feedback
appear well differentiated, the early pattern of invasion into amplification to produce more fibrin, and stimulates antico-
the liver may be misdiagnosed on fine-needle biopsies as agulants and the fibrinolytic system to regulate overall clot
Kupffer cell hyperplasia or an inflammatory process. IHC has formation. Thrombin has additional roles in cell proliferation,
been helpful for characterizing the distribution of neoplastic inflammation, and repair that are mediated through its ability
cells in the spleen and liver. to engage protease-activated receptors (PARs) on target cells
Immunohistochemically, the neoplastic hemophagocytic (Fig. 2-240).
histiocytes most closely resemble macrophages of the splenic During disease, there are many possible derangements that
red pulp and bone marrow, are positive for CD11d and CD18, can occur, depending on the nature of the abnormality, and
and have variable expression of CD1a, but are negative for whether it remains localized or becomes disseminated sys-
CD11c, which is positive in interstitial dendritic cells. Although temically. As a result, disorders of the hemostatic system can
antibodies for canine CD11d are available for formalin-fixed range from poorly detectable but significant pathology, to
tissues, there is no feline counterpart and definite confirmation overt and potentially catastrophic hemorrhage and/or throm-
of hemophagocytic histiocytic sarcomas in cats is still missing. bosis. A brief review of important physiology, pathophysiol-
ogy, and disorders follows.
Further reading
Hélie P, et al. Congenital cutaneous histiocytosis in a piglet. Vet Pathol
2013;51:812-815.
Ide K, et al. Disseminated histiocytic sarcoma with excessive hemo-
phagocytosis in a cat. J Vet Med Sci 2009;71:817-820.
Kato Y, et al. The class A macrophage scavenger receptor CD204 is a
useful immunohistochemical marker of canine histiocytic sarcoma.
J Comp Pathol 2013;148:188-196.
Moore PF, et al. Canine cutaneous histiocytoma is an epidermotropic
Langerhans cell histiocytosis that expresses CD1 and specific beta
2-integrin molecules. Am J Pathol 1996;148:1699-1708.
Pinard J, et al. Histiocytic sarcoma in the tarsus of a cat. Vet Pathol
2006;43:1014-1017.
Weiss DJ. Flow cytometric evaluation of hemophagocytic disorders in
canine bone marrow. Vet Clin Pathol 2002;31:36.
256 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
Procoagulant
Inflammation
Tissue repair
Kallikrein/bradykinin
THROMBIN Release of
PAF synthesis
growth factors
Neutrophil activation
Anticoagulation
Activation of Activation of
TM–protein
TM – protein C–protein
C – proteinSS fibrinolysis
Figure 2-240 Multiple functions of thrombin that include modulation of coagulation, anticoagula-
tion, inflammation, and tissue repair. PAF, platelet activating factor; TM, thrombomodulin.
with von Willebrand factor (vWF) released from endothelial are others, thrombin is considered the most potent platelet
cells, initiates platelet adhesion, aggregation, and granule agonist.
content release at the site of vascular injury. Simultaneously,
tissue factor and procoagulant platelet phospholipids become Aggregation
available on cell surfaces to initiate thrombin, and then fibrin, Further recruitment of circulating platelets and their incorpo-
formation. ration into developing platelet aggregates around the site of
already adherent platelets depends on the local accumulation
Adhesion of platelet agonists and the generation of procoagulant activity
Platelets are derived from megakaryocytes and circulate as provided by integrin and phospholipid exposure on the surface
small discoid cells in an unactivated state. When activated, of activated platelets. Local agonists include adenosine diphos-
they undergo a shape change, becoming more spherical and phate (ADP), serotonin, and epinephrine, which are pre-
with extensions, which is mediated by actin and myosin fila- formed in platelet-dense granules, and newly synthesized
ments in the cytoplasm. This is accompanied by alterations in agonists, such as platelet-activating factor (PAF) and thrombox-
the cell membrane conformation that activates platelet mem- ane A2 (TxA2). These agonists interact with their own
brane glycoprotein (GP), or integrin, receptors. These receptors G-coupled protein receptors to initiate inside-out signaling.
mediate platelet adhesion to exposed tissue that then pro- The activator-receptor interactions increase the avidity of the
motes further recruitment and adhesion of additional glycoprotein-integrin receptors for their ligands and addition-
platelets. ally initiate intracellular downstream signaling via several
The 2 main proteins required for adhesion of platelets to pathways involving the activation of phospholipases, protein
each other and to damaged endothelial cells and exposed kinase K (PKC), and adenylate cyclase.
fibroblasts are fibrinogen and vWF. Glycoprotein Ib-IX-V is a Platelets are maintained in an unactivated state by
constitutively active receptor that causes rapid platelet adhe- regulation of cytoplasmic levels of calcium and cyclic AMP
sion to exposed vWF. This receptor is important in blood (cAMP). Upon activation, phospholipase C–mediated hydro-
vessels with high shear forces because it facilitates stabiliza- lysis of the membrane phospholipid phosphatidylinositol-4,5-
tion of platelet aggregates. The most abundant platelet integrin, bisphosphate (PIP2), results in the release of 2 secondary
αIIbβIII (or GPIIb/IIIa), undergoes a conformational change messengers, inositol-1,4,5-triphosphate (IP3) and diacylglyc-
during platelet activation to bind fibrinogen, and to a lesser erol (DAG); phospholipase A2 hydrolyses phosphatidylcho-
extent vWF. This receptor is also expressed in the open cana- line to PAF and the TxA2 precursor, arachidonic acid.
licular system, a feature of most mammalian platelets, which Intracellular IP3 directly induces calcium release from storage
expands the platelet surface area once shape change occurs. pools in dense granules; DAG indirectly induces the same
When fibrinogen binds to αIIbβIII, it connects adjacent plate- response through activation of PKC. An increase in free cyto-
lets, which is critical for the development of platelet plasmic calcium, with concurrent reduction in intracellular
aggregates. cAMP, is a universal response among mammalian platelets and
Platelets possess specific membrane thrombin receptors. explains why drugs that function as calcium channel blockers
These receptors are members of the G-protein–coupled impact platelet aggregation. Nonsteroidal anti-inflammatory
receptor family that are characterized by a single polypeptide drugs such as aspirin, which inhibit reactivity of cyclooxygen-
with a 7-transmembrane domain. Thrombin receptors are ase enzyme (COX-1), do not interfere with the aggregation
referred to as PARs, because the receptors only acquire trans- response in platelets from those species, for instance, cow, rat,
membrane signaling functions after thrombin has cleaved and some dogs, that are relatively insensitive to TxA2 as an
a peptide from the extracellular domain. Although there agonist.
Disorders of Hemostasis 257
Vascular Tissue
damage repair Vessel wall
Endothelium
Vascular lumen
TF
FVII PL
FVIIa FIX FIXa FIX
FVIIIa FVIII PDGF
TF-FVIIa Ca2+ EGF
PL
FX FXa FX
Secretion
FVa FV
Ca2+
Fibrinogen Fibrin
(soluble) Adhesion
FXIII FXIIIa
Fibrin Aggregation
(insoluble)
Thrombus formation
Figure 2-241 The tissue factor (extrinsic) pathway that leads to thrombin generation and platelet
activation following vascular damage. The oval structures represent activated phospholipid-
expressing cells. EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PL, phos-
pholipid; TF, tissue factor.
Platelets are additionally essential for endothelial repair disorders involving predominantly thrombin and fibrin gen-
and eventual clot retraction. During aggregation, mediators eration because platelet adhesion and aggregation responses
such as platelet-derived growth factor (PDGF) and epidermal are adequate to seal small lesions in vessels low blood pressure.
growth factor (EGF) are released from α-granules (Fig. 2-241). For larger wounds, and in vessels with higher blood pressure,
Platelet cytoskeleton proteins actin and myosin, in the presence hemostasis requires fully functional platelet aggregation and
of increased cytoplasmic calcium, interact in a manner similar fibrin formation so that a stable thrombus can form. Platelet
to that in myocytes. The activation of these contractile pro- function disorders associated with prolonged bleeding times,
teins results in the shrinkage of the platelet–fibrin meshwork, and normal platelet counts and coagulation profiles, may be
which results in contraction of the clot. In conjunction with the result of defects in platelet adhesion, aggregation, or
fibrinolysis, the fibrin clot is eventually removed when repair granule release.
is complete.
Evaluation of platelet function
Platelet concentration is assessed with an automated platelet
Further reading count and blood smear examination, typically performed as
Boudreaux MK. Platelet structure. In: Weiss DJ, Wardrop KJ, editors. part of a complete blood count (CBC). However, enumeration
Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley- alone is not sufficient to explain all platelet-related bleeding
Blackwell; 2010. p. 561-568. disorders, because functional defects can occur despite adequate
Boudreaux MK, Catalfamo JL. Platelet biochemistry, signal transduc- numbers.
tion, and function. In: Weiss DJ, Wardrop KJ, editors. Schalm’s Platelet function tests are best reserved for patients with
Veterinary Hematology. 6th ed. Ames, Iowa: Wiley-Blackwell; 2010. normal platelet concentration, but clinical signs supportive of
p. 569-575. a platelet disorder. The buccal mucosal bleeding time (BMBT)
Goggs R, Poole AW. Platelet signaling—a primer. J Vet Emerg Crit Care is the time for bleeding to stop after a standardized cut is
2012;221:5-29. made with a commercial spring-loaded device in the mucosal
surface of the upper lip. The BMBT is prolonged when there
is decreased concentration and/or dysfunction of platelets, or
Platelet disorders if there is reduced activity of adhesive proteins, such as vWF.
Bleeding associated with decreased numbers of functional This is a simple and inexpensive test, but difficult to standard-
platelets is characterized by petechial and ecchymotic hemor- ize because of inter-operator and animal variability.
rhages, which form small pinpoint to coalescing endothelial The gold standard for assessment of platelet function is the
lesions in mucous membranes and capillary beds. Epistaxis, platelet aggregation test. The ability of platelets to aggregate in
melena, hematuria, and cutaneous bruising can also be response to in vitro stimulation with various agonists can be
observed. This type of bleeding is not observed in coagulation determined in citrated whole blood (impedance) or
258 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
platelet-rich plasma (light transmission), but because this Secondary immune-mediated thrombocytopenia can be
requires specialized instrumentation and timely evaluation, its caused by antiplatelet antibodies or may be the result of anti-
usefulness tends to be limited to research laboratories. body binding to non–self-antigens that become absorbed onto
The Platelet Function Analyzer (PFA) 100 and 200 models platelet membranes. These antibodies are produced in response
provide a benchtop point-of-care alternative to the BMBT, but to infectious agents, drug exposure, or neoplasia. For example,
tend to be only available in larger referral centers. Similarly, many rickettsial agents are associated with thrombocytopenia,
platelet function can be assessed using viscoelastic technology, and development of petechiae and ecchymoses can occur in
such as thromboelastography (TEG), although the contribution dogs with these infections. Thrombocytopenia associated with
of platelets to the overall tracing can be difficult to easily systemic lupus erythematosus (SLE) has been reported in
discern and may be compensated for by other components of dogs, cats, and horses. Thrombocytopenia may accompany
hemostasis in this in vitro setting. immune-mediated hemolytic anemia in dogs for a few reasons,
but it is suspected some dogs have concurrent immune-
Thrombocytopenia mediated platelet destruction.
In the absence of any other underlying coagulopathy or plate- Drug-induced thrombocytopenia occurs when administration
let dysfunction, petechial hemorrhages are usually not of medications either suppresses platelet production in the
observed in animals unless the platelet count falls below bone marrow, or increases the rate of platelet destruction as
25-30 × 109/L. In healthy animals, ~30-40% of the total plate- a consequence of drug-dependent antibodies that bind to
let pool is sequestered in the spleen, so apparent thrombocy- complementary antigenic sites on platelet membranes. Mac-
topenia may be observed when conditions causing splenomegaly rophages in the liver and spleen recognize, engage, and remove
occur, by resulting in an increase in the splenic platelet pool. these altered platelets, resulting in thrombocytopenia.
However, because overall platelet mass is not decreased, clini-
cal signs should not occur in this situation.
Inherited thrombocytopenia has been reported in Cavalier Further reading
King Charles Spaniels. In this breed, the autosomal recessive Botsch V, et al. Retrospective study of 871 dogs with thrombocytope-
trait in β1-tubulin is asymptomatic, and is characterized by nia. Vet Rec 2009;164:647-651.
fewer, but larger, platelets (macrothrombocytopenia). No bleed- Christopherson PW, et al. Evaluation and clinical application of platelet
ing occurs because the cells, although decreased in number, function testing in small animal practice. Vet Clin North Am Small
have increased volume. Overall platelet mass is maintained. Anim Pract 2012;42:173-188.
Other breeds, including Norfolk Terriers, may have a similar Gelain ME, et al. A novel point mutation in the (1-tubulin gene in
defect. May-Hegglin anomaly is another disorder that may asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers.
result in macrothrombocytopenia. A single Pug dog was Vet Clin Pathol 2014;43:317-321.
reported to have neutrophil inclusions and large platelets Scott MA, Jutkowitz LA. Immune-mediated thrombocytopenia. In:
typical of those observed in people. The lesion is the result of Weiss DJ, Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th
a mutation in the MYH-9 gene encoding nonmuscle myosin ed. Ames: Wiley-Blackwell; 2010. p. 586-595.
heavy-chain IIA.
Acquired thrombocytopenia is one of the most commonly
recognized hematologic disorders. Thrombocytopenia associ- von Willebrand disease
ated with decreased platelet production in the bone marrow von Willebrand disease (vWD) occurs because of a deficiency or
may be the result of megakaryocyte hypoplasia for various functional variation in von Willebrand factor (vWF). Considered
reasons. However, thrombocytopenia can also occur because an extrinsic platelet disorder, bleeding in vWD is the result of
of decreased platelet survival in peripheral blood that can be failure of platelets to adhere and form aggregates at sites of
immune-mediated, infectious agent–mediated, or drug- vascular injury. Although rare in cats, horses, and cattle, vWD
mediated. If mean platelet volume (MPV) is increased in a is the most common inherited bleeding disorder in dogs. It occurs
thrombocytopenic animal, and is not associated with a breed- in many breeds, with highest prevalence in Doberman Pin-
associated defect, then active thrombopoiesis is suggested, and schers. In dogs, as in people, it is a heterogeneous group of
a bone marrow disorder is less likely. disorders that are classified into 3 types on the basis of severity
Immune-mediated thrombocytopenia (ITP) has been reported of bleeding, mode of inheritance, and specific abnormalities of
in many breeds of dogs and in both young and old animals, the vWF protein. The vWF protein is primarily synthesized in
but may be over-represented in middle-aged females. Primary endothelial cells as 2 subunits that subsequently undergo post-
idiopathic, or autoimmune thrombocytopenia, is caused by the translational assembly into dimers and multimers ranging up
development of autoantibodies without an apparent underly- to 100 vWF subunits that are stored in and subsequently
ing disease, and may be the result of a loss of immune system released from Weibel-Palade bodies in endothelial cells. The
tolerance for platelet antigens. Dogs develop severe thrombo- larger-molecular-weight multimers are most effective in pro-
cytopenia and variable anemia, because of hemorrhage. There moting platelet adhesion.
is currently no specific diagnostic test for ITP, and it continues The release of vWF following endothelial cell stimulation
to be one of exclusion of other causes. occurs with a variety of compounds, such as thrombin, hista-
Neonatal alloimmune thrombocytopenia has been reported mine, estrogen, thyroxine, and the vasopressin analogue
in pigs and horses. In pigs, the disorder usually occurs after 2 1-desamino-8-D-arginine vasopressin (DDAVP). Strenuous
or more pregnancies. Piglets are frequently born healthy but exercise also induces an increase in plasma vWF activity. In
develop thrombocytopenia by 1 week of age. Diagnosis of the some species, such as humans and cats, platelets act as an
disorder is one of exclusion, sepsis being the usual differential, additional pool of circulating vWF because they contain
because infections are the most common cause of thrombo- megakaryocyte-derived vWF in their α-granules. However,
cytopenia in this species. canine platelets contain only very small amounts of vWF.
258.e1
Further reading
Herring J, McMichael M. Diagnostic approach to small animal bleeding
disorders. Top Compan Anim Med 2012;27:73-80.
Pedersen HD, et al. Idiopathic asymptomatic thrombocytopenia in
Cavalier King Charles Spaniels is an autosomal recessive trait. J Vet
Intern Med 2002;16:169-173.
Disorders of Hemostasis 259
Plasma vWF circulates in a noncovalent complex with clotting cattle, subcutaneous hematomas and prolonged hemorrhage
factor VIII (FVIII), which stabilizes and prolongs the circulat- from puncture wounds, such as vaccination, ear tagging, and
ing half-life of FVIII. insect bites, are typically encountered.
Type 1 vWD, which is characterized by decreased activity Glanzmann thrombasthenia has been documented predom-
of vWF antigen and a proportional decrease in all multimeric inantly in the Otterhound and Great Pyrenees dog breeds,
forms, is transmitted in an incompletely dominant pattern. In with a few isolated cases reported in horses. The disorder is
contrast, the more clinically severe forms of vWD, types 2 and characterized by a decrease in the number of platelet αIIbβ3
3, are recessive traits. In type 3, plasma vWF is virtually absent, (GPIIb/IIIa) membrane receptors for fibrinogen. Therefore
whereas in type 2, high-molecular-weight multimers are dis- platelets from homozygous-deficient animals exhibit normal
proportionately decreased, and plasma vWF antigen activity shape-change response following stimulation with agonists
is reduced. In all forms of the disease, bleeding may be exac- such as ADP, collagen, thrombin, or PAF, but fail to form
erbated by concurrent thrombocytopenia or administration of stable aggregates. Clot retraction is also impaired or absent.
drugs, such as nonsteroidal anti-inflammatory drugs, which Because platelet morphology and concentration is normal, a
impair platelet function. definitive diagnosis requires the analysis of platelet mem-
Acquired vWD has been reported as a result of increased branes by flow cytometry, using antibodies specific for α- and
degradation of multimers by the enzyme ADAMTS13 (a dis- β-subunits of the receptor. All the mutations described thus
integin and metalloproteinase with thrombospondin repeats), far are in the gene encoding GPIIb.
primarily in high-shear conditions, such as those induced with The bleeding disorder component of Chediak-Higashi syn-
cardiac valve disease. In ponies, administration of hydroxyeth- drome (CHS) is the result of a dense-granule storage pool
ylene starch solutions as blood volume expanders can also deficiency. The disease has been identified in Hereford,
induce a transient decrease in circulating vWF levels. Tetra- Brangus, and Japanese Black cattle, in Aleutian mink, Persian
starch administration in dogs with systemic inflammation cats, blue and silver foxes, killer whales, and mice. Dense
induced a similar effect. granules are either absent or indistinct in platelets from
Prolonged BMBT accompanied by a normal platelet count, affected animals. The in vitro aggregation response to ADP is
and coagulation profile is suggestive of vWD. A prolonged reduced as a result of a decrease in the secretion of ATP, ADP,
closure time with the PFA analyzer is also a supportive, but and serotonin, which may or may not be accompanied by a
not specific, result. Diagnosis can only be confirmed by specific decrease in intracellular calcium mobilization.
assay of plasma vWF antigen activity by ELISA. A collagen- A defect in the P2Y12 receptor for ADP on the platelet
binding assay is also available at specialty laboratories to assist surface membrane has been recently described in a Greater
in confirmation of the functional defect that occurs in type 2 Swiss Mountain dog. There had been no prior bleeding epi-
vWD. Because vWF is antigenically distinct among mamma- sodes, but excessive hemorrhage was noted after ovariohyster-
lian species, plasma samples must be analyzed with appropri- ectomy, which prompted further investigation. The same
ate reagents. Molecular testing for vWF based on known defect was present in both related and unrelated dogs of the
mutations is available for some breeds of dogs. same breed.
Defective intracellular signaling transduction pathways have
been identified as the cause of platelet dysfunction in Basset
Further reading hounds, Landseer–European Continental Type (ECT), and
Eskimo Spitz dogs, as well as in both purebred and crossbred
Brooks MB, Catalfamo JL. von Willebrand disease. In: Weiss DJ,
Simmental cattle. These result from various mutations in the
Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
gene encoding calcium diacylglycerol guanine nucleotide
Ames, Iowa: Wiley-Blackwell; 2010. p. 612-618.
exchange factor I (CalDAG-GEFI). This factor is required for
Burgess HJ, et al. Evaluation of laboratory methods to improve char-
activation of Rap1b, which then produces a conformation
acterization of dogs with von Willebrand disease. Can J Vet Res
change in GPIIb-IIIa, which permits fibrinogen binding. All
2009;73:252-259.
have impaired aggregation responses to most agonists, except
Lozier JN, Nichols TC. Animal models of hemophilia and related bleed-
for thrombin. In Basset Hounds, heterozygote prevalence
ing disorders. Semin Hematol 2013;50:175-184.
approaches 25-30%. Only Landseer-ECT dogs are affected,
and the prevalence in this breed is ~10%. In the Spitz dog,
the mutation is distinct from that in Basset Hounds and Land-
Intrinsic disorders of platelet function seers, and much less prevalent. Affected Simmental cattle may
Inherited intrinsic platelet function disorders are relatively have mild to severe bleeding, and also have a distinct CalDAG-
rare in domestic animals, but have been identified in several GEFI mutation from the dog breeds.
breeds of dogs, horses, and in cattle. Four types of platelet A defect in platelet procoagulant activity has been identified
dysfunction are recognized: disorders of platelet membrane gly- in a colony of German Shepherd dogs. Similar to the disorder
coproteins, storage pool deficiencies, impairment of intracellular in people called Scott syndrome, platelet morphology is
signaling, and defective platelet procoagulant activity. All appear normal, and platelet function testing determined by BMBT,
to be inherited as autosomal traits. Because each results in clot retraction, PFA, thromboelastography, and aggregation is
platelet dysfunction, clinical signs are similar among the unaffected. The defect is in the exposure of phosphatidylser-
defects and cause mucosal bleeding and can be more diffuse ine on the platelet surface during activation. Because of this,
than the petechial hemorrhages observed with thrombocyto- the platelets cannot provide an appropriate phospholipid
penia alone. Gingival hemorrhage can occur during shedding context for the formation of the tenase and prothrombinase
of deciduous teeth in puppies. Epistaxis, cutaneous ecchymo- complexes, which reduces the rate of thrombin generation and
ses, hematuria, and prolonged or excessive bleeding at sites of fibrin formation. The syndrome therefore causes bleeding more
surgery or trauma are common in adult dogs. In horses and typically observed with thrombin and fibrin formation
259.e1
Further reading
Gauthier V, et al. Effect of synthetic colloid administration on coagula-
tion in healthy dogs and dogs with systemic inflammation. J Vet
Intern Med 2015;29:276-285.
260 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
impairment, such as epistaxis, hyphema, hematoma, and pro- Disorders causing hyper-reactivity of platelets include sys-
longed bleeding with cutaneous bruising after surgery. temic inflammatory disease, neoplasia, protein-losing nephrop-
athy, and diabetes mellitus.
Further reading
Boudreaux MK. Inherited intrinsic platelet disorders. In: Weiss DJ, Further reading
Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
Fry MM. Acquired platelet dysfunction. In: Weiss DJ, Wardrop KJ,
Ames, Iowa: Wiley-Blackwell; 2010. p. 619-625.
editors. Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa:
Gentry PA, et al. An inherited platelet function defect in a Simmental
Wiley-Blackwell; 2010. p. 626-631.
crossbred herd. Can J Vet Res 1997;61:128-133.
Walz PH, et al. Effect of experimentally induced type II bovine viral
diarrhea virus infection on platelet function in calves. Am J Vet Res
1999;60:1396-1401.
Acquired platelet disorders
Besides purposeful inhibition of platelet function with anti-
platelet drugs, acquired platelet dysfunction can occur secondary
to other underlying disorders. In many instances, transient Thrombin formation
defects in platelet responses likely occur, but are rarely docu- Initiation
mented. This is in part because of the relatively short half-life Exposure of blood to tissue factor (TF), which becomes
of a circulating platelet, so that new, fully functional platelets expressed on the membrane of activated endothelial cells or
are replenishing the circulating pool, and to the fact that monocytes at sites of vascular injury or during inflammation,
although one intracellular signaling pathway may be altered, respectively, initiates coagulation in vivo. This mechanism of
another may compensate. Furthermore, without other abnor- thrombin generation is termed the tissue factor or extrinsic
malities such as vWD or thrombocytopenia, partial or tran- pathway.
sient suppression of platelet reactivity may not be enough to In the resting state, TF is a transmembrane glycoprotein
induce clinical signs. that is sequestered or inactive in endothelial cells and mono-
Uremia resulting from renal failure has been identified as cytes (and possibly other leukocytes), perhaps because of lack
a risk factor for platelet dysfunction. Although abnormal of appropriate procoagulant phospholipids on the membrane
BMBT, platelet adhesion, and aggregation have been reported surface. Upon activation, the extracellular domain of TF is
in uremic dogs, the specific mechanisms involved have not yet expressed on the cell surface in a configuration that facilitates
been identified. binding of TF to inactive factor VII (FVII), or the active form
Certain infectious agents have been implicated as causing of the enzyme, FVIIa. Although FVII is the predominant form
platelet dysfunction. In calves infected with noncytopathic of the protein in blood, ~1% circulates as FVIIa. Binding of
type 2 bovine viral diarrhea virus, bleeding was thought to FVII and FVIIa with TF initiates coagulation by activating
occur because of combined thrombocytopenia and impaired additional TF-FVIIa molecules and by converting both factor
aggregation. Dogs infected with Ehrlichia canis or Ehrlichia IX (FIX) and factor X (FX) to their activated forms, FIXa and
platys develop thrombocytopenia and exhibit a reduction in FXa, respectively (see Fig. 2-241).
both platelet adhesiveness and aggregation. The mechanism is Factors IXa and Xa can either remain cell associated or
not entirely clear, but may be the result of antiplatelet they can diffuse into blood and bind to the surface of nearby
antibodies. activated platelets that have aggregated at the site of vascular
Other potential causes of platelet dysfunction include damage. If they diffuse further away from the developing clot,
receptor-binding interference from increased fibrinolytic products, an inhibitor inactivates them, to prevent widespread clot for-
such as occur with disseminated intravascular coagulation and mation. Prothrombin (factor II) is rapidly converted to throm-
liver disease; defective adhesion and aggregation associated bin by the prothrombinase complex that consists of FXa,
with leukemias; and coating of platelets with protein in condi- phospholipid, calcium, and cofactor factor V (FV). During
tions causing monoclonal gammopathy. platelet activation, negatively charged phospholipids, such as
Many drugs are known to inhibit platelet function, either phosphatidylserine, become exposed on the platelet surface.
as an intentional therapeutic benefit, or as an undesired side These phospholipids serve as binding sites for complex forma-
effect. Nonsteroidal anti-inflammatory drugs, such as aspirin tion of coagulation factors, protein cofactors, and calcium,
and meloxicam, that inhibit the endogenous platelet cyclo- which are essential for the rapid propagation of fibrin and
oxygenase enzymes, inhibit platelet aggregation in most thrombus formation.
species. There is species variation in this response, and bovine The small amount of thrombin generated by the prothrom-
platelets tend to be unresponsive to the inhibitory effects of binase complex initiates a positive feedback reaction that
aspirin. Drugs such as clopidogrel inhibit ADP-induced plate- accelerates the rate of prothrombin conversion and causes an
let activity by irreversibly binding to P2Y12 receptors. Penicil- increase in the amount of thrombin generated that subse-
lin antibiotics can bind to platelet membranes and inhibits quently increases the rate of fibrin formation (see Fig. 2-241).
glycoprotein receptor-mediated adhesion and aggregation. Thrombin also directly increases the activity of the prothrom-
There are many drugs that can impact platelet function, binase complex by activating FX to FXa and via proteolytic
including barbiturates, calcium-channel blockers, hydroxy- cleavage of FV to a more reactive form (FVa). Thrombin
ethyl starches, to name a few. further facilitates thrombus formation at a site of vascular
Although not given as much consideration, platelet hyper- damage by promoting localized platelet activation, adhesion,
reactivity can contribute to abnormal hemostasis through and secretory reactions that culminate in platelet aggregation
enhanced platelet function, and may result in thrombosis. (see Fig. 2-241).
260.e1
Further reading
Boudreaux MK. Characteristics, diagnosis, and treatment of inherited
platelet disorders in mammals. J Am Vet Med Assoc 2008;
233:1251-1259.
Boudreaux MK, Lipscomb DL. Clinical, biochemical, and molecular
aspects of Glanzmann’s thrombasthenia in humans and dogs. Vet
Pathol 2001;38:249-260.
260.e2
Further reading
Kavanagh C, et al. Coagulation in hepatobiliary disease. J Vet Emerg
Crit Care (San Antonio) 2011;21:589-604.
Mullins KB, et al. Effects of carprofen, meloxicam and deracoxib on
platelet function in dogs. Vet Anaesth Analg 2012;39:206-217.
Disorders of Hemostasis 261
Amplification of thrombin generation resulting in ability to cleave FXI to its proteolytically active
The small amount of thrombin formation in the initiation form, FXIa, and to convert PK to kallikrein. This reaction is
phase cannot maintain further thrombin production enough accelerated by HMWK. FXIIa can convert HMWK to a modi-
to ensure that sufficient fibrin is made to prevent hemorrhage. fied form, HMWKa, that exhibits high surface-binding affinity
This is because of the anticoagulant protein tissue factor and brings large amounts of both FXI and PK to the charged
pathway inhibitor (TFPI) that circulates in blood bound to surface in proximity to already adherent FXIIa. FXIa, in the
lipoproteins and platelets, and is present on endothelial cell presence of calcium, is a potent activator of circulating FIX
membranes with heparan sulfate. TFPI binds to FXa, and then and thus promotes downstream thrombin formation. Direct
forms the FXa-TFPI-FVIIa complex, that effectively inhibits activation of FXI by thrombin is another amplification loop,
TF pathway thrombin generation. However, the other path- which, in turn, results in the generation of additional FIXa
ways that result in activation of FX, and hence thrombin (see Fig. 2-242).
production, drive its further production instead (see Fig. The complete role of the contact activation pathway is not
2-241). fully understood because it does not appear to be important
Thrombin feedback not only activates FV, but it also acti- for most circumstances requiring in vivo thrombin generation.
vates factor IX, which converts FVIII to its active form, FVIIIa Some species, including cetacean and nonmammalian verte-
(see Fig. 2-241). Factor VIII usually circulates bound to von brates do not have detectable FXII activity; cats with severe
Willebrand factor (vWF), but after activation by thrombin, FXII deficiency do not exhibit a bleeding phenotype. However,
FVIIIa dissociates and forms a complex with FIXa, calcium, kallikrein not only functions as an activator of the fibrinolytic
and phospholipid exposed on the surface of thrombin- system, but it also stimulates both chemotaxis and degranula-
activated platelets. This is referred to as the tenase complex, tion of neutrophils attracted to sites of vascular injury (see Fig.
which cleaves FX at the same reactive site as TF-VIIa and 2-242). Hence the contact activation pathway links inflamma-
hence also produces FXa. This FXa generation results in for- tion, thrombin formation, and fibrinolysis.
mation of further prothrombinase complexes, providing a There is some evidence to suggest that this pathway may
rapid burst of thrombin formation. be involved in pathologic thrombus development, because FXII-
A tenase complex leading to thrombin formation can also deficient mice were protected from thrombus formation in an
be generated by the contact activation or intrinsic pathway. atherosclerosis model. This has also been observed in primates
The contact activation pathway includes factor XII (FXII) and where FXII activity was inhibited. Other studies have dem-
factor XI (FXI), prekallikrein (PK), and the protein cofactor onstrated that bacteria may directly engage the contact
high-molecular-weight kininogen (HMWK) (Fig. 2-242). This pathway via polyphosphate binding. These phosphates are
pathway is initiated when FXII interacts with a negatively similar to those contained within platelet-dense granules.
charged surface (such as damaged endothelium, activated Polyphosphates and histamine have both been demonstrated
neutrophils, polyphosphates) and becomes activated (XIIa), to directly active FXII (see Fig. 2-242).
Vessel wall
Endothelium
Vascular lumen
HMWK PolyP HMWK PolyP
FXIIa tPa FXIIa
FXII FXII
FXIa FXI
PK
Plasminogen Plasminogen
(fibrin bound) (soluble)
Plasmin
2-Antiplasmin
Fibrin Fibrin degradation
products/D-dimer
Thrombus dissolution
Figure 2-242 Interactions between the contact activation (intrinsic) pathway and the fibrinolytic
system. Solid lines represent activation reactions; dashed lines represent inhibitory reactions.
HMWK, high-molecular-weight kininogen; PAI-1, plasminogen activator inhibitor-1; PK, prekal-
likrein; PolyP, polyphosphates; TAFI, thrombin-activatable fibrinolysis inhibitor; tPA, tissue-type
plasminogen activator.
262 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
Vessel wall
Endothelium
Vascular lumen
TF FVIIa Thrombin Thrombomodulin
TFPI
Delay of
TM-T TAFI activation
fibrinolysis
FX FXa
APC Protein C
PS
AT
PS
FVIIIai FVIIIa FIXa
FVa FVai
FXa FX
Prothrombin Thrombin
Antithrombin/
heparans
Thrombin-antithrombin
Fibrinogen Fibrin
Figure 2-243 The major anticoagulant pathways. Solid lines represent activation reactions, and
dashed lines represent inhibitory reactions. APC, activated protein C; AT, antithrombin; FV, factor
V; FVai, inhibitory form of FV; FVIIIai, inhibitory form of FVIII; PS, protein S; TAFI, thrombin-
activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; TM-T, thrombomodulin-
thrombin complex.
262.e1
Further reading
Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb
Haemost 2001;85:958-965.
Disorders of Hemostasis 263
Further reading
Herring J, McMichael M. Diagnostic approach to small animal bleeding
disorders. Top Compan Anim Med 2012;27:73-80.
Lubas G, et al. Laboratory testing of coagulation disorders. In: Weiss
DJ, Wardrop KJ, editors. Schalm’s Veterinary Hematology. 6th ed.
Ames, Iowa: Wiley-Blackwell; 2010. p. 1082-1100.
264 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
observations that FXII activity is absent in nonmammalian none is the active coenzyme, and its oxidation into vitamin K
species such as birds, reptiles, and amphibians. 2,3 epoxide produces the carboxylation reaction. Vitamin K
Factor VII deficiency has only been documented in dogs and is a fat-soluble vitamin, and is widely available in green leafy
people. It has been reported in Beagles, Alaskan Malamutes, plants and vegetables oils and, like γ-glutamyl carboxylase, is
Boxers, Bulldogs, Miniature Schnauzers, and mixed-breed widely distributed throughout the body. Impaired carboxyl-
dogs, and is inherited as an autosomal trait. Adult dogs with ation of vitamin K–dependent coagulation proteins is occa-
the trait usually have plasma FVII activity of at least 5% of sionally the result of dietary deficiency or impaired
normal pooled plasma, which appears sufficient to initiate gastrointestinal absorption of vitamin K, but is more often
thrombin generation and induce fibrin formation unless there caused by ingestion of certain anticoagulant rodenticides.
are other concurrent abnormalities. For example, FVII defi- These vitamin K antagonists inhibit the recycling of vitamin
ciency was diagnosed in a mixed-breed dog that exhibited K 2,3 epoxide back to the hydroquinone form through inhibi-
abnormal bleeding following routine castration and failed to tion of vitamin K epoxide reductase. The gradual reduction in
respond to vitamin K therapy. FVII deficiency is generally mild vitamin K hydroquinone leads to a decrease in the active
and characterized by bruising. Prolonged vaginal bleeding after forms of vitamin K. Because the function of Gla residues in
whelping can occur in affected bitches. The diagnosis is sus- FVII, FIX, FX, and prothrombin is to facilitate binding to
pected based on signalment and history, with prolonged PT negatively charged phospholipids on the surface of activated
and normal APTT. Decreased FVII activity can be documented endothelium or platelets, the rate of thrombin formation is
with a specific factor assay. reduced. The nonfunctional forms of these proteins are col-
Severe factor X deficiency is inherited as an autosomal lectively referred to as PIVKAs (proteins induced by vitamin K
recessive trait, and tends to be lethal in affected dogs because antagonism). There is a plasma-based assay for detecting these
of its importance for thrombin generation. Dogs with <10% inactive forms.
of normal plasma FX activity are usually stillborn or die Rodenticide intoxication is the most common cause of vitamin
from bleeding as neonates. The defect has been reported in K antagonism in dogs, but it has also been reported in cats,
Jack Russell Terriers and in mixed-breed dogs. Because FX is horses, and pigs. The first generation rodenticides (such as
part of the common pathway, both the APTT and PT are warfarin) had relatively low toxicity and biological half-lives
prolonged. of <24 hours, which meant that vitamin K therapy often
Vitamin-K-dependent γ-glutamyl carboxylase deficiency has resulted in rapid and effective resolution of signs. The devel-
been identified in Devon Rex cats, Rambouillet sheep, and in opment of rodent resistance to these compounds led to the
a single Labrador Retriever dog. Lack of adequate activity of development of subsequent-generation agents, such as broma-
this enzyme results in synthesis of quantitatively normal, but diolone, brodifacoum, and diphacinone, which are more
nonfunctional, vitamin K–dependent coagulation proteins potent, have longer half-lives, and which therefore require
(FII, FVII, FIX, FX). In homozygous-deficient sheep, low more aggressive longer-term vitamin K therapy in affected
levels of activity of all 4 affected proteins are typically found, animals.
whereas heterozygous carrier animals may have normal factor Clinical signs are dependent on the quantity and type of
activities. Lamb mortality can be high, and is related to umbil- agent ingested, and can range from mild hemorrhage to severe
ical and subcutaneous tissue hemorrhages. In affected Devon spontaneous bleeding in the form of epistaxis, melena, and
Rex kittens, bleeding is severe or fatal and typically manifests hematuria. It may be several days after ingestion before clini-
as hematomas and hemarthroses, as well as hemothorax and cal signs occur and appear acute in onset. If bleeding is severe,
hemoabdomen. Administration of vitamin K1 results in rapid anemia, weakness, and pallor develop; dyspnea can be associ-
recovery of circulating vitamin K–dependent factor activity to ated with hypovolemia from hemothorax. Hemarthrosis has
near-normal levels. In the affected dog, circulating activity been reported to occur in some cases.
only increased to 50-60% of normal canine pooled plasma Cattle, pigs, and rabbits are susceptible to vitamin K antag-
even after 3 months of vitamin K1 therapy. onism if hay or silage containing moldy sweet clover is ingested.
Sweet clover contains coumarin, which is converted to dicu-
marol. Young calves are more susceptible to dicumarol than
Further reading are the dams, whereas sheep and horses appear resistant to
Barr JW, McMichael M. Inherited disorders of hemostasis in dogs and this form of vitamin K antagonism.
cats. Top Compan Anim Med 2012;27:53-58. Because FVII has the shortest circulating half-life (~4-6
Bender DE, et al. Molecular characterization of cat factor XII gene and hours), it is the first factor to have decreased biological activ-
identification of a mutation causing factor XII deficiency in a ity. Therefore, in the initial stages of vitamin K antagonism,
domestic shorthair cat colony. Vet Pathol 2014;52:312-320. the PT may be prolonged, whereas the APTT is within refer-
Giger U. Hereditary blood diseases. In: Feldman B, et al., editors. ence intervals. However, the APTT soon becomes prolonged
Schalm’s Veterinary Hematology. 5th ed. Philadelphia: Lippincott as well because FIX and FX have plasma half-lives of only
Williams & Wilkins; 2000. p. 955-959. 14-18 hours. Toxicologic evaluation of stomach contents can
Lozier JN, Nichols TC. Animal models of hemophilia and related bleed- determine the specific agent ingested, which can be useful
ing disorders. Semin Hematol 2013;50:175-184. information for deciding on the duration of therapy.
Liver disease. Although many coagulation proteins are
made in hepatocytes, hemorrhage related to liver disease is
Acquired disorders infrequent in domestic animals. This may be in part because
Vitamin K antagonism. The primary function of vitamin K severe loss of hepatic parenchyma (<30% remaining) must
in animals is as a cofactor for γ-glutamyl carboxylase, the enzyme have occurred before impairment of protein synthesis is suf-
required for post-translational carboxylation of glutamate ficiently affected to prolong the PT and APTT. Additionally,
(Gla) residues into γ-carboxyglutamate. Vitamin K hydroqui- synthesis of inhibitory proteins, such as antithrombin and
264.e1
Further reading
Baker DC, et al. Hereditary deficiency of vitamin-K-dependent coagula-
tion factors in Rambouillet sheep. Blood Coag Fibrinol 1999;10:
75-80.
Gentry PA, Ross ML. Coagulation factor XI deficiency in Holstein cattle:
expression and distribution of factor XI activity. Can J Vet Res
1995;58:242-247.
Macpherson R, et al. Factor VII deficiency in a mixed breed dog. Can
Vet J 1999;40:503-505.
Mason DJ, et al. Vitamin-K dependent coagulopathy in a Black Labra-
dor Retriever. J Vet Intern Med 2002;16:485-488.
Soute BAM, et al. Congenital deficiency of all vitamin K-dependent
blood coagulation factors due to a defective vitamin K dependent
carboxylase in Devon Rex cats. Thromb Haemost 1992;68:
521-525.
Disorders of Hemostasis 265
protein C, and fibrinolytic proteins, such as antiplasmin, will medicine. Thromboembolism (TE) does occur in animals,
also be reduced, potentially resulting in a rebalanced system. usually as a secondary consequence of cardiac disease, immune-
Also, in some inflammatory diseases, the liver can increase the mediated hemolytic anemia, neoplasia, hyperadrenocorticism,
rate of synthesis of specific clotting factors (acute phase protein-losing nephropathy and enteropathy, and sepsis.
response), including fibrinogen, FVIII, and vWF, which together Canine immune-mediated hemolytic anemia is a known risk
can promote the efficiency of clot formation. Despite this, it factor for development of pulmonary TE. Increased expres-
is commonly advised to screen for hemostatic competency sion of tissue factor, phospholipid-expressing microparticles,
with PT and PTT prior to liver biopsy, because complications and platelet hyperactivity have been proposed as underling
of underlying disease may easily disturb this rebalanced predisposing mechanisms. Immunosuppressive doses of gluco-
system. However, there is often no clear correlation between the corticoids used for treatment of this disease have also been
results of the screening tests and risk of bleeding postbiopsy. suggested to promote hypercoagulability, but the association
In a study of 45 cats with liver disease, 98% exhibited at and mechanism has not been definitively proven to date.
least one coagulation test abnormality. The more severe the Elevated fibrinogen concentration, and hypercoagulable
liver disease, the more likely the cat was to develop clinical TEG tracings have been observed in dogs with hyperadreno-
bleeding. Interestingly, one of the more frequent abnormalities corticism, but the overall risk of TE remains unclear. Decreased
noted was decreased FXIII activity, which was present with antithrombin has been proposed in the development of a
both inflammatory and neoplastic processes. Because of a con- hypercoagulable state in dogs with this disease, but this has
stellation of other findings, it was concluded that, overall, not been borne out in some studies.
coagulation abnormalities in this cohort of cats with liver
disease were the result of consumption rather than decreased
synthesis. Further reading
Coagulation was assessed with thromboelastography Kidd L, Mackman N. Prothrombotic mechanisms and anticoagulant
(TEG) in 10 dogs with extrahepatic bile duct obstruction. It therapy in dogs with immune-mediated hemolytic anemia. J Vet
was concluded that many of these dogs were actually in a Emerg Crit Care (San Antonio) 2013;23:3-13.
hypercoagulable state rather than being predisposed to hem- Mendez-Angulo JL, et al. Thromboelastography in healthy, sick non-
orrhage. Decreased production of inhibitor proteins may be septic and septic neonatal foals. Aust Vet J 2011;89:500-505.
to blame. These findings reinforce the idea that hemostatic altera- Park FM, et al. Hypercoagulability and ACTH-dependent hyperadreno-
tions in hepatobiliary disease are not necessarily predictable, and corticism in dogs. J Vet Intern Med 2013;27:1136-1142.
are likely multifactorial.
Cholestasis resulting in poor vitamin K absorption, and
therefore formation of inactive FII, FVII, FIX, and FX, may Regulation of coagulation:
occur in animals with chronic partial or complete biliary endogenous anticoagulants
obstruction. Vitamin K therapy given parenterally can restore To prevent widespread and over-exuberant clot formation
production of activatable proteins. when procoagulant mechanisms are invoked, inhibition of acti-
vated enzymes, such as FXa and thrombin, is essential because
they can diffuse away from a developing thrombus into the
Further reading general circulation. There are 3 important mechanisms that
DeClementi C, Sobczak BR. Common rodenticide toxicoses in small perform this function, including antithrombin/heparin, the
animals. Vet Clin North Am Small Anim Pract 2012;42:349-360. protein C pathway, and tissue factor pathway inhibitor (TFPI).
Dircks B, et al. Haemostatic abnormalities in cats with naturally occur- Antithrombin (AT) is the major inhibitor of both thrombin
ring liver diseases. Vet J 2012;193:103-108. and thrombin generation. It is a member of the serine protease
Mayhew PD, et al. Evaluation of coagulation in dogs with partial or inhibitor family of proteins that also includes α1-antitrypsin,
complete extrahepatic biliary tract obstruction by means of throm- α2-antiplasmin, and α2-macroglobulin. Plasma AT is an α2-
boelastography. J Am Vet Med Assoc 2013;242:778-785. globulin produced by hepatocytes and endothelial cells. It
predominantly inhibits thrombin, FIXa, and FXa, with addi-
tional weak inhibition of other activated factors, including the
Disorders of fibrin formation TF-FVIIa complex. The inhibitory action of AT arises from
Hereditary fibrinogen defects are rare, and have only been rec- the interaction of its reactive arginine residue with a serine
ognized in goats and dogs. Afibrinogenemia has been reported residue at the reactive site on thrombin, in a 1 : 1 ratio. The
in a herd of Saanen goats, in which it was associated with thrombin-AT (TAT) complex prevents thrombin’s ability to cleave
severe umbilical bleeding, hemarthroses, and subcutaneous fibrinogen to fibrin (see Fig. 2-243). The inhibitory effect of AT
and oral bleeding. Inherited hypofibrinogenemia has been is enhanced by heparan sulfate complexes on the surface of
diagnosed in Bernese Mountain, Lhasa Apso, Vizsla, and Collie activated endothelial cells. Intravenously administered heparin,
dogs. Similar to dysfibrinogenemia in an inbred Borzoi dog or heparin released from mast cells, can also increase the rate
family and in a Border Leicester lamb, these fibrinogen abnor- of formation of TAT complexes. Any TAT complexes are
malities cause only mild bleeding that can be exacerbated by removed from circulation via the mononuclear phagocyte
stress, trauma, or surgery. Decreased fibrinogen concentration system or by becoming bound to the endothelial cells, which
is more commonly because of decreased synthesis from severe results in endocytosis and lysosomal degradation.
liver disease, or increased consumption with disseminated The protein C pathway regulates coagulation by inactivating
intravascular coagulation. FVa and FVIIIa. Protein C is synthesized in the liver as a
Hyperfibrinogenemia as a positive acute-phase response is vitamin K–dependent zymogen. It is converted to an activated
common in many domestic animals; however, thromboem- form, APC, on the surface of endothelial cells by thrombin
bolic complications are infrequently reported in veterinary that has become bound to a membrane protein called
265.e1
Further reading
Kavanagh C, et al. Coagulation in hepatobiliary disease. J Vet Emerg
Crit Care (San Antonio) 2011;21:589-604.
Waddell LS, et al. Anticoagulant rodenticide screening in dogs: 123
cases (1996-2003). J Am Vet Med Assoc 2013;242:516-521.
265.e2
Further reading
Goodwin LV, et al. Hypercoagulability in dogs with protein-losing enter-
opathy. J Vet Intern Med 2011;25:273-277.
Rose L, et al. Effect of canine hyperadrenocorticism on coagulation
parameters. J Vet Intern Med 2013;27:207-211.
266 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
Further reading
Fry MM, et al. Protein C activity in dogs: adaptation of a commercial
human colorimetric assay and evaluation of effects of storage time
and temperature. Vet Med Int 2011;2011:751849.
Toulza O, et al. Evaluation of plasma protein C activity for detection of
hepatobiliary disease and portosystemic shunting in dogs. J Am Vet
Med Assoc 2006;229:1761-1771.
Disorders of Hemostasis 267
only to prevent blood loss but also to provide a scaffold for responses induced include leukocyte recruitment, release of
cells required during the subsequent healing process. Plasmin additional cytokines, and production of reactive oxygen
and uPA are important for the slow dissolution of fibrin that species. Systemic thrombin generation can result in widespread
occurs once underlying tissue repair has occurred. Also in cleavage of fibrinogen and deposition of fibrin strands in the
contrast to tPA, uPA has no specific affinity for fibrin and microvasculature of various end organs. The formation of fibrin
thus can activate circulating and fibrin-bound plasminogen strands can benefit the host by encapsulating bacteria; however,
indiscriminately. if large numbers of bacteria are protected from phagocytosis
Initially, any plasmin generated outside a fibrin clot is once they are sequestered, additional bacterial proliferation
quickly neutralized by α2-antiplasmin. However, if the forma- can occur with further damaging effects. Intravascular fibrin
tion of plasmin exceeds inhibitor availability, it will begin to strands can also have other deleterious effects, including alter-
degrade other plasma proteins, such as fibrinogen, FV, and ation of blood flow and erythrocyte fragmentation.
FVIII. Some bacteria produce plasminogen activators that can Platelets are also recognized as inflammatory cells, through
act exogenously, thereby inducing inappropriate plasmin for- release of certain granule contents, for instance, histamine and
mation. An example is streptokinase, which is produced by serotonin, or through the formation of cell membrane–derived
strains of streptococci that use plasmin to their advantage to neutrophil and monocyte agonists, for instance, PAF and leu-
increase invasiveness. In many mammals, streptokinase acts by kotrienes. After activation, mononuclear phagocytes can produce
forming a 1 : 1 complex with either plasminogen or plasmin. and release a wide range of inflammatory mediators, including
In this form, the general proteolytic action of streptokinase is interleukin-6, which can stimulate increased hepatocyte
decreased, but its plasminogen-activating activity is increased fibrinogen synthesis; PAF and prostaglandins, which can induce
several fold. further platelet activation; and tumor necrosis factor, which
Primary disorders of the fibrinolytic system have not been can initiate fibrinolysis through the release of plasminogen
characterized in domestic animals. However, alterations of activators. Thus, in the initial phase of inflammation, a balance
fibrinolysis associated with severe inflammation are frequently between procoagulant activity, fibrin formation, and the lysis of
recognized with disseminated intravascular coagulation. formed fibrin can be maintained. However, within several hours
Laboratory assessment of fibrinolysis in animals is limited to of the initiation of an inflammatory response, the fibrinolytic
a few assays, and include determination of fibrin(ogen) degra- system is suppressed as a result of the increased synthesis and
dation products (FDPs) and D-dimers. FDPs derive from both release of PAI-1. The fact that thrombosis is not a consistent
fibrinogen and fibrin strands; D-dimers form only when cross- clinical observation during inflammation can be explained by
linked fibrin is degraded. Fibrinolysis can also be assessed using the thrombin- and/or cytokine-induced activation of the anti-
global assays of hemostasis such as thromboelastography. coagulant protein C pathway (see Fig. 2-243). The suppres-
sion of both thrombin formation and plasmin generation helps
maintain hemostatic balance.
Further reading Neoplasia can also precipitate dysequilibrium of procoagulant,
Schaller J, Gerber SS. The plasmin-antiplasmin system: structural and anticoagulant, and fibrinolytic proteins, similar to that which
functional aspects. Cell Mol Life Sci 2011;68:785-801. occurs during systemic inflammation. The association between
Smith S. Overview of hemostasis. In: Weiss DJ, Wardrop KJ, editors. hemostatic abnormalities and neoplasia is less well understood
Schalm’s Veterinary Hematology. 6th ed. Ames, Iowa: Wiley- in domestic animals, although bleeding can be a clinical sign
Blackwell; 2010. p. 635-653. in animals with tumors such as hemangiosarcoma, multiple
Stokol T, et al. Evaluation of latex agglutination kits for detection of myeloma, and mast cell tumors. Hemostatic laboratory abnor-
fibrin(ogen) degradation products and D-dimer in healthy horses malities are frequently present in animals with neoplasia. For
and horses with severe colic. Vet Clin Pathol 2005;34:375-382. example, in a study of 71 dogs with various tumors, the major-
ity exhibited evidence of hypercoagulability on TEG, along
with prolonged APTT and increased fibrinogen. Dogs with
Systemic inflammation and neoplasia: metastatic disease tended to have increases in fibrinolysis indi-
dysregulation of hemostasis cators. Chemotherapeutic drugs and radiation can also impair
Inflammatory mediators, especially if disseminated widely, can the hemostatic process. For example, L-asparaginase, which
alter hemostatic equilibrium and cause either hemorrhagic or inhibits protein synthesis, and actinomycin D, which directly
thrombotic complications. The role of the contact activation or antagonizes vitamin K, can produce transient reductions in
intrinsic pathway as a link between hemostasis and inflamma- activity of multiple clotting factors. Tumor-induced inhibitory
tion has long been recognized. In addition to initiating throm- antibody production can also contribute to hemorrhage. These
bin formation through the FXI-tenase pathway (see Fig. inhibitors, or circulating anticoagulants, may either be immu-
2-242), activation of FXII results in conversion of PK to kal- noglobulins directed against functional epitopes of clotting
likrein, which converts high-molecular-weight kininogen to the factors or antiphospholipid antibodies that interfere with the
inflammatory mediator bradykinin. Recent reports suggest normal formation of the tenase and prothrombinase com-
that both factor XII and kallikrein can promote activation of plexes (see Fig. 2-241).
FIX and prothrombin via FXIa, in the presence of polyphos- Disseminated intravascular coagulation (DIC) is an
phates, such as those found in bacteria or in platelet acquired syndrome that occurs when excessive systemic acti-
granules. vation of procoagulant mechanisms result in widespread fibrin
An increase in TF expression on the cell membrane of formation, which may or may not eventually be accompanied
monocytes and endothelial cells occurs in response to both by inhibitor consumption and altered fibrinolysis (see also Vol.
gram-negative and gram-positive bacteria. This can result in 3, Cardiovascular system). Thrombosis and/or hemorrhage
activation of FVII, FX, and thrombin, setting off a series of may occur at multiple sites, which often cause end-organ
intracellular signaling cascades in leukocytes. Inflammatory dysfunction or complete failure. DIC is a potential
268 CHAPTER 2 • Hematopoietic System Disorders of Hemostasis
complication of any underlying disorder that results in an fibrin degradation products (FDPs) and D-dimers. A hypoco-
increase in expression of tissue factor, or activation of other agulable tracing would be apparent on thromboelastography
proteases that can activate clotting on a systemic basis. In with prolonged R time and decreased maximum amplitude
horses, DIC has been reported most commonly as a sequel to (MA).
intestinal disease and colic. In dogs, almost half of those with The fibrinolytic system is also activated in the initial phase of
immune-mediated hemolytic anemia exhibit evidence of a DIC, resulting in increased amounts of intravascular plasmin
hypercoagulable state at the time of clinical presentation. being generated. Excessive fibrinolysis may exacerbate bleed-
Animals with sepsis and systemic inflammatory response syn- ing in later stages. During plasmin proteolysis of fibrinogen
drome are at increased risk for DIC and frequently have many and fibrin, peptide fragments, known as FDPs and D-dimers,
abnormal hemostasis assay results. are released (see Fig. 2-243). Excessive generation of plasmin
In the initial stages of DIC, increased thrombin generation and production of FDPs both contribute to end-organ failure,
is compensated for by the anticoagulant systems, such as TFPI, which is often the ultimate cause of death in animals with
APC, and antithrombin (see Fig. 2-243). Laboratory results at advanced DIC. For example, plasmin can induce vascular and
this stage can vary, but a hypercoagulable tracing may be cellular damage through activation of matrix metalloprotein-
observed with thromboelastography. Further supportive labo- ases that degrade a wide range of cytoskeletal filaments. FDPs
ratory diagnosis at this stage would require evaluation of can enhance local inflammatory reactions by triggering the
markers such as thrombin-antithrombin (TAT) complexes release of interleukin-1 (IL-1) and IL-6 from monocytes and
(see Fig. 2-243) and peptide fragments such as prothrombin macrophages, and can also interfere with platelet function.
fragment 1 + 2, which are released during activation of pro-
coagulant factors. These latter tests are, however, not widely
available for animals. Further reading
If increased thrombin generation persists, DIC may progress Andreasen EB, et al. Haemostatic alterations in a group of canine
to an overt hypocoagulable phase. When inhibitor consumption cancer patients are associated with cancer type and disease pro-
outweighs production because of increased attempts to con- gression. Acta Vet Scand 2012;54:3.
strain further clotting, thrombin generation and fibrin forma- Cesarini C, et al. Association of admission plasma D-dimer concentra-
tion proceed in an unrestricted manner. This results in tion with diagnosis and outcome in horses with colic. J Vet Intern
thrombocytopenia and consumption of all procoagulant pro- Med 2010;24:1490-1497.
teins, hence the use of the term consumptive, or consumption, Piek CJ, et al. High intravascular tissue factor expression in dogs with
coagulopathy to characterize this stage of DIC. Ultimately, this idiopathic immune-mediated haemolytic anaemia. Vet Immunol
results in multisite spontaneous bleeding, and anemia can develop Immunopathol 2011;144:346-354.
because of blood loss. Laboratory abnormalities are more pre-
dictable at this stage, and include decreased platelet count,
prolonged PT and APTT, decreased fibrinogen concentration, For more information, please visit the companion site:
decreased antithrombin and protein C activity, and increased PathologyofDomesticAnimals.com.
268.e1
Further reading
Puy C, et al. Factor XII promotes blood coagulation independent of
factor XI in the presence of long-chain polyphosphates. J Thromb
Haemost 2013;11:1341-1352.
Ralph AG, Brainard BM. Update on disseminated intravascular coagula-
tion: when to consider it, when to expect it, when to treat it. Top
Compan Anim Med 2012;27:65-72.
CHAP TER 3
Endocrine Glands
Thomas J. Rosol • Andrea Gröne
269
270 CHAPTER 3 • Endocrine Glands General Considerations
Neoplasms of the adrenal cortex 343 Neoplasms of cells of the sympathetic nervous
Myelolipoma 343 system in adrenal medulla 352
Cortical adenoma 344 Neuroblastoma 352
Cortical carcinoma 345 Ganglioneuroma 353
Hyperadrenocorticism 346 Tumors metastatic to the adrenal medulla 353
Adrenal tumors in ferrets 347 PARAGANGLIOMAS (CHEMODECTOMAS) 354
ADRENAL MEDULLA 348 Development, structure, and function 354
Development, structure, and function 348 Aortic body adenoma and carcinoma 354
Embryonic development and structure 348 Carotid body adenoma and carcinoma 355
Biosynthesis of catecholamine hormones 348 Heart-base tumors derived from ectopic thyroid 356
Neoplasms of adrenal medullary secretory cells 349 Extra-adrenal paragangliomas 356
Pheochromocytoma and malignant pheochromocytoma 349 Orbital (extra-adrenal) paragangliomas 356
Mechanisms of adrenal medullary tumor development 351 MULTIPLE ENDOCRINE NEOPLASIA (MEN) 356
Adrenal medullary hyperplasia 352
Types of hormones
GENERAL CONSIDERATIONS
Polypeptide hormones
Endocrine glands are collections of specialized cells that syn- The primary site of action for polypeptide hormones is the plasma
thesize, store, and release their secretions directly into the membrane of target cells. Receptor proteins for the hormone
bloodstream. They are sensing and signaling organs capable of are present on the outer surface of the plasma membrane.
responding to changes in the internal and external environ- These hormones are water soluble and have a short half-life in
ment to coordinate a multiplicity of activities that maintain blood that is usually measured in minutes.
homeostasis. Polypeptide hormones activate target cells by binding to
Secretions of endocrine glands are peptide, steroid, catechol- receptors that belong to the superfamily of G protein–coupled
amine, or iodothyronine hormones that are transported by the receptors. Activation of these receptors is followed by a
blood to influence the functional activity of target cells elsewhere cascade of intracellular signaling steps. Heterotrimeric G pro-
in the body. Other populations of cells are concerned with teins consist of various α, β, and γ subunits that are involved
hormone degradation after it has exerted its physiologic func- in conferring specificity to the signaling system (Fig. 3-1). For
tion. This is accomplished by peptidases on the cell surface, example, Gαs activates adenylyl cyclase isoforms, and Gαq
uptake by cells and degradation by lysosomal enzymes, or activates phospholipase C, thereby stimulating different intra-
conjugation with glucuronide or sulfate and excretion in the cellular signaling pathways. Downstream responses include
bile or urine. activation of nuclear factor κB (NFκB), mitogen-activated
Endocrine glands are small compared with other organs, protein (MAP) kinases, the Wnt/β-catenin pathways, or others.
widely distributed in the body, and connected with one The specificity of hormone signaling depends on the presence of
another by the bloodstream. They are richly supplied with the receptor on target cells and ligand preference of the receptor.
blood, and there is a close anatomic relationship between For example, the melanocortin receptor family exists in 5
endocrine cells and the capillary network. To facilitate rapid isoforms that are expressed on melanocytes as well as
N GPCR Adenylyl
Phospholipase C (↑) cyclase (↑) extracellular
DAG
C ATP intracellular
PKC q s
(active) GTP GTP
Ca2 GDP cAMP
IP3
G proteins PKA PKA
(active)
Ca2
lymphocytes, the brain, and adrenal cortex. It has a variety of ibly bind to high-affinity, specific binding proteins for trans-
ligands; however, binding to the melanocortin receptor (MR2) port in plasma.
in the adrenal cortex is restricted to adrenocorticotropic
hormone (ACTH). In addition, the level of receptor expres- Catecholamine and iodothyronine hormones
sion and receptor conformation, which can be influenced by These hormones are tyrosine derivatives. They account for
ligands or the presence of accessory or scaffolding proteins, approximately 5% of mammalian hormones and include the
ensure that hormones exert their specific effects after receptor catecholamines (epinephrine, norepinephrine) secreted by the
binding. adrenal medulla, and iodothyronines (thyroxine [T4] and triio-
Endocrine cells that produce polypeptide hormones have dothyronine [T3]) produced by follicular cells of the thyroid
a well-developed endoplasmic reticulum with many attached gland. Catecholamines share similar mechanisms of action
ribosomes, where the hormone is assembled, and a prominent with polypeptide hormones, whereas iodothyronines more
Golgi apparatus for packaging hormone into granules for closely resemble the steroid hormones.
intracellular storage and transport. Secretory granules are
unique to polypeptide hormone- and catecholamine-secreting
endocrine cells and provide a mechanism for intracellular Proliferative lesions in endocrine glands
storage of substantial amounts of preformed active hormone. Characteristics
The membrane-limited granules are macromolecular aggrega- Endocrinologically active (functional) neoplasms derived
tions of active hormone, often associated with a specific from polypeptide hormone–secreting endocrine cells consist
binding protein and other biologically active factors. When the of one predominant cell type and usually are associated clini-
cell receives a signal for hormone secretion, secretory granules cally with the autonomous secretion of one polypeptide
are directed by microtubules to the periphery of the endocrine hormone. However, there is evidence from immunohisto-
cell. The limiting membrane of the granule then fuses with chemical and electron microscopic investigations that some
the plasma membrane of the cell. The hormone-containing endocrine tumors are composed of more than one type of
granule core is extruded into the extracellular perivascular neoplastic cell and are capable of synthesizing multiple
space by emiocytosis (secretion of entire secretory granules into hormones.
the extracellular space) or exocytosis (fusion with the cell The histologic separation of nodular hyperplasia, adenoma,
membrane and release of granule contents into the extracel- and carcinoma often is more difficult in endocrine glands than in
lular fluid). The granule core is subsequently fragmented, and most other organs of the body. For many endocrine glands (espe-
hormone is rapidly transported through capillary fenestrae cially thyroid C cells, secretory cells of the adrenal medulla,
into the circulation. Hormone synthesized in excess of require- and specific trophic hormone–secreting cells of the adenohy-
ment is degraded by fusion of the hormone-containing gran- pophysis), there is a continuous spectrum of proliferative
ules with lysosomes, a process termed crinophagy. lesions between focal hyperplasia and adenomas derived from
a specific population of cells.
Steroid hormones It is a common feature of endocrine glands that prolonged
Steroid hormone–secreting endocrine cells are characterized by stimulation of a population of secretory cells predisposes to the
large lipid vacuoles in the cytoplasm that contain cholesterol subsequent development of a higher than expected incidence of
esters and other precursor molecules. The lipid vacuoles are in tumors. Long-term stimulation leads to the development of
close proximity to an extensive tubular network of smooth clones of cells within the hyperplastic endocrine gland that
endoplasmic reticulum and large mitochondria that contain grow more rapidly and are more susceptible to neoplastic
the hydroxylase and dehydrogenase cytochrome P450 enzyme transformation when exposed to promoting carcinogens.
systems. These enzymes function to attach or modify various Nodular hyperplasia usually appears as multiple small foci,
side chains to the basic steroid molecule. Steroid-producing in one or both (for paired) endocrine gland(s), that are well
cells lack secretory granules and do not store significant demarcated but not encapsulated from adjacent normal cells.
amounts of preformed hormone. They are dependent on con- Cells comprising an area of nodular hyperplasia closely resem-
tinued biosynthesis to maintain the normal secretory rate for ble the cell of origin; however, the cytoplasmic area may be
a particular hormone. slightly enlarged and the nucleus more hyperchromatic than
Steroid hormones originating from cholesterol precursor in the normal endocrine cell.
molecules account for ~15% of mammalian hormones. They Adenomas are solitary nodules, in one (or occasionally
are lipid soluble, which facilitates their transport through the both for paired) endocrine gland(s), that are larger than the
cell membrane. In the cytoplasm, steroid hormones bind to multiple foci of nodular hyperplasia. They are sharply demar-
receptors that form homodimers or heterodimers, migrate to cated from the adjacent normal glandular parenchyma, often
the nucleus, and function as nuclear receptors and transcrip- by a thin, partial to complete, fibrous capsule. The adjacent
tion factors. The steroid hormone receptors have binding parenchyma is compressed to various degrees, depending
sites for the steroid hormone, specific regions of the genomic upon the size of the adenoma. Cells comprising an adenoma
DNA, and accessory regulatory proteins. After binding to the closely resemble the cell of origin morphologically and in their
genomic DNA and accessory proteins, the receptor complexes architectural pattern of arrangement; however, there often are
either upregulate or downregulate gene transcription of multiple histologic differences, such as multiple layers of cells lining
genes and direct protein synthesis by the target cells. Recent follicles or vascular trabeculae and solid clusters of secretory
evidence suggests that nongenomic steroid hormone signaling cells subdivided into packets by a fine fibrovascular stroma.
exists under specific circumstances. The nongenomic cellular Carcinomas usually are larger than adenomas and produce
responses to steroid hormones are very fast and may involve enlargement in one (or occasionally both, for paired) endo-
cell membrane–binding proteins. Steroid hormones have a crine gland(s). The separation between adenoma and carci-
long half-life in blood (typically measured in hours) and revers- noma of an endocrine gland often is more difficult than in
272 CHAPTER 3 • Endocrine Glands General Considerations
other tissues. Histopathologic features that are indicative of leading to hypercalcemia, which results in soft tissue miner-
malignancy in an endocrine tumor include intraglandular inva- alization and the development of renal calculi. The acceler-
sion, invasion into and through the capsule of the gland with ated osteoclastic resorption of bone results in marked thinning
growth in the periglandular fibrous and adipose connective and osteoclastic tunneling of cortical bone, and predisposes
tissues, formation of tumor cell thrombi within vessels (espe- bone to the development of pathologic fractures in chronic
cially muscular walled), and particularly the establishment of cases.
metastases at distant sites. The growth of neoplastic cells in a The autonomous hypersecretion of thyroxine and triiodothy-
subendothelial location in highly vascular benign endocrine ronine is a common endocrinopathy in older cats. This hyper-
tumors should not be mistaken for vascular invasion, and secretion is associated with a spectrum of proliferative lesions
clusters of neoplastic cells may be artifactually forced into the of thyroid follicular cells. The majority of the functional
lumen of thin-walled vessels and be misinterpreted as tumor thyroid lesions are multifocal hyperplasia or adenomas derived
cell emboli. Malignant endocrine cells often are more pleo- from follicular cells, which can be controlled surgically, chemi-
morphic (including oval or spindle shaped) than normal, but cally, or with radioactive iodide. Thyroid follicular adenocar-
nuclear pleomorphism is not a consistent criterion to distin- cinomas that metastasize to regional lymph nodes are rare in
guish adenomas and carcinomas. Mitotic figures may be fre- cats. The functional disturbances of hyperactivity, weight loss
quent in malignant endocrine cells, but the significance of this despite increased appetite, hyperthermia, and tachycardia
criterion can vary considerably with the degree of background reflect long-term stimulation of multiple populations of target
stimulation of the endocrine gland. cells by the abnormally elevated blood levels of thyroid
hormones.
Functional aspects of endocrine tumors
Many neoplasms derived from endocrine glands are endocri- Secondary hyperfunction of an endocrine gland
nologically active (functional), secrete an excessive amount of In secondary hyperfunction of an endocrine gland, a lesion in
hormone either continuously or episodically, and result in one organ (e.g., adenohypophysis) secretes an excess of a
clinical syndromes of hormone excess. Many examples occur trophic hormone that leads to long-term stimulation and
in different animal species, including hyperadrenocorticism hypersecretion of hormone by a target organ. An example of
associated with either ACTH-secreting pituitary corticotroph this pathogenic mechanism in animals is the ACTH-secreting
adenomas or adrenocortical neoplasms in dogs, hypoglycemia tumor derived from pituitary corticotrophs in the pars distalis or
with β-cell neoplasms of the pancreatic islets in dogs and intermedia of dogs. The clinical signs and lesions in the animal
ferrets, hyperthyroidism associated with adenomas, and carci- primarily are the result of the elevated blood cortisol levels
nomas derived from thyroid follicular cells in cats, among associated with the ACTH-stimulated hypertrophy and
many others. hyperplasia of the zonae fasciculata and reticularis of the
Measurement of hormone levels in serum or plasma in the adrenal cortex (see Fig. 3-101D). The syndrome of cortisol
basal, suppressed, or stimulated state and, in some instances, excess in dogs is characterized by progressive alopecia, hyper-
hormonal metabolites in the urine over a 24-hour period of excre- pigmentation, and muscle wasting caused by the protein cata-
tion is essential to confirm that an endocrine tumor is releasing bolic effects of glucocorticoids (see Fig. 3-104). Some dogs
hormone at an abnormally elevated rate. An endocrine tumor have a similar marked adrenocortical enlargement and clinical
also can be interpreted as being endocrinologically active if evidence of cortisol excess, but without a tumor in the pitu-
either the rim of normal tissue around the tumor or the oppo- itary gland. These dogs may have a change in their set point
site of paired endocrine glands undergoes atrophy because of to the negative feedback signal (e.g., blood cortisol). This can
negative feedback inhibition by the elevated hormone levels be caused by an abnormal accumulation of certain neurotrans-
or an altered blood constituent. In response to the autono- mitter substances (e.g., serotonin) near neurosecretory neurons
mous secretion of hormone by the tumor, these non-neoplastic in the hypothalamus that secrete corticotrophic hormone–
secretory cells become smaller than normal, especially in the releasing factor. The end result is corticotroph hyperplasia,
cytoplasmic area, and eventually the number of cells is elevated ACTH levels in the blood, and long-term stimulation
decreased. Functional pituitary neoplasms secreting an excess of the adrenal cortex, which results in hyperplasia of the zona
of a specific trophic hormone (e.g., ACTH) will be associated fasciculata and zona reticularis and the clinical syndrome of
with hypertrophy and hyperplasia of target cells in the adrenal cortisol excess.
cortex (zonae fasciculata and reticularis).
Primary hypofunction of an endocrine gland
In primary hypofunction of an endocrine gland, hormone
Mechanisms of endocrine disease secretion is subnormal because of extensive destruction of
Primary hyperfunction of an endocrine gland secretory cells by a disease process, the failure of an endocrine
In primary hyperfunction of an endocrine gland, cells (often gland to develop properly, or the result of a specific biochemi-
neoplastic and derived from the gland) synthesize and secrete cal defect in the synthetic pathway of a hormone.
hormone at an autonomous rate in excess of the body’s ability • Immune-mediated injury causes hypofunction of several
to use and subsequently degrade the hormone, thereby result- endocrine glands in animals, including the parathyroid
ing in functional disturbances of hormone excess. These include gland, adrenal cortex, and thyroid gland. Thyroiditis caused
hyperfunction of parathyroid chief cells, thyroid C (parafol- by this mechanism is characterized by marked infiltration
licular) cells, β cells of the pancreatic islets, secretory cells of of lymphocytes and plasma cells with progressive destruc-
the adrenal medulla, and follicular cells of the thyroid, among tion of secretory parenchyma.
others. • Failure of development also results in primary hypofunction
The autonomous secretion of parathyroid hormone results in of an endocrine gland. An example of this mechanism in
progressive and generalized demineralization of the skeleton, animals is the failure of oropharyngeal ectoderm to
General Considerations 273
differentiate into trophic hormone–secreting cells of the yellow-brown rim composed of a moderately thickened
adenohypophysis in dogs, resulting in pituitary dwarfism capsule and secretory cells of the outer (aldosterone-
and a failure to attain somatic maturation (see Fig. 3-8A, producing) layer, the zona glomerulosa, which is under limited
B). A large, multicompartmented cyst is present on the ACTH control (see Fig. 3-19). The zonae fasciculata and
ventral aspect of the brain in the pituitary region of reticularis are severely atrophied compared with those in
these dogs. The cyst compresses the normally developed normal adrenal glands, secrete subnormal amounts of gluco-
neurohypophysis and results in disturbances of water corticoid hormones, and have a blunted increase in cortisol or
metabolism. corticosterone following the administration of exogenous
• Another form of primary hypofunction is failure of hormone ACTH. By comparison, thyroid glands in animals with large
synthesis caused by a genetic defect in a biosynthetic pathway pituitary adenomas disrupting normal trophic hormone (e.g.,
or lack of a specific enzyme. A well-documented example of TSH) production are either near-normal size or only slightly
this condition is vitamin D–dependent rickets in pigs, reduced in size to a much lesser degree than is the adrenal
which is caused by lack of 25-hydroxycholecalciferol- cortex. The majority of thyroid follicles are large, lined by
1-α-hydroxylase in the proximal convoluted tubules of flattened (atrophic) cuboidal follicular cells, and distended
the kidney. This enzyme is needed to synthesize the with densely stained colloid because of a lack of TSH.
hormonal form of active vitamin D (calcitriol). Blood Calcitonin-secreting thyroid C cells function normally because
calcium and phosphate levels progressively decrease they are not controlled by pituitary trophic hormones. Semi-
because of the subnormal ability of the pig to convert niferous tubules in the testis are small with little evidence of
25-hydroxycholecalciferol to the biologically active hor- active spermatogenesis, and the ovarian cortex is devoid of
monal form (1,25-dihydroxycholecalciferol; calcitriol) in functional ovarian follicles.
the kidney. The lowered blood concentrations of calcium Secondary hypofunction of an endocrine gland also occurs
and phosphate lead to a failure of mineralization of osteoid when insufficient iodide ion is available for thyroid follicular
and persistence of cartilage in the physes, resulting in cells to synthesize adequate amounts of thyroid hormones to
severe deformities in the skeleton (see Vol. 1, Bones and meet the animal’s daily requirements. The thyroid gland
joints). attempts to compensate by increasing the efficiency of iodide
• Congenital dyshormonogenic goiter in sheep, goats, and trapping and by preferentially synthesizing more T3 than T4,
cattle is an example of primary hypofunction caused by thereby saving a molecule of iodide for every molecule of
failure of hormone synthesis. The low blood thyroxine (T4) thyroid hormone produced. Dietary iodine deficiency resulting
and triiodothyronine (T3) levels and clinical evidence of in diffuse hyperplastic goiter (see Fig. 3-67) was common in
severe hypothyroidism in these animals are the result of an many areas of the world before the widespread addition of
inability of follicular cells to synthesize thyroglobulin. The iodized salt to animal diets and still occurs worldwide in
molecular defect is faulty processing of the primary tran- domestic animals and humans living in iodine-deficient areas.
scripts for thyroglobulin messenger ribonucleic acid Marginally iodine-deficient diets that contain goitrogenic
(mRNA) and aberrant transport of mRNA from the compounds may cause severe thyroid follicular cell hyperpla-
nucleus to ribosomes. This results in subnormal amounts sia and goiter. Goitrogenic substances include thiouracil, sul-
of thyroglobulin mRNA in follicular cells, particularly fonamides, and a number of plants of the family Brassicaceae.
mRNA that is attached to membranes of the endoplasmic Offspring of females fed iodine-deficient diets are likely to
reticulum in the cytoplasm. These animals do not have a develop severe thyroidal follicular cell hyperplasia and have
defect in the ability of the thyroid to concentrate 131I; clinical signs of hypothyroidism. The affected lobes are firm
however, there is a greatly reduced ability to iodinate and dark red because an extensive interfollicular capillary
tyrosyl residues and form thyroid hormones. In the hypo- network develops under the influence of long-term TSH stim-
thalamus and adenohypophysis, subnormal blood levels of ulation. Follicles are irregular in size and shape in hyperplastic
thyroxine and triiodothyronine, result in an increased goiter because they contain various amounts of lightly eosino-
secretion of thyroid-stimulating hormone (TSH) and sub- philic and vacuolated colloid. Some follicles collapse because
sequently activation of the thyroid follicular cells, causing of the lack of colloid. Their lining epithelial cells are columnar
intense hyperplasia (see Fig. 3-69). and have deeply eosinophilic cytoplasm and small hyperchro-
matic nuclei. The follicles are lined by single or multiple layers
Secondary hypofunction of an endocrine gland of hyperplastic follicular cells that form papillary projections
In secondary hypofunction of an endocrine gland, a destructive into the lumens of some follicles.
lesion in one organ, such as the pituitary, interferes with the secre-
tion of trophic hormone. This results in hypofunction of the Endocrine hyperactivity secondary to diseases of
target endocrine glands. Large, endocrinologically inactive, other organs
pituitary neoplasms in adult dogs, cats, and other animal A common example of endocrine hyperactivity secondary to
species may interfere with the secretion of the multiple pitu- diseases of other organs in animals is the hyperparathyroidism
itary trophic hormones and result in clinically detectable that develops secondary to chronic renal failure or nutritional
hypofunction of the adrenal cortex, follicular cells of the imbalances. In the renal form, there is retention of blood
thyroid, and gonads. phosphate and inadequate production of the active form of
Target endocrine organs respond dramatically to a lack of vitamin D (1,25-dihydroxycholecalciferol; calcitriol) by the
normal production of pituitary trophic hormones. The adrenal renal tubules. This results in reduced negative feedback of the
glands of animals with large nonfunctional pituitary adenomas parathyroid gland chief cells because of the lack of calcitriol
are small and may be difficult to find at autopsy. The adrenals and persistent activation of the parathyroid hormone gene and
consist primarily of medullary tissue surrounded by a narrow stimulation of chief cell proliferation. Some animals with
zone of atrophic cortex. The adrenal cortex appears as a thin chronic renal disease may also have hypocalcemia, but this is
274 CHAPTER 3 • Endocrine Glands General Considerations
not a consistent finding. All parathyroid glands are affected. factors, and 1,25-dihydroxyvitamin D3 (calcitriol) may have
They are enlarged initially because of organellar hypertrophy synergistic or cooperative actions with PTHrP.
and later chief cell hyperplasia. Although skeletal involvement
is generalized with hyperparathyroidism, it does not affect all Endocrine dysfunction resulting from failure of
parts uniformly. Bone lesions include resorption of bone from target cell response
alveolar sockets and loss of lamina dura dentes that occur early Endocrine dysfunction resulting from a failure of target cell
in the course of the disease. This results in loose teeth that response has been recognized coincident with a more com-
may be dislodged easily and interfere with mastication. plete understanding of how hormones convey their biological
Because of the accelerated rate of resorption, cancellous bones message. Insulin resistance associated with obesity in both
of the maxilla and mandible become weakened, are readily animals and humans can result from nonresponsive receptors
pliable (“rubber jaw”), and the jaws fail to close properly. on the surface of target cells. The absence of vitamin D recep-
Nutritional hyperparathyroidism develops in animals fed tors results in vitamin D–dependent rickets, type II, also called
abnormal diets that are low in calcium, high in phosphate or vitamin D–resistant rickets (VDRR). New World primates
oxalate, or deficient in vitamin D for certain nonhuman pri- have a relative end-organ resistance to calcitriol and require
mates. Unsupplemented all-meat diets fed to carnivores fail high levels of vitamin D3 in their diet. The common marmoset
to supply the daily requirements for calcium, leading to pro- has been shown to represent a model of vitamin D–dependent
gressive hypocalcemia that stimulates the parathyroid gland rickets, type II. Marmosets have increased serum calcitriol
to increased activity. After a carnivore is fed an imbalanced concentrations compared to rhesus monkeys, and some mar-
diet for several weeks to months, its skeleton becomes severely mosets developed osteomalacia even when on high vitamin
demineralized and predisposed to fractures. The cortices D3 diets.
of long bones are thin and the medullary cavity widened
because of intense osteoclastic resorption of bone that is stim- Failure of fetal endocrine function
ulated indirectly by the increased secretion of parathyroid Subnormal function of the fetal endocrine system, especially in
hormone. ruminants, may disrupt normal fetal development and result in
prolongation of the gestation period. In Guernsey and Jersey
Hypersecretion of hormones by cattle, a genetic failure of development (aplasia) of the adeno-
non-endocrine tumors hypophysis results in a lack of fetal pituitary trophic hormone
Certain neoplasms of non-endocrine tissues in both animals secretion during the last trimester and hypoplastic develop-
and humans either secrete hormones or molecules that share ment of target endocrine organs (e.g., adrenal cortex, thyroid
chemical and/or biological characteristics with the “native” follicular cells, gonads). Fetal development is normal up to
hormones secreted by an endocrine gland. Most of the humoral approximately 7 months of gestation, but subsequently fetal
substances secreted by non-endocrine tumors are peptides growth ceases regardless of how long the viable fetus is
rather than steroids, iodothyronines, or catecholamines, which retained in utero.
require more complex biosynthetic pathways. For example, Prolongation of gestation also occurs in ewes that ingest
humoral hypercalcemia of malignancy (HHM) is a clinical the plant Veratrum californicum early in gestation. Toxins in
syndrome produced primarily by the autonomous secretion of the plant cause extensive malformations of the central nervous
parathyroid hormone–related protein (PTHrP) by cancer system (CNS) and hypothalamus in lambs. Although the
cells. PTHrP binds and activates the parathyroid hormone adenohypophysis is present, it is unable to secrete normal
(PTH) receptor in target cells (e.g., bone and kidney) with amounts of trophic hormones (e.g., ACTH) because it lacks
equal potency to PTH and results in persistent, often life- the necessary fine control derived from the releasing hor-
threatening, hypercalcemia. mones of the hypothalamus. Target endocrine organs in the
Humoral hypercalcemia of malignancy is associated with fetus are hypoplastic and the adrenal cortex does not differ-
diverse malignant neoplasms in animal and human patients. entiate completely into the 3 distinctive zones that secrete
HHM occurs commonly in dogs with T-cell lymphoma and corticosteroid hormones. The plant contains potent steroidal
adenocarcinomas derived from apocrine glands of the anal sac. alkaloids that inhibit neural tube development when ingested
Characteristic findings in patients with HHM include hyper- by the ewe between days 9 and 14 of gestation. Cyclopia and
calcemia, hypophosphatemia, hypercalciuria (often with extensive CNS malformations are found in lambs. Arhinen-
decreased fractional calcium excretion), increased fractional cephaly and lack of development of nasal bones accompany
excretion of phosphate, and increased osteoclastic bone the formation of a proboscis-like structure. The lambs retained
resorption. The direct effects of PTHrP on bone and kidney, and in the uterus continue to grow beyond the normal gestation
indirect effects on the intestine produce hypercalcemia. Increased period.
osteoclastic bone resorption is a consistent finding in HHM The concepts that have emerged from the study of these
with increased calcium release from bone. The kidney plays a naturally occurring diseases are (1) fetal hormones are neces-
critical role in the pathogenesis of hypercalcemia and hypo- sary for final growth and development in utero in certain
phosphatemia, because renal calcium reabsorption is stimu- animals and (2) normal parturition at term requires an intact
lated by PTHrP and phosphate reabsorption is inhibited as fetal hypothalamic-adenohypophyseal-adrenocortical axis in
a result of binding to and activation of the renal PTH recep- these species working in concert with trophoblasts of the
tors. In some forms of HHM, there is increased serum 1,25- placenta. Although the presence or absence of functional
dihydroxyvitamin D3 that may increase calcium absorption adenohypophyseal tissue determines whether the fetus con-
from the intestine. Although excessive secretion of biologi- tinues to grow in utero, the pathogenesis of prolongation of
cally active PTHrP plays a central role in the pathogenesis of the gestational interval is similar in these 2 examples. The
hypercalcemia in most forms of HHM, cytokines such as subnormal development of the fetal adrenal cortex results in
interleukin-1, tumor necrosis factor-α, transforming growth inadequate secretion of cortisol and failure to induce the
General Considerations 275
Pituitary
C
TSH
(↓) T4-/T3
M Thyroid T4-/T3 Thyroid
hyperplasia/neoplasia
T4
Xenobiotic (↑) UDP-Glucuronyl transferase
chemical
Bile
T4-Glucuronide
T4-Glucuronide
Figure 3-2 Failure of fetal endocrine function. Adrenal cortical
Feces
hypoplasia in a calf with prolonged gestation. The adrenal cortex
(C) is markedly reduced in thickness, and the adrenal medulla Figure 3-3 Hepatic microsomal enzyme induction by the chronic
(M) is relatively more prominent. Bar = 1 cm. Note that the administration of xenobiotics (goitrogens) in rodents, leading to
adrenal cortex is darker than the medulla in cattle. thyroid follicular cell hyperplasia, and to neoplasia with use of
large doses of compound. T3, triiodothyronine; T4, thyroxine;
TSH, thyroid-stimulating hormone.
17-α-hydroxylase in the placenta that converts precursor mol-
ecules (e.g., progesterone) to estrogen. The fetal adrenal gland
is small, and there is incomplete development of the distinct mechanism, but blood hormone levels are persistently ele-
zones of the cortex (Fig. 3-2). The dam’s circulating proges- vated, thereby simulating a syndrome of hypersecretion,
terone is maintained near mid-gestational concentrations, and resulting from a decreased rate of hormone degradation.
there is a lack of the marked increase in estrogens that nor- The classic example of this pathogenic mechanism is the
mally occurs near term and results in parturition by stimulat- syndrome of feminization resulting from hyperestrogenism
ing the local synthesis of prostaglandins in the uterus. associated with cirrhosis and decreased hepatic degradation of
estrogens.
Endocrine dysfunction resulting from abnormal
degradation of hormone Syndromes of iatrogenic hormone excess
Increased degradation of hormone. The long-term adminis- Direct effects. The administration of hormone, either directly
tration of various xenobiotics (e.g., phenobarbital and others) or indirectly, influences the activity of target cells with this
results in the induction of liver enzymes (e.g., T4–uridine mechanism and results in important functional disturbances.
diphosphate [UDP]-glucuronyl transferase) that increases the It is well recognized that the administration of potent prepara-
degradation of T4, especially in laboratory rats, and to a lesser tions of adrenocortical steroids at inappropriately high daily
degree in dogs. Endocrine gland and target cell function are doses for prolonged intervals in the symptomatic treatment of
normal. The chronic disruption of the thyroid-pituitary axis various diseases can produce most of the functional distur-
and augmented TSH secretion in rodents, especially male rats, bances associated with endogenous hypersecretion of cortisol.
often increases the development of thyroid follicular cell Similarly, the administration of excessively large doses of
tumors in chronic toxicity and oncogenicity studies with insulin can result in hypoglycemia, and an excess of exogenous
certain drugs and chemicals. Hepatic microsomal enzymes T4 or T3 may result in hyperthyroidism, especially in certain
play an important role in thyroid hormone economy because species (e.g., cats) that have limited capacity to conjugate T4
glucuronidation is the rate-limiting step in the biliary excre- with glucuronic acid and enhance biliary excretion.
tion of T4 and sulfation, primarily by phenol sulfotransferase, Indirect effects. The administration of progestins to dogs
for the excretion of T3. Long-term exposure of rats to a wide indirectly results in a syndrome of growth hormone excess.
variety of different chemicals induces these enzyme pathways The injection of medroxyprogesterone acetate for the preven-
and results in chronic stimulation of the thyroid by disrupting tion of estrus in dogs stimulates expression of the growth
the hypothalamic-pituitary-thyroid axis. The resulting chronic hormone gene in the mammary gland leading to an elevation
stimulation of the thyroid by increased circulating levels of in circulating growth hormone levels, and results in the classic
TSH in rats often results in a greater risk of developing tumors clinical manifestations and lesions of acromegaly (e.g., exces-
derived from follicular cells in chronic toxicity/carcinogenicity sive skin folds, respiratory stridor resulting from increased soft
studies with these compounds (Fig. 3-3). The chronic admin- tissue in oropharyngeal region, expansion of interdental spaces,
istration of phenylbutazone, a nonhormonal antipyretic com- and hyperglycemia) (see Fig. 3-16).
pound used in the medical management of inflammatory
conditions of the musculoskeletal system, especially in horses,
which is a hepatic microsomal enzyme inducer, often results Further reading
in moderate thyroid enlargement by a similar mechanism. Capen CC. Toxic responses of the endocrine system. In: Klaassen CD,
Decreased degradation of hormone. The rate of secretion editor. Casarett and Doull’s Toxicology: The Basic Science of Poisons.
of hormone by an endocrine gland may be normal with this 7th ed. New York: McGraw Hill; 2007. p. 807-879.
275.e1
Further reading
Cooray SN, Clark AJL. Melanocortin receptors and their accessory
proteins. Mol Cell Endocrinol 2011;331:215-221.
Gayrard V, et al. Competitive binding to plasma thyroid hormone trans-
port proteins and thyroid dysfunction by phenylbutazone used as
a probe. Gen Comp Endocrinol 2011;174:225-231.
Gröne A, et al. Altered parathyroid hormone-related protein secretion
and mRNA expression in squamous cell carcinoma cells in vitro. Eur
J Endocrinol 1996;135:498-505.
Kooistra HS, et al. Progestin-induced growth hormone (GH) production
in the treatment of dogs with congenital GH deficiency. Domest
Anim Endocrinol 1998;15:93-102.
Kumar R, McEwan IJ. Allosteric modulators of steroid hormone
receptors: structural dynamics and gene regulation. Endocr Rev
2012;33:271-299.
Mol JA, et al. Progestin-induced mammary growth hormone produc-
tion. Adv Exp Med Biol 2000;480:71-76.
Morris DD, Garcia M. Thyroid-stimulating hormone response test in
healthy horses, and effect of phenylbutazone on equine thyroid
hormones. Am J Vet Res 1983;44:503-507.
Rijnberk A, et al. Acromegaly associated with transient overproduction
of growth hormone in a dog. J Am Vet Med Assoc 1980;177:534-
557.
Rosol TJ, Capen CC. Calcium-regulating hormones and diseases of
abnormal mineral (calcium, phosphorus, magnesium) metabolism.
In: Kaneko JJ, et al., editors. Clinical Biochemistry of Domestic
Animals. 5th ed. New York: Academic Press; 1997. p. 619-702.
Rosol TJ, et al. Parathyroid hormone (PTH)-related protein, PTH, and
1,25-dihydroxyvitamin D in dogs with cancer-associated hypercal-
cemia. Endocrinology 1992;131:1157-1164.
Spiegel AM. Inborn errors of signal transduction: mutations in G pro-
teins and G protein-coupled receptors as a cause of disease. J Inher
Metab Dis 1997;20:113-121.
Tennent BJ, Beamer WG. Ovarian tumors not induced by irradiation
and gonadotropins in hypogonadal (hpg) mice. Biol Reprod
1986;34:751-760.
Vilardaga J-P, et al. Molecular basis of parathyroid hormone receptor
signaling and trafficking: a family B GPCR paradigm. Cell Mol Life
Sci 2011;68:1-13.
Wettschureck N, Offermanns S. Mammalian G proteins and their cell
type specific functions. Physiol Rev 2005;85:1159-1204.
Winkler I, et al. Pseudovitamin D deficiency rickets in pigs: in vitro
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activity. Zentralbl Veterinärmed [A] 1982;29:81-88.
276 CHAPTER 3 • Endocrine Glands Pituitary Gland
Grammatopoulos DK. Insights into mechanisms of corticotropin- The pituitary gland has 2 preformed cavities, the residual
releasing hormone receptor signal transduction. Br J Pharmacol lumen of Rathke’s pouch (adenohypophyseal cleft, not present
2011;166:85-97. in the horse) and the infundibular recess of the third ventricle
Groeneweg FL, et al. Mineralocorticoid and glucocorticoid receptors at (central cavity). Separation of the developing adenohypophy-
the neuronal membrane, regulators of nongenomic corticosteroid sis from the oropharynx is completed by formation of the
signaling. Mol Cell Endocrinol 2012;350:299-309. sphenoid bone.
Rosol TJ, Capen CC. Biology of disease: mechanisms of cancer-induced
hypercalcemia. Lab Invest 1992;67:680-702. Structure of the adenohypophysis
Rosol TJ, et al. Endocrine system. In: Haschek WM, et al., editors. The adenohypophysis consists of 3 parts: the pars distalis, pars
Haschek and Rousseaux’s Handbook of Toxicologic Pathology. tuberalis, and pars intermedia. In many species, the adenohy-
Elsevier/Academic Press; 2013. p. 2391-2492. pophysis completely surrounds the pars nervosa of the neu-
Taylor CW, Tovey SC. From parathyroid hormone to cytosolic Ca2+ rohypophyseal system.
signals. Biochem Soc Trans 2012;40:147-152. • The pars distalis is the largest region of the adenohypophy-
sis and contains the multiple populations of endocrine cells
that secrete the different pituitary trophic hormones. The
PITUITARY GLAND secretory cells are supplied with abundant capillaries that
have fenestrae in their peripheral cytoplasmic extensions
Although the pituitary gland is partially derived from the and are supported by the cytoplasmic processes of keratin-
oropharyngeal ectoderm, it is completely separated from the positive folliculostellate (follicular or sustentacular) cells. The
oral cavity in adult animals. It is situated in the sella turcica, functions of folliculostellate cells are still poorly defined,
a concavity of the sphenoid bone, and enveloped by an but they are considered supporting cells of the secretory
extension of dura mater. The pituitary gland (hypophysis) cells and the source of follicles that occasionally form in
is subdivided anatomically into the adenohypophysis and the adenohypophysis. The stellate cells may be phagocytic,
neurohypophysis. especially for hormonal secretory granules, and serve as
dendritic cells. In addition, they possibly represent organ-
specific stem cells.
Development, structure, and function • The pars intermedia forms the junction between the pars
Embryologic development of the pituitary gland distalis and pars nervosa. It lines the residual lumen of
The pituitary gland develops embryologically from a dorsal Rathke’s pouch and contains both secretory and stellate
evagination of oropharyngeal ectoderm (Rathke’s pouch) (Fig. cells.
3-4) and a ventral downgrowth of diencephalic neuroecto- • The pars tuberalis consists of dorsal projections of cells
derm. The rostral part of the adenohypophyseal vesicle pro- along the infundibular stalk. It functions primarily as a
liferates and forms the pars distalis and is responsible for the scaffold for the capillary network of the hypophyseal
secretion of multiple trophic hormones. The point of fusion portal system during its course from the median eminence
of the 2 primordia develops into the pars intermedia. The pars to the pars distalis, but also contains secretory and
nervosa originates from the neuroectoderm and is connected stellate cells.
to the overlying hypothalamus through the infundibular stalk.
Functional cytology of the adenohypophysis
The multiple populations of endocrine cells in the pars distalis
Brain originate from stem cells and develop, depending on the pres-
ence and absence of transcriptional activators and signaling
Infundibulum molecules. The development of somatotrophs (producing
Rathke's pouch
growth hormone [GH]), lactotrophs (producing prolactin
[PRL]) and thyrotrophs (producing thyrotropin [TSH]) is
dependent on the transcription factor, Pit1 , followed by a
divergence between somatotrophs/lactotrophs and thyro-
trophs that is regulated by GATA2 (Fig. 3-5). The develop-
ment of corticotrophs (producing adrenocorticotropic
hormone, ACTH), melanotrophs (producing melanocyte-
stimulating hormone, MSH) and gonadotrophs (producing
luteinizing hormone [LH], and follicle-stimulating hormone
[FSH]) is Pit1 independent, and further division between
corticotrophs/melanotrophs and gonadotrophs is regulated by
transcription factors, including Tbx19 and Sf1 (see Fig. 3-5).
Third ventricle Pars nervosa Corticotrophs and melanotrophs produce a common precur-
Pars tuberalis sor molecule, pro-opiomelanocortin (POMC) that is differen-
Central cavity
tially processed to ACTH, MSH, and additional peptides,
Pars distalis Pars intermedia which is dependent on the presence of specific proteinases,
such as proconvertase 1 and 2.
The endocrine cells of the pars distalis can be identified by
Figure 3-4 Embryologic development of the pituitary gland. immunohistochemical demonstration of hormones. Secretory
(From Villee CA, et al.: General Zoology, 2nd ed. Philadelphia, cells in the adenohypophysis are morphologically subdivided
1963, W.B. Saunders.) into acidophils, basophils, and chromophobes based on the
Pituitary Gland 277
III ventricle
PRL-RH
TRH
PRL-RIF
CRH (Dopamine)
Median eminence
Rostral
hypophyseal
artery Pars tuberalis
Pars distalis
PRL-RH Pars
GH-RH PRL-RIF LH-RH
TRH CRH nervosa
GH-RIH (Dopamine) (FSH)
Corticotrophs
Somatotrophs Luteotrophs (POMC)
Gonadotrophs Thyrotrophs
precursor molecule, termed propressophysin. The hormones Arteriolar branches penetrate the pars tuberalis, lose their
are packaged into membrane-limited neurosecretory granules muscular coat, and form a capillary plexus near the median
and transported to the pars nervosa by axonal processes of the eminence. These vessels subsequently drain into hypophyseal
neurosecretory neurons. These axons terminate on fenestrated portal veins that supply the pars distalis and transport the
capillaries in the pars nervosa and release ADH or oxytocin hypothalamic releasing hormones to the pituitary. A small
into the circulation. artery that arises from the caudal hypophyseal artery may
ADH is transported by the bloodstream to its site of action provide a minor blood supply to the adenohypophysis.
in the kidney, where it binds to specific receptors on epithelial
cells in the distal part of the nephron and collecting ducts. The
overall effect of ADH on the kidney is to increase the active Diseases of the pituitary gland
renal tubular reabsorption of water from the glomerular Hypophyseal changes associated with alterations in
filtrate. target organs
In response to surgical removal or disease processes in a target
Blood supply to the pituitary gland endocrine organ of the pituitary, there is a progressive decline
The neurohypophysis in most animals is supplied directly by in the circulating concentration of hormone produced by the
the caudal hypophyseal arteries that branch from the internal target organ. This reduction in circulating hormone level is
carotid arteries. Branches of the rostral hypophyseal arteries detected by the hypothalamic-adenohypophyseal system and
originate from the internal carotid arteries and form the results in structural changes in the specific trophic hormone–
caudal communicating arteries of the circle of Willis. secreting cell population in the pars distalis.
Pituitary Gland 279
Pituitary cysts
NT
Cysts derived from the distal (“sellar”) end of the cranio-
pharyngeal duct. Cysts may develop from remnants of the
distal craniopharyngeal duct, which normally disappears by
birth in most animal species. The cysts are lined by cuboidal
to columnar, often ciliated, epithelium and contain mucin. In
A
dogs, especially of the brachycephalic breeds, cysts from these
remnants are often found at the periphery of the pars tuberalis
and pars distalis. Cystic remnants of the craniopharyngeal duct
NS
in one survey were found in about 50% of dogs of several
breeds.
Craniopharyngeal duct cysts occasionally become large
enough to exert pressure on the infundibular stalk and
hypophyseal portal system, median eminence, or pars distalis.
Structures adjacent to the cysts atrophy to variable degrees
NS because of compression and interference with the blood
supply. Disruption of a large cyst with escape of the protein-
Figure 3-7 Structural characteristics of a neurosecretory neuron. aceous contents into adjacent tissues may incite local inflam-
Nerve cell body (N, nucleus) has dendritic and axonal (A) pro- mation with subsequent fibrosis that may interfere with
cesses, arrays of rough endoplasmic reticulum (ER), a prominent pituitary function. Clinical signs can include visual difficulties
Golgi apparatus (GA), and large mitochondria (M). Hormone- resulting from pressure on the optic chiasm, diabetes insipi-
containing, membrane-limited neurosecretory granules (NS) are dus, obesity, and hypofunction of the adenohypophysis leading
transported along the axon to the site of release in the pars to gonadal atrophy, decreased basal metabolic rate, and
nervosa. L, lysosomes; NT, neural tubules. hypoglycemia.
Cysts derived from the proximal end of the craniopharyn-
geal duct (pharyngeal hypophysis). The proximal portion of
The initial reaction is rapid release of storage granules the adenohypophyseal anlage may persist in the dorsal aspect
containing preformed trophic hormone from one population of the oral cavity in adults as undifferentiated remnants of
of endocrine cells in the pars distalis. For example, only thy- cells along the craniopharyngeal canal or as differentiated cells
rotrophic basophils degranulate following thyroidectomy or similar to those of the definitive adenohypophysis. These rem-
thyroid disease, corticotrophic chromophobes degranulate nants, called the pharyngeal hypophysis, have been described
after adrenalectomy, and gonadotrophic basophils release their in dogs, cats, other animal species, and humans. The pharyn-
secretory granules in response to gonadectomy. After an inter- geal hypophysis is physically separated from the sellar adeno-
val of several days following surgical ablation or extensive hypophysis in dogs, but in cats, these structures may be
destruction of a target endocrine organ, the corresponding continuous because of persistence of the craniopharyngeal
degranulated trophic hormone–secreting cell in the pars dis- canal.
talis undergoes hypertrophy with expansion of the cytoplas- The pharyngeal hypophysis is seen most often in brachyce-
mic area in response to the sustained increased demand for phalic breeds of dogs. It is a tubular structure lined by ciliated
the particular trophic hormone. The abundant cytoplasm con- columnar epithelium, located on the midline of the nasophar-
tains extensive organelles concerned with hormonal synthesis ynx, and is frequently continuous with a multilocular cyst that
(rough endoplasmic reticulum) and packaging into secretory is lined by ciliated cuboidal or columnar epithelium. The cyst
granules (Golgi apparatus) plus large mitochondria. contains colloid material and cellular debris. A mass of dif-
If the demand for trophic hormone secretion is sustained ferentiated acidophilic, basophilic, and chromophobic cells,
for days or weeks, one specific population of endocrine similar to those of the sellar adenohypophysis, usually extends
cells in the pars distalis undergoes hyperplasia. Groups of from the cyst wall.
hyperplastic trophic hormone–secreting cells are present, scat- Cysts (up to several centimeters in diameter) may be
tered as small nests throughout an otherwise normal pars derived from the oropharyngeal end of the craniopharyngeal
distalis. In response to long-term (weeks to months) stimula- duct and project as a space-occupying mass into the nasophar-
tion, the hypertrophied cytoplasm of the cells becomes vacu- ynx in dogs. The predominant clinical sign may be related to
olated because of the extensive distention of profiles of rough respiratory distress resulting from ventral displacement of the
endoplasmic reticulum with finely granular, moderately soft palate and occlusion of the caudal nares. The cyst wall
280 CHAPTER 3 • Endocrine Glands Pituitary Gland
A B
Figure 3-8 Failure of oropharyngeal ectoderm to differentiate into trophic hormone–secreting
cells of the adenohypophysis in a German Shepherd dog with dwarfism. A. Sagittal section. Pars
nervosa compressed by mucin-filled cyst. B. Ventral view of cyst. Bars = 1 cm.
Cortisol
Cortisol
ACTH
ACTH
on the severity of hormonal insufficiency. There are few tra-
beculae in the primary and secondary spongiosa of the
metaphysis of long bones, and osteoblasts are decreased in
dwarf pups when compared with normal littermates. The
external genitalia usually remain infantile. The testes and penis Normal Adrenal cortical adenoma
are small, mineralization of the os penis is delayed or incom- or carcinoma
plete, and the penile sheath is flaccid. In females, the ovarian
cortex is hypoplastic and estrus irregular or absent. Cutaneous Adenoma Hypothalamus
lesions include hyperkeratosis, follicular keratosis, hyperpig- (?)
mentation, adnexal atrophy and loss of elastin fibers, and the
Cortisol
Cortisol
ACTH
ACTH
loose network of collagen fibers in the dermis. Hair shafts are
absent, and hair follicles are primarily in the telogen (resting)
phase of the growth cycle. The shortened life span in dogs
with pituitary dwarfism results not only from the panhypopi-
tuitarism but also from the resulting secondary endocrine
dysfunction, such as hypothyroidism and hypoadrenocorti- Corticotroph adenoma, Idiopathic cortical
cism. The variation in severity and onset of the lesions in adenohypophysis hyperplasia
pituitary dwarfism appears to be related to the degree of
penetrance of the defect. The degree to which the oropharyn-
( ) ( )
geal epithelium fails to differentiate is variable, as is the rapid-
ity with which the mucin-filled cysts enlarge and exert
Cortisol
Cortisol
ACTH
ACTH
pressure on adjacent structures. Lung
Cysts associated with pituitary dwarfism morphologically
are distinct from the cysts that develop following the abnor-
mal accumulation of colloid in the residual lumen of Rathke’s ACTH
pouch. The normally developed pars distalis and pars nervosa Iatrogenic + +
are compressed to various degrees by the abnormal accumula-
tion of colloid in a normal cavity of the pituitary. Ectopic ACTH secretion
Figure 3-10 Multiple pathogenic mechanisms of cortisol excess
Neoplastic diseases of the pituitary in dogs. ACTH, adrenocorticotropic hormone.
The consequences of pituitary neoplasms depend on their
functionality. Effects of hormone-producing neoplasms are
usually mediated via the target organs, whereas nonfunctional
neoplasms cause disturbances because of local effects, such as
compression and destruction of adjacent tissues. Most func-
tional tumors express only one hormone; however, plurihor-
monal tumors also occur.
pituitary mass and invagination into the infundibular cavity; Hepatomegaly resulting from increased fat and glycogen
dilation of the infundibular recess and the third ventricle, with deposition plus vacuolation of hepatocytes produces a dis-
eventual compression or replacement of the hypothalamus; tended, often pendulous, abdomen. Functional alterations of
and possible extension of the tumor into the thalamus. In the the skin, muscle, lung, and other tissues are the direct effects
larger neoplasms, there are often focal areas of hemorrhage, of elevated blood cortisol levels.
necrosis, liquefaction, and mineralization. Growth of the pitu- Adenomas of the pars intermedia in dogs result in only
itary tumor along the basilar aspects of the brain may result moderate enlargement of the pituitary gland. Nonbrachyce-
in incorporation of the second, third, and fourth cranial nerves, phalic breeds of dogs develop adenomas in the pars intermedia
leading to disturbances of their function. more often than brachycephalic breeds.
Bilateral enlargement of the adrenal glands occurs in dogs The pars distalis is readily identifiable and sharply demar-
with functional corticotroph adenomas (see Fig. 3-101D). cated from the rostral margin of the neoplasm. The tumor
This enlargement often is striking and is due to increased may extend across the residual hypophyseal lumen and
cortical parenchyma, primarily in the zonae fasciculata and result in compression atrophy, but usually does not invade the
reticularis. Nodules of yellow-orange cortical tissue often are parenchyma of the pars distalis (Fig. 3-12A). The neurohy-
found outside the capsule in the periadrenal fat, as well as pophysis is incorporated within the tumor, but the infundibu-
extending down into the adrenal medulla. The corticomedul- lar stalk is intact. Degenerative changes within the neoplasm
lary junction is irregular, and the medulla is compressed. are minimal.
Pituitary corticotroph adenomas are composed of well- Adenomas of the pars intermedia in dogs appear to arise
differentiated, large or small, cells supported by fine connective from the lining epithelium of the residual hypophyseal lumen
tissue septa. They can be divided into sinusoidal and diffuse covering the pars nervosa. They often are relatively small and
types on the basis of the predominant pattern of cellular more strictly localized than corticotroph adenomas arising in
architecture. The cytoplasm of the tumor cells usually is the pars distalis of dogs, but are not encapsulated. The histo-
devoid of secretory granules detectable by routine histochemi- logic appearance is different from corticotroph adenomas of
cal procedures used for pituitary cytology. However, pituitary the pars distalis, in that there are numerous colloid-filled follicles
corticotroph adenomas arising in both the pars distalis and the interspersed between nests of large neoplastic cells (Fig. 3-12B).
pars intermedia associated with the syndrome of cortisol The follicles are lined by simple cuboidal to columnar epithe-
excess in dogs are composed of polyhedral cells that immu- lium, which may be partly ciliated, and contain interspersed
nohistochemically stain selectively for pro-opiomelanocortin mucin-secreting goblet cells. The follicular colloid is eosino-
(POMC), ACTH, and MSH. POMC immunostaining of the philic to amphophilic and PAS positive. Endocrinologically
adenoma cells is usually the most robust. Nodules of focal active (ACTH-secreting) adenomas of the pars intermedia
hyperplasia and microadenomas, composed of similar ACTH/ in dogs have prominent groups of large corticotrophs with
MSH cells, often are present in the adenohypophysis of older abundant eosinophilic cytoplasm interspersed with variable
dogs. numbers of smaller, more basophilic cells and widely scattered
Although remnants of the pars distalis can be identified follicles. Dense bands of fibrous connective tissue are occa-
near the periphery of corticotroph adenomas, the demarcation sionally interspersed between the follicles and nests of chro-
between the neoplasm and pars distalis often is not distinct. mophobic cells, particularly in the endocrinologically inactive
The pars distalis either is partly replaced by the neoplasm or adenomas of the pars intermedia.
severely compressed. The pars nervosa and infundibular stalk Adenomas of the pars intermedia in dogs either are endo-
either are infiltrated and disrupted by tumor cells or com- crinologically inactive and associated with various degrees of
pletely incorporated within the larger neoplasms. hypopituitarism and diabetes insipidus, or endocrinologically
Hormone-containing secretory granules can be demonstrated active and secrete excessive ACTH, leading to bilateral adre-
by electron microscopy in functional corticotroph adenomas of nocortical hyperplasia and hyperadrenocorticism. The clinical
dogs. The granules vary in number from cell to cell, are spheri- signs in the dogs with functional adenomas are similar to those
cal, and are surrounded by a delicate limiting membrane. They described for corticotroph adenomas of the pars distalis. Cor-
are small (mean diameter, 170 nm), electron dense, often situ- ticotroph adenomas associated with Cushing’s disease are
ated peripherally in the cell, and may have a prominent characterized by strong immunostaining for ACTH and weak-
submembranous space. to-moderate immunostaining for α-MSH.
A number of distinctive clinical and functional alterations Corticotroph adenomas similar to those in dogs have been
develop in dogs with corticotroph (ACTH-secreting) adeno- reported in cats, although they are less common. Observed
mas, resulting in the syndrome of hyperadrenocorticism. Cen- differences in clinical presentation are most likely due to the
tripetal redistribution of adipose tissue leads to prominent fat greater tolerance of cats to high levels of steroids. In the horse,
pads on the dorsal midline of the neck, giving the neck and corticotroph adenomas are rarely reported in the pars
shoulders a thick appearance. Appetite and intake of food distalis.
often are increased, either as a direct result of the hyperadre-
nocorticism or involvement of hypothalamic appetite control Pars intermedia (melanotroph) adenoma
centers by a large pituitary tumor. The muscles of the extremi- Adenomas derived from cells of the pars intermedia are the most
ties and abdomen are weakened and atrophied. The loss of common type of pituitary tumor in horses, and produce various
abdominal muscles and muscles of the appendicular skeleton POMC-derived peptides, and cause the clinical syndrome of
results in gradual abdominal enlargement (“pot belly”), lordo- pituitary pars intermedia dysfunction (PPID). The adenomas
sis, muscle trembling, and a straight-legged skeletal-braced develop frequently in older horses, with females affected more
posture to support the body’s weight. Profound atrophy of frequently than males. The tumor has also been reported in
the temporal muscles may result in concave indentations onagers (Equus hemionus onager). Adenomas of the pars inter-
and readily palpable prominences of underlying skull bones. media in horses can be large tumors that extend out of the
A B
H
C
D
E F
Figure 3-12 A, B. Corticotroph adenoma of pars intermedia in a dog. A. Central neoplasm sharply
demarcated from pars distalis. Rathke’s pouch (right of tumor) is dilated and contains eosinophilic
fluid. The clear cleft between the adenoma and pars distalis (left) is an artifact. B. Pars intermedia
adenoma with colloid-filled follicles and infiltration and compression of the pars nervosa (top).
C-G. Adenomas and hyperplasia of pars intermedia in a horse. C. Note the large adenoma (large
arrowhead) compressing the pars nervosa (N); smaller adenomas (small arrowheads); and thick-
ened and hyperplastic region of the pars intermedia (H). The pars distalis is displaced cranially
(left) and caudally (right). D. Pars intermedia adenoma with polygonal to fusiform tumor cells
containing abundant eosinophilic cytoplasm. E. Macroscopic image of a multinodular pars inter-
media adenoma with infiltration of the pars nervosa (center). Compressed pars distalis is present
at left and ventral edges. F. Abundant expression of α-melanocyte-stimulating hormone (α-MSH)
in the pars intermedia adenoma. Immunohistochemistry. Continued
284 CHAPTER 3 • Endocrine Glands Pituitary Gland
sella turcica and severely compress the overlying hypothala- more sarcomatous pattern and palisade around vessels. The
mus. The adenomas are yellow to white, multinodular, and cytoplasm is lightly eosinophilic and granular. Electron micros-
incorporate the pars nervosa (Fig. 3-12C). On sectioning of copy of the large cells comprising adenomas of the pars inter-
the pituitary mass, the pars distalis usually can be identified media in horses reveals that the rough endoplasmic reticulum
as a compressed subcapsular rim of tissue on the rostral margin and Golgi apparatus are particularly well developed, suggest-
(see Fig. 3-12C). A sharp line of demarcation remains between ing they are synthesizing abundant POMC and packaging
the neoplasm, which is partly encapsulated, and the com- considerable amounts of peptide hormones for secretion. The
pressed and atrophic pars distalis. The tumors are subdivided neoplastic cells contain numerous membrane-limited secre-
into nodules or compartments by fine septa of connective tory granules in their cytoplasm with a mean diameter of
tissue that contain numerous capillaries and rare inflammatory ~300 nm that are surrounded by a closely applied limiting
cells. Tumor cells are large cylindrical, spindle shaped, or poly- membrane.
hedral, with an oval hyperchromatic nucleus (Fig. 3-12D). The clinical syndrome of PPID is characterized by polyuria,
The histologic pattern is often reminiscent of the prominent polydipsia, laminitis, increased appetite, muscle weakness,
pars intermedia of normal horses. Occasionally, cuboidal cells somnolence, intermittent hyperpyrexia, and generalized
form follicular structures that contain dense eosinophilic hyperhidrosis. The most striking change is hypertrichosis (hir-
colloid. In other areas, the spindle-shaped cells may assume a sutism) because of failure of the seasonal shedding of hair (Fig.
3-13). The hair over most of the trunk and extremities is long
(up to 9-10 cm), abnormally thick, wavy, and often matted.
Biopsy of skin reveals normal hair follicles uniformly in the
anagen phase, normal epidermis and dermal collagen, and
absence of the characteristic skin lesions observed in dogs with
Cushing’s disease caused by cortisol excess. Horses with larger
tumors may have hyperglycemia (insulin-resistant) and gly-
cosuria, most likely the result of downregulation of insulin
receptors on target cells induced by the chronic excessive
intake of food and hyperinsulinemia. The disturbances in
carbohydrate metabolism, ravenous appetite, hypertrichosis,
and hyperhidrosis are considered to be primarily a reflection of
deranged hypothalamic function caused by the compressive and
destructive effects of the large pituitary tumors. Adenomas of the
pars intermedia in horses often expand dorsally because of the
incomplete diaphragma sellae, and result in localized necrosis
of nuclei in this important regulatory center as a result of
G compression of the overlying hypothalamus. The hypothala-
Figure 3-12, cont’d G. Restriction of adrenocorticotropic mus is the primary autonomic center for homeostatic regula-
hormone staining to non-neoplastic areas of the pars distalis tion of body temperature, appetite, and cyclic shedding of hair,
(arrowheads). Immunohistochemistry. among many other functions.
Figure 3-13 Hypertrichosis (“hirsutism”) in a horse, resulting from failure of the cyclic shedding
of hair, associated with an adenoma of the pars intermedia.
Pituitary Gland 285
Pro-opiomelanocortin (pro-OMC)
() Dopaminergic
Pars Pars control
distalis intermedia
PD
ACTH α-MSH
β-LPH CLIP (/)
() γ-LPH β-MSH
β-Endorphin
[Plasma cortisol]
Figure 3-14 Post-translational processing of pro-
opiomelanocortin (POMC) produced in pars distalis and pars A
intermedia. The plasma concentration of cortisol regulates pro-
cessing in the pars distalis, whereas the pars intermedia is primar-
ily under dopamine control. ACTH, adrenocorticotropic hormone;
CLIP, corticotropin-like intermediate lobe peptide; LPH, lipotro-
pin; α-MSH, α-melanocyte-stimulating hormone.
Figure 3-16 Iatrogenic acromegaly in a Beagle. Note the coarse- Figure 3-17 Enlargement and deepening of sella turcica (arrow-
ness of facial features and marked thickening and folding of the heads) in a ewe, associated with a large acidophil adenoma
skin of the face. These characteristic changes are the result of the (prolactin-secreting cells) of the pituitary gland that remained
protein anabolic effects of growth hormone, produced in excess confined to this region because of the complete diaphragma sellae.
by hyperplastic mammary ductular epithelial cells that have been
stimulated by the exogenous administration of medroxyproges-
terone acetate. Inset: Note gingival hyperplasia, increased separa- prognathia inferior. In addition, it is associated with prolifera-
tion of the frontal incisors, and macroglossia. tion of joint cartilage, leading to degenerative arthropathy, and
kidney disease resulting from periglomerular fibrosis and
mesangial proliferation.
interspersed between numerous blood-filled sinusoids. The Acidophil adenomas in sheep may attain considerable size
fibrous stroma is sparse. Although the degree of cytoplasmic (see Fig. 3-15A) and remain confined to the sella turcica
granulation of acidophils varies from cell to cell, the predomi- because sheep have a complete diaphragma sellae separating
nant type of neoplastic acidophil usually contains many sec- the pituitary fossa from the brain. The remaining adenohy-
retary granules. The nuclei of the densely granulated acidophils pophysis and neurohypophysis are compressed severely, and
are small, oval, and hyperchromatic. Sparsely granulated the sella turcica is enlarged and deepened due to pressure-
(“chromophobic”) cells are interspersed between the densely induced osteolysis (Fig. 3-17).
granulated acidophils. Their cytoplasm is more abundant and Tumors arising from somatotrophs occur in young to
lightly eosinophilic but contains only an occasional secretory middle-aged budgerigars (Melopsittacus undulates). These are
granule. Secretory granules of acidophils are bright red when usually adenomas, but metastasizing carcinomas are also
stained with acid fuchsin-aniline blue (Fig. 3-15B) and with reported. The pituitary gland is replaced by the neoplasm that
Crossman’s modification of Mallory’s trichrome. Orange-G often extends into adjacent structures. Neoplastic cells are
stains the granules an intense yellow-orange, but they are PAS polygonal with presence of karyomegalic cells. Most neoplas-
negative. Colloid-containing follicles lined by follicular cells are tic cells stain positive for GH. Clinical signs include difficulties
found occasionally within acidophil adenomas in dogs. The flying, ataxia, and blindness, and are caused by local expansion
colloid is intensely PAS positive. Numerous sinusoids are dis- of the tumor.
tended with erythrocytes, detached neoplastic cells, and large
masses of fibrin. The pars nervosa and infundibular stalk are Thyrotroph adenoma
infiltrated at the periphery by neoplastic cells, compressed, Thyrotroph adenoma has been reported from a cynomolgus
and partly replaced by fibrous astrocytes. monkey (Macaca fascicularis). Production of TSH by a
Functional disturbances resulting from hypersecretion of pituitary adenoma was present in combination with other
GH have been reported in cats and dogs. Acromegaly is a hormones, including FSH, prolactin (PRL), or ACTH in the
disease characterized by an overgrowth of connective tissue, monkey. In dogs, reactive thyrotroph hyperplasia is seen
increased appositional growth of bone, coarsening of facial in response to hypothyroidism. Basophil adenomas in
features, gingival hyperplasia and increased separation of people also may secrete TSH, resulting in bilateral enlarge-
teeth, macroglossia, and enlargement of viscera resulting from ment of both thyroid lobes (“goiter”). Serum thyroxine,
chronic excessive secretion of GH (Fig. 3-16). In dogs, this is triiodothyronine, and TSH are elevated and may be respon
usually due to tumors from organs other than the pituitary, sive to thyrotropin-releasing hormone (TRH) from the
such as the mammary gland, but in cats, somatotroph adenoma hypothalamus.
is a common cause. Functional acidophil adenomas in cats
secrete excess GH, which results in downregulation of insulin Lactotroph adenoma
receptors and resistance to the action of insulin at the target Pituitary adenomas that produce PRL occur in cynomolgus
cell level. Somatotroph adenomas are considered to be a pre- monkeys, rarely in small ruminants, and frequently in aged
disposing cause of insulin-resistant diabetes mellitus in cats. rats. Tumors in the monkeys had polygonal cells arranged in
Tumor cells are immunohistochemically positive for GH. The cords and nests with minimal anisocytosis and anisokaryosis
circulating GH and IGF-1 levels are severely elevated. Clinical and few, if any, mitotic figures. Necrosis, hemorrhage, inflam-
evidence of acromegaly includes an enlarged abdomen and mation, or acinar formation was absent. Goats with acidophil
Pituitary Gland 287
pituitary adenomas may have increased serum PRL levels and Hormonally inactive adenoma of the pars distalis
inappropriate lactation. Nonfunctional pituitary tumors occur in dogs, cats, laboratory
rodents, and parakeets, but are uncommon in other species.
Suprasellar germ cell tumor (craniopharyngioma) They are also called null-cell adenomas resulting from the lack
This tumor occurs in young animals and is present in either a of hormones as demonstrated by immunohistochemistry.
suprasellar or infrasellar location (Fig. 3-18A). It is one cause Although these chromophobe adenomas appear to be hormonally
of panhypopituitarism and dwarfism in young dogs due to inactive, they may cause significant functional disturbances and
subnormal secretion of somatotropin and other trophic hor- clinical signs by compression of adjacent portions of the pituitary
mones beginning at an early age, prior to closure of the growth gland and dorsal extension into the overlying brain.
plates. Pleomorphic tumors in the suprasellar region often are Nonfunctional pituitary adenomas result in clinical distur-
large and grow along the ventral aspect of the brain, where bances either by interfering with secretion of pituitary trophic
they can incorporate several cranial nerves. In addition, they hormones and diminishing target organ function or dysfunc-
extend dorsally into the hypothalamus and thalamus. The tion of the central nervous system. Affected animals often
clinical signs resulting from this type of rapidly growing tumor are depressed, have incoordination and other disturbances of
in the pituitary region often are a combination of: balance, are weak, and may collapse with exercise. In long-
1. Lack of secretion of pituitary trophic hormones, resulting standing cases, there may be evidence of blindness with dilated
in trophic atrophy and subnormal function of the adrenal and fixed pupils caused by compression and disruption of
cortex and thyroid, gonadal atrophy, and failure to attain optic nerves by dorsal extension of the pituitary tumor.
somatic maturation because of a lack of GH secretion. Animals with hormonally inactive pituitary adenomas
2. Disturbances in water metabolism (polyuria, polydipsia, often have progressive loss of weight, with muscle atrophy
low urine-specific gravity and osmolality) from interfer- because of lack of the protein anabolic effects of GH. Com-
ence with the release and synthesis of antidiuretic hormone pression of the cells that secrete gonadotrophic hormones or
(ADH) by the large tumor. the corresponding hypothalamic releasing hormone(s) results
288 CHAPTER 3 • Endocrine Glands Pituitary Gland
C F R M
SG
A B
Figure 3-25 A. Cross-section of axonal process in pars nervosa of dog with hypophyseal diabetes
insipidus associated with a pituitary adenoma. Axonal swelling contains few neurosecretory gran-
ules with dense cores, but occasional irregularly shaped, empty vesicles (arrow). B. Cross-section
of axonal process in pars nervosa of normal dog, illustrating numerous membrane-bound, antidi-
uretic hormone–containing, neurosecretory granules (SG). Electron micrographs.
Calcium-Regulating Hormones 291
Extracellular Ca
Ca Ca
PTH
↓ Ca
Calcitriol
Ca
Ca
Calcitonin
In the nephrogenic form of diabetes insipidus, blood Rosol TJ, et al. Endocrine system. In: Haschek WM, et al., editors.
levels of ADH are normal or elevated, but target cells in the Haschek and Rousseaux’s Handbook of Toxicologic Pathology. Else-
distal nephron and collecting ducts are unable to respond vier/ Academic Press; 2013. p. 2391-2492.
because of a lack of adenylyl cyclase in the plasma Voorbij AMWY, Kooistra HS. Pituitary dwarfism in German shepherd
membrane. dogs. J Vet Clin Sci 2009;2:4-11.
Animals with diabetes insipidus excrete large volumes of Voorbij AMWY, et al. Pituitary dwarfism in Saarloos and Czechoslova-
hypotonic urine, which in turn obliges them to take in equally kian Wolfdogs is associated with a mutation in LHX3. J Vet Intern
large amounts of water to prevent hyperosmolality of body Med 2014;28:1770-1774.
fluids and dehydration. Urine osmolality is decreased below Yeung CM, et al. Cells of the anterior pituitary. Int J Biochem Cell Biol
normal plasma osmolality (~300 mmol/L) in both hypophy- 2006;38:1441-1449.
seal and nephrogenic forms of diabetes insipidus. In response
to water deprivation, urine osmolality remains below that of
plasma in both forms in contrast to what is observed in normal
CALCIUM-REGULATING HORMONES
animals. The elevation of urine osmolality above that of plasma
in response to exogenous ADH in the hypophyseal form, but not Calcium ion plays a key role in many fundamental biological
in nephrogenic diabetes insipidus, allows separation of these 2 processes, including muscle contraction, blood coagulation,
forms of the disease. enzyme activity, neural excitability, hormone release, and
Tumors of the neurohypophysis are called pituicytomas; membrane permeability, in addition to being an essential
they are very rare in animals. Morphologically they resemble structural component of the skeleton. To maintain a constant
astrocytomas (Fig. 3-26). Immunohistochemically, they are concentration of calcium, despite variations in intake and
positive for glial fibrillary acidic protein (GFAP). excretion, endocrine control mechanisms have evolved that
primarily consist of the interactions of 3 major hormones (Fig.
3-27). Although the roles of parathyroid hormone, calcitonin,
Further reading calcitriol (the active form of vitamin D: 1,25-dihydroxyvitamin
Asa SL, Ezzat S. The pathogenesis of pituitary tumours. Nat Rev Cancer D), and fibroblast growth factor-23 (FGF23) frequently are
2002;2:836-849. emphasized in the control of blood calcium; other hormones,
Barnhart KF, et al. Symptomatic granular cell tumor involving the pitu- such as adrenal corticosteroids, estrogen, thyroxine, somatotropin,
itary gland in a dog: a case report and review of the literature. Vet and glucagon, also contribute to the maintenance of calcium
Pathol 2001;38:332-336. homeostasis under certain conditions.
Devnath S, Inoue K. An insight to pituitary folliculo-stellate cells. J Calcium (Ca) serves 2 primary functions in the body: (1)
Neuroendocrinol 2008;20:687-691. for structural integrity of bones and teeth, and (2) as a messenger
Florio T. Adult pituitary stem cells: from pituitary plasticity to adenoma or regulatory ion. The 10,000-fold concentration gradient of
development. Neuroendocrinology 2011;94:265-277. calcium ion (Ca2+) between the extracellular fluid (1.2 mmol/L)
Fracassi F, et al. Pituitary macroadenoma in a cat with diabetes mellitus, and the cytoplasm (100 nmol/L) permits Ca2+ to function as
hypercortisolism and neurological signs. J Vet Med A Physiol Pathol a signaling ion to activate intracellular processes. The lipid
Clin Med 2007;54:359-363. bilayer of the cell membrane has a low permeability to Ca2+;
Glover CM, et al. Extrapituitary and pituitary pathological findings in therefore influx of Ca2+ into the cytoplasm is controlled by a
horses with pituitary pars intermedia dysfunction: a retrospective heterogeneous group of Ca channels regulated by membrane
study. J Eq Vet Sci 2009;29:146-153. potential, cell membrane receptors, or intracellular secondary
Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol messengers. Influx of Ca2+ into cells can (1) regulate cellular
2011;7:257-266. function by interactions with Ca-binding proteins (e.g.,
Niessen SJM, et al. Feline acromegaly: an underdiagnosed endocri- calmodulin) and Ca-sensitive protein kinases, and (2) stimu-
nopathy? J Vet Intern Medicine 2007;21:899-905. late biologic responses, such as neurotransmitter release,
291.e1
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Bexton S. Clinical and laboratory findings in a Eurasian badger (Meles Langohr IM, et al. Somatotroph pituitary tumors in budgerigars (Mel-
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Binns W, et al. Effects of teratogenic agents in range plants. Cancer Laroque P, et al. Morphological changes in the pituitary gland of dogs
Res 1968;28:2323-2326. chronically exposed to exogenous growth hormone. Toxicol Pathol
Capen CC. Functional and pathologic interrelationships of the pituitary 1998;26:201-206.
gland and hypothalamus in animals. In: Jones TC, et al., editors. Lipman NS, et al. Prolactin-secreting pituitary adenomas with mammary
Endocrine System. Series II. Monographs on Pathology of Labora- dysplasia in New Zealand white rabbits. Lab Anim Sci 1994;44:114-
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Cross E, et al. Feline pituitary-dependent hyperadrenocorticism and McFarlane D, et al. Nitration and increased alpha-synuclein expression
insulin resistance due to a plurihormonal adenoma. Top Companion associated with dopaminergic neurodegeneration in equine pitu-
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adenohypophysis of dogs with induced primary hypothyroidism: Meij BP, et al. Results of transsphenoidal hypophysectomy in 52 dogs
loss of TSH hypersecretion, hypersomatotropism, hypoprolac- with pituitary-dependent hyperadrenocorticism. Vet Surg 1998;27:
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Domest Anim Endocrinol 2008;35:98-111. Miller CC, et al. Lactation associated with acidophilic pituitary adenoma,
El Etreby MF, et al. Functional morphology of spontaneous hyperplastic pheochromocytoma, and cystic endometrial hyperplasia in two
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Elliott DA, et al. Prevalence of pituitary tumors among diabetic cats nocorticotrophic hormone response to domperidone administration
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292 CHAPTER 3 • Endocrine Glands Calcium-Regulating Hormones
contraction, and secretion. Ionized calcium (Ca2+) also plays an either numerous lipid bodies and lipofuscin granules or aggre-
important role in cell adhesion and blood coagulation. In addi- gations of glycogen. Active chief cells are in the minority in
tion, Ca2+ may regulate cellular function by binding to a the parathyroid glands of most species. The cytoplasm of
G-protein–linked Ca2+-sensing receptor in the cell membrane, active chief cells has increased electron density because of the
such as in parathyroid chief cells or renal epithelial cells. close proximity of organelles and secretory granules, increased
It is critical for cells to maintain the normal low level of density of the cytoplasmic matrix, and loss of glycogen par-
intracellular Ca2+. If cellular calcium homeostasis fails because ticles and lipid bodies.
of anoxia, an energy-deprived state, or perturbed membrane The second cell type in the parathyroid glands of certain
integrity, cell viability is threatened because of uncontrolled species, including humans, is the oxyphil cell. These cells are
entry of Ca2+ through the plasma membrane or from intracel- absent in rats, chickens, and many species of lower animals.
lular stores. Oxyphil cells tend to increase with age and occur either singly
There are 2 sources of calcium in bone that can enter the or in small groups interspersed between chief cells. They are
circulation: (1) readily mobilizable Ca salts in the extracellular larger than chief cells, and their abundant eosinophilic cyto-
fluid, and (2) hydroxyapatite crystals that require digestion by plasm is filled with numerous large, often bizarre-shaped,
osteoclasts before Ca2+ can be released from bone. The nature mitochondria (Fig. 3-30). Glycogen particles and free ribo-
and regulation of the readily mobilizable Ca in bone is poorly somes are interspersed between the mitochondria. Granular
understood; however, it is present in small amounts and likely endoplasmic reticulum, Golgi apparatuses, and secretory
plays a role in the fine regulation of serum Ca concentration. granules are poorly developed in oxyphil cells of normal
If there is a significant need for Ca from bone, it must come parathyroid glands. Oxyphil cells have a higher oxidative and
from osteoclastic resorption of hydroxyapatite crystals. In hydrolytic enzyme activity than chief cells, associated with the
adult animals, there is a stable balance between Ca deposition marked increase in numbers of mitochondria. Oxyphil cells
associated with bone formation by osteoblasts and Ca release are immunohistochemically positive for parathyroid hormone
associated with osteoclastic bone resorption. In young animals, (PTH), the calcium-sensing receptor (CaSR), vitamin D
bone has a positive Ca balance, given the relative excess of receptor (VDR), and 1-α-hydroxylase. Expression of these
bone formation. Conditions that result in excessive bone molecules, with the exception of VDR, is higher in oxyphil
resorption (e.g., humoral hypercalcemia of malignancy, osteo- cells than in chief cells. The functional consequences of these
lytic bone metastases, or primary hyperparathyroidism), can findings are unclear; however, humans with chronic kidney
release large amounts of Ca from bone and contribute to the disease (CKD) have increased oxyphil cell numbers.
development of life-threatening hypercalcemia. Cells are observed with cytoplasmic characteristics inter-
mediate between those of chief and oxyphil cells. These tran-
sitional oxyphil cells have numerous mitochondria, but other
Parathyroid glands and parathyroid hormone organelles are also present, including rough endoplasmic retic-
Development and structure ulum, Golgi apparatuses, and secretory granules. Oxyphil cells
Parathyroids are of entodermal origin and derived from the are not altered in response to either short-term hypocalcemia
third and fourth pharyngeal pouches in close association with or hypercalcemia in animals. Therefore oxyphil cells do not
the primordia of the thymus (Fig. 3-28). The anatomic loca- appear to be degenerate chief cells, but rather occur as a result
tion of parathyroid glands varies in relation to thyroids and of aging or some other metabolic derangement.
related structures in various species of animals (Fig. 3-29).
The parathyroid glands contain a single basic type of secretory Biosynthesis and secretion of parathyroid hormone
cell, the chief cell, which is concerned with the elaboration of a The principal product of the parathyroid gland is parathyroid
single hormone. Inactive chief cells are cuboidal and have simple hormone (PTH). Together with other hormones, such as cal-
interdigitations between contiguous cells. The relatively electron- citriol, calcitonin, and FGF23, it plays a major role in calcium
transparent cytoplasm contains poorly developed organelles, and, indirectly, phosphate metabolism (Fig. 3-31). Much of
and secretory granules are sparse. The cytoplasm often has the current knowledge about the regulation of these hor-
mones has been acquired by investigating naturally occurring
diseases and genetically modified knock-out mouse models.
The production of PTH involves the biosynthesis of a large
Cranial
precursor on ribosomes of the rough endoplasmic reticulum
in chief cells. This initial translation product is pre-proPTH.
Foramen cecum It is composed of 115 amino acids and contains a hydrophobic
I signal sequence of 25 amino acid residues that facilitates the
II Thyroglossal duct penetration and discharge of the nascent peptide into the
External parathyroid cisternal space of the rough endoplasmic reticulum. Pre-
gland (III) III
Internal parathyroid
IV proPTH is rapidly converted (within 1 minute or less) to
gland (IV)
V proPTH by the proteolytic cleavage of 25 amino acids from
Thymus Thymus the NH2-terminal end. ProPTH is composed of 90 amino acids
Ultimobranchial body and moves within the rough endoplasmic reticulum to the
Golgi apparatus. Enzymes within the Golgi apparatus cleave
Left thyroid lobe Right thyroid lobe
a hexapeptide from the NH2-terminal (biologically active)
end of the molecule, forming active PTH, which is packaged
Caudal into membrane-limited, secretory granules in the Golgi appa-
Figure 3-28 Embryologic development of thyroid and parathy- ratus for subsequent storage in chief cells. Under certain
roid glands. conditions of increased demand, PTH may be released
Calcium-Regulating Hormones 293
Thymus
ePTG
PTG
(upper) iPTG
TG TG
Ovine
Thymus
ePTG
ePTG ePTG
iPTG iPTG
TG TG
Isthmus
Canine Feline
Thymus
PTG
ePTG
TG
iPTG
Common
carotid a. Common
carotid a.
Bovine Porcine
Figure 3-29 Anatomic location of parathyroids and thyroids in various species. a, artery, ePTG,
external parathyroid gland, iPTG, internal parathyroid gland, TG, thyroid gland. (Modified from
Grau H, Dellmann HD. Species differentiation of the parathyroid glands of our domestic animals
(German). Z Mikrosk Anat Forsch 1958;64:192-214.)
1-hydroxylase
calcitriol
PTH
FGF23
directly from chief cells without being packaged into secretory sigmoidal relationship between serum [Ca2+] and PTH secre-
granules. tion permits the chief cells to respond rapidly to a reduction
Biologically active PTH secreted by chief cells is a straight- in serum Ca2+. The major inhibitors of PTH synthesis and secre-
chain polypeptide consisting of 84 amino acid residues with tion are increased serum [Ca2+] and calcitriol. Inhibition of PTH
a molecular weight of 9,500. The molecule is rapidly cleaved synthesis by calcitriol completes an important endocrine feed-
into amino-terminal and carboxyl-terminal fragments in the back loop between the parathyroid chief cells and the renal
peripheral circulation and especially in the liver. The purpose epithelial cells, because PTH stimulates renal production of
of this fragmentation is uncertain because the biologically calcitriol (see Fig. 3-31). A newly discovered hormone pro-
active amino-terminal fragment (1-34) is no more active than duced by osteocytes in bone is FGF23, which increases renal
the entire (1-84) PTH molecule. The plasma half-life of the phosphate excretion and decreases PTH mRNA expression
N-terminal fragment is considerably shorter than that of the and secretion after binding to the FGF receptor 1 (FGFR1)
biologically inactive carboxyl-terminal fragment of parathy- on renal epithelial and chief cells. The FGFR1 functions in
roid hormone. The C-terminal portion of PTH is degraded concert with the transmembrane protein Klotho.
primarily in the kidney and accumulates in the circulation of
animals with chronic renal disease. Biological action of parathyroid hormone
Chief cells synthesize and secrete another major protein, Parathyroid hormone is the principal hormone involved in the
termed chromogranin A. It has a higher molecular weight than minute-to-minute, fine regulation of blood Ca2+. It exerts its
PTH, being composed of 430-448 amino acids, and is co-stored biologic actions by directly influencing the function of target
and secreted with parathyroid hormone. A similar molecule has cells, primarily in bone and kidney, and indirectly in the intes-
been found in secretory granules of a wide variety of peptide– tine. The action of PTH on bone is to mobilize calcium from
hormone-secreting cells (e.g., thyroid C cells, pancreatic islets, skeletal reserves into extracellular fluids.
adrenal medulla, endocrine cells of the gastrointestinal tract), The response of bone to parathyroid hormone is biphasic.
and in neurotransmitter secretory vesicles of sympathetic The immediate effects are the result of increasing the activity
nerves. A proteolytic cleavage product of chromogranin A of existing osteoclasts and osteocytes present in bone. This
inhibits PTH secretion from chief cells. These findings suggest results in an increased flow of calcium from deep in the bone
that one function of chromogranin A is to act locally in an through the coordinated action of osteocytes and endosteal
autocrine manner to inhibit the secretion of active hormone, lining cells (inactive osteoblasts). Osteoclasts are primarily
such as PTH, by endocrine cells. responsible for the long-term action of parathyroid hormone
Secretory cells in the parathyroids of most animals store on increasing bone resorption and overall bone remodeling. If
relatively small amounts of preformed hormone but are the increase in parathyroid hormone is sustained, the active
capable of responding to minor fluctuations in Ca2+ concentra- osteoclast pool in the bone is increased. A long-term increase
tion by rapidly altering the rate of hormonal secretion, and in PTH secretion, such as occurs with certain disease condi-
more slowly by altering the rate of hormonal synthesis. The tions, may also result in the formation of greater numbers of
parathyroids have a unique feedback control system based pri- osteoblasts with a resultant increase in bone formation as well
marily on the concentration of calcium (and to a lesser extent of as resorption. However, bone resorption usually is greater than
magnesium) ion in blood. If the blood calcium is elevated, then bone formation, leading to a net negative skeletal balance.
circulating levels of parathyroid hormone rapidly and mark- Osteoclasts are primarily responsible for the catabolic action
edly decrease, but a basal level of secretion is always main- of PTH on bone by increasing resorption. PTH not only stimu-
tained. Conversely, if the blood calcium is lowered, parathyroid lates increased activity of preformed osteoclasts, but increases
hormone levels increase. The concentration of blood phospho- their differentiation from precursor cells of the osteoclast
rus has no direct regulatory influence on the synthesis and lineage. However, receptors for PTH are present on osteo-
secretion of PTH; however, certain disease conditions with blasts, not on osteoclasts. Isolated osteoclasts respond to PTH
hyperphosphatemia are associated clinically with secondary only in the presence of osteoblasts. Bone resorption is a
hyperparathyroidism. An elevated blood phosphorus level complex process that involves the activation of multiple genes
may lead indirectly to parathyroid stimulation by virtue of its and the action of several hormones. The receptor ligand
ability to lower blood calcium according to the mass-law (receptor activator of nuclear factor κB [NFκB] ligand
equation when the serum is saturated with these 2 ions. [RANKL]) is a member of the tumor necrosis factor (TNF)
Hyperphosphatemia also suppresses the rate of formation of superfamily and a membrane-bound protein on osteoblasts
calcitriol in the kidney, which contributes to the development that serves as a common mediator for osteoclastic bone
of hypocalcemia and parathyroid stimulation. resorption. This ligand is produced by osteoblast lineage cells
Serum calcium ion (Ca2+) binds to a cell membrane calcium and stimulates differentiation of cells of the osteoclast lineage,
ion receptor on the chief cell, which permits serum Ca2+ to regulate enhances the functional activity of mature osteoclasts, and
chief cell function. The receptor is present on the plasma mem- prolongs osteoclast life by inhibiting apoptosis. Expression
branes of parathyroid chief cells, renal epithelial cells, thyroid of RANKL in osteoblasts/stromal cells is upregulated by
C cells, and other cells that respond to extracellular Ca2+. multiple osteotrophic factors, such as PTH, calcitriol, TNF,
Mutations in one or both of the Ca2+-sensing receptor genes interleukin-1 (IL-1), IL-6, and IL-11. RANKL is identical to
in humans result in familial hypocalciuric hypercalcemia or TNF-related activation-induced cytokine (TRANCE), which
neonatal severe hypercalcemia, respectively. Interaction of stimulates T-cell growth and dendritic cell function.
serum Ca2+ with its receptor on chief cells results in the for- The membrane receptor (RANK) for RANKL is on cells
mation of an inverse sigmoidal relationship between serum of the osteoclast lineage. Binding of RANKL to its receptor
Ca2+ and PTH concentrations. The serum [Ca2+] that results activates signaling pathways in osteoclasts that lead to
in half-maximal PTH secretion is defined as the serum increased functional activity. Osteoclast precursors express
calcium “set-point” and is stable for an individual animal. The RANK, recognize RANKL through cell-to-cell interaction
Calcium-Regulating Hormones 295
with osteoblasts/stromal cells, and differentiate into osteo- hepatocytes. Serum 25-hydroxycholecalciferol concentration
clasts in the presence of macrophage-colony stimulating factor is the best indicator of nutritional vitamin D adequacy in an
(M-CSF). Mice made deficient in RANK by targeted deletion animal. Animals that have ingested excess vitamin D may have
of the gene develop severe osteopetrosis as a result of decreased serum 25-cholecalciferol up to 20-fold greater than normal.
osteoclast function. The inactive metabolite, 25-hydroxycholecalciferol,
Osteoprotegerin (OPG) (“decoy receptor” for RANKL) is is transported to the kidney and hydroxylated to 1,25-
a novel member of the TNF receptor superfamily produced dihydroxycholecalciferol (calcitriol). This is catalyzed by 25-
by cells of the osteoblast lineage/stromal cells and is a negative hydroxycholecalciferol-1-α-hydroxylase (1-α-hydroxylase) in
regulator of bone resorption. When this soluble receptor binds mitochondria, primarily in cells of the proximal convoluted
to RANKL, it prevents it from binding to its receptor, RANK. tubule. The conversion of 25(OH)D3 to 1,25(OH)2D3 (cal-
Overexpression of this decoy receptor in transgenic mice leads citriol) is the rate-limiting step in vitamin D metabolism. The
to osteopetrosis associated with decreased osteoclastic bone control of this final step in the metabolic activation is complex
resorption. In contrast, targeted gene ablation results in osteo- and is regulated in part by the plasma calcium concentration
porosis and arterial mineralization. Osteoclast formation and its influence on the rate of secretion of PTH. PTH stimu-
appears to be determined by the ratio of RANKL to OPG, lates the activity of the 1-α-hydroxylase and the formation of
and alterations in this ratio may be a major cause of bone loss calcitriol. Low blood phosphate increases the formation of
in certain metabolic disorders, such as estrogen deficiency and calcitriol, whereas high blood phosphate suppresses the activ-
glucocorticoid excess. ity of the 1-α-hydroxylase. Serum calcitriol levels are influ-
Binding of PTH to the PTH1 receptors on bone cells results enced by FGF23, which decreases the activity of the renal
in the activation of adenylyl cyclase in the plasma membrane, 1-α-hydroxylase. In addition, FGF23 increases the expression
which catalyzes the conversion of ATP to 3′,5′-adenosine of the 24-hydroxylases, which hydroxylates carbon 24 and
monophosphate (cAMP). PTH also induces an increase in inactivates calcitriol.
cytoplasmic Ca2+ and stimulates phosphatidylinositol turn- Other hormones also may increase the activity of renal
over. Calcium concentration in the osteoblast may also be 1-α-hydroxylase and the formation of calcitriol under certain
increased by the activation of protein kinase C, resulting in conditions. Prolactin, estradiol, placental lactogen, and somato-
the production of inositol triphosphate and subsequent release tropin all enhance 1-α-hydroxylase activity. Increased secre-
of calcium from the endoplasmic reticulum. tion of these hormones, either alone or in combination,
Parathyroid hormone has a rapid (5-10 minutes) and direct appears to be important in the efficient adaptation to major
effect on renal tubular function, leading to decreased reab- calcium demands, such as pregnancy, lactation, and growth.
sorption of phosphate and phosphaturia. The site where PTH
blocks tubular reabsorption of phosphate has been localized Biological action of calcitriol
to the proximal tubule of the nephron. PTH binds to the Calcitriol increases the absorption of calcium and phosphate
PTH1 receptor on the basolateral aspect of renal epithelial from the intestine. From a functional point of view, calcitriol
cells. The PTH1 receptor belongs to the family of G protein– can be thought to bring about the retention of sufficient mineral
linked receptors with 7 transmembrane spanning domains ions to ensure mineralization of bone matrix, whereas parathy-
that activate adenylyl cyclase. PTH also increases the reab- roid hormone maintains the proper ratio of calcium to phosphate
sorption of renal tubular calcium because of a direct action in extracellular fluids.
on the distal convoluted tubule, which is also coupled to an Intestinal cells that transport calcium from the lumen to
increase in intracellular cAMP. the blood stream in response to calcitriol synthesize a specific
The other important effect of parathyroid hormone calcium-binding protein (CaBP, calbindin). CaBP is at the
is the regulation of the conversion of inactive 25- luminal aspect of intestinal absorptive cells, where it com-
hydroxycholecalciferol to biologically active 1,25- plexes with calcium ions for transport to the basolateral aspect
dihydroxycholecalciferol (calcitriol). of the cell. Calcium-binding protein has also been isolated
from kidney, parathyroid gland, bone, cartilage, and the shell
gland of laying hens. The absorptive capacity of the intestine for
Cholecalciferol (vitamin D3) calcium is a direct function of the amount of CaBP present. The
Biosynthesis of 1,25-dihydroxycholecalciferol physiologic function of CaBP may be to protect absorptive
(calcitriol) cells against high cytosolic concentrations of Ca2+. At the
The second major hormone involved in the regulation of basilar aspect of intestinal absorptive cells, calcium is
calcium metabolism and skeletal remodeling is the active form exchanged for sodium and enters the extracellular fluids.
of vitamin D, calcitriol. Calcitriol acts on bone both directly and indirectly. Cal-
Cholecalciferol is ingested in small amounts in the diet and citriol stimulates osteoclastic bone resorption by inducing
can be synthesized in the epidermis from precursor molecules. RANKL and increasing the number and activity of osteoclasts.
This reaction is catalyzed by ultraviolet irradiation (wave- In contrast, calcitriol stimulates FGF23 expression by osteo-
lengths 290-320 nm) from the sun. A high-affinity vitamin cytes in bone, which inhibits PTH secretion, inhibits renal
D–binding protein transports cholecalciferol in the blood. 1-α-hydroxylase, and increases renal phosphate excretion.
Vitamin D must be metabolically activated before it can Small amounts of calcitriol are necessary to permit osteolytic
produce its known physiologic functions. Endogenous chole- cells to respond to parathyroid hormone (“permissive effect”)
calciferol synthesized in the skin from 7-dehydrocholesterol under physiologic conditions. Both 25-hydroxycholecalciferol
also is protein-bound for transport to the liver. In the liver, and calcitriol, in pharmacologic doses, stimulate osteoclastic
cholecalciferol is converted to 25-hydroxycholecalciferol by a resorption of bone.
hepatic microsomal enzyme, cholecalciferol-25-hydroxylase, Less is known regarding the action of calcitriol on the
which is associated with the endoplasmic reticulum in kidney, but it appears to stimulate the retention of calcium by
296 CHAPTER 3 • Endocrine Glands Calcium-Regulating Hormones
increasing renal tubular reabsorption, probably in the distal PTH results in reduced FGF23 concentrations and decreased
part of the nephron. renal Klotho expression.
Calcitriol has important effects on the parathyroid chief Diseases associated with mutations in either Klotho or
cells, where it inhibits PTH synthesis and secretion and FGF23 are described in humans. Familial hyperphosphatemic
increases of the expression of the VDR, CaSR, and Klotho. tumoral calcinosis is caused by inactivation of the FGF23 gene,
but also occurs with inactivation of Klotho. A gain-of-function
Disorders of vitamin D metabolism mutation of FGF23 leads to autosomal dominant hypophos-
Lack of vitamin D causes rickets and osteomalacia in young phatemic rickets caused by renal loss of phosphate. FGF23
and mature animals, respectively (see Vol. 1, Bones and joints). levels were analyzed in cats and appear to be elevated in cases
Deficiency of vitamin D results not only from simple dietary of CKD. Some mesenchymal tumors secrete excessive FGF23
lack or inadequate exposure to sunlight, but also from a defi- and cause tumor-associated hypophosphatemia. The detection
ciency of the hydroxylase enzymes essential for metabolic of FGF23 and its mechanisms of action has propelled bone
activation of precursor molecules. Vitamin D–dependent from being viewed as mainly providing storage for calcium
rickets, type I, in both pigs and humans, is a familial disease and phosphate to being an active partner in the parathyroid
inherited as an autosomal recessive disorder. Newborn pigs gland (PTG)-kidney-bone axis and function as an endocrine
appear healthy and have normal blood calcium and phosphate organ.
concentrations. At 4-6 weeks of age, blood Ca and P decrease,
serum alkaline phosphatase activity increases, and clinically
detectable rickets develops during the following 3-4 weeks. Thyroid C cells and calcitonin
The pigs develop deformities of bone in the axial and appen- Development and structure of thyroid C cells
dicular skeleton, severe pain, and classic lesions of rickets. Another calcium-regulating hormone, calcitonin, which is
Serum 25-cholecalciferol levels are markedly increased com- secreted by the thyroid C cells in response to hypercalcemia,
pared to those of control pigs, whereas serum calcitriol levels lowers plasma calcium. C cells are distinct from follicular
are depressed in rachitic pigs compared with normal pigs. cells. They are situated either within the follicular wall
Homozygous animals have no renal 1-α-hydroxylase. Vitamin between follicular cells or as small groups between follicles.
D–dependent rickets caused by mutations in the CYP27B1 They do not border the follicular colloid directly, and their
gene that encodes the renal 1-α-hydroxylase has been identi- secretory polarity is oriented toward the interfollicular
fied in individual cats. capillaries.
Vitamin D–dependent rickets, type II, also called vitamin The ultimobranchial body (last, and usually fifth, pharyn-
D–resistant rickets (VDRR), is a group of disorders resulting geal pouch), which delivers the neural crest–derived C cells
from defective VDRs. The disease is characterized by increased to the postnatal thyroid gland, fuses with each thyroid lobe at
serum calcitriol levels, hypocalcemia, secondary hyperpara- the hilus and distributes C cells throughout each lobe to
thyroidism, and clinically by rickets or osteomalacia. New various degrees in different species. In submammalian species,
World primates have a relative end-organ resistance to cal- C cells and calcitonin activity remain segregated in the ulti-
citriol and require high levels of vitamin D3 in their diet. The mobranchial gland, which is anatomically distinct from both
common marmoset has been shown to represent a model of the thyroid and the parathyroid glands.
vitamin D–dependent rickets, type II. Marmosets have In the dog and other species, nodular aggregates of C cells
increased serum calcitriol concentrations compared to rhesus frequently persist along the course of the blood vessels to the
monkeys, and some marmosets developed osteomalacia even hilus of the thyroid, which occasionally contain ultimobranchial-
when on high vitamin D3 diets. Vitamin D–dependent rickets, derived, colloid-containing follicles. Islands of C cells, termed
type II, has also been reported in individual cats. C-cell complexes, are present in the thyroid glands (especially
prominent in dogs) often near the internal parathyroid gland
Fibroblast growth factor-23 (FGF23) and should not be misinterpreted as areas of C-cell hyperpla-
Fibroblast growth factor-23 is a 32-kDa protein that is pro- sia. C-cell complexes contain follicular cells (that stain posi-
duced by osteocytes and osteoblasts. It belongs to the so- tive for thyroglobulin), typical C cells, stellate cells that form
called endocrine FGFs and requires a cofactor to activate its follicle-like structures (that stain positive for somatostatin),
receptor FGFR1. The presence of the cofactor, the membrane- and undifferentiated cells. The C-cell complex may be the
spanning protein Klotho, defines the cells on which FGF23 origin of the unique mixed thyroid carcinoma in human
can act. These include the parathyroid chief cells and proximal patients or ultimobranchial thyroid neoplasms in bulls that are
renal tubules as well as tissues not primarily involved in composed of cells that have positive immunoreactivity for
mineral metabolism, such as the choroid plexus and vascular both thyroglobulin and calcitonin. This suggests that the ulti-
tissue. mobranchial body may contribute to the formation of thyroid
FGF23 regulates serum phosphate by negative feedback follicles in certain areas of the thyroid lobes.
mechanisms involving the kidney and parathyroid. In the Cysts derived from remnants of the ultimobranchial body
kidney, FGF23 increases phosphate excretion in the proximal can be observed in the postnatal thyroid and are lined by
tubules by inducing the expression of cotransporters in the squamous epithelium and contain keratin debris. Occasional
brush border. In addition, FGF23 suppresses calcitriol produc- follicles derived from ultimobranchial primordia contain het-
tion in the kidney by inhibiting the 1-α-hydroxylase and erogeneous material and scattered ciliated epithelial cells in
promoting calcitriol catabolism by increasing 24-hydroxylase the follicular wall.
activity. FGF23 decreases PTH mRNA expression and secre- The concentration of Ca2+ in plasma and extracellular fluids
tion in chief cells. Production of FGF23 in the bone is stimu- is the principal physiologic stimulus for the secretion of calcitonin
lated by calcitriol and PTH. In bone, FGF23 expression is by C cells. The rate of calcitonin secretion is increased greatly
activated by the VDR/retinoic X receptor complex. Decreased in response to elevations in blood calcium. C cells have the
Calcium-Regulating Hormones 297
Figure 3-33 Parathyroid gland from a dog, with multinucleated Figure 3-35 Lymphocytic parathyroiditis in a dog with hypocal-
syncytial cells. The cytoplasm of syncytial cells is densely eosino- cemia. There is marked lymphoplasmacytic inflammation and no
philic, and the plasma membranes between adjacent cells are normal chief cells remaining. There are multiple areas of nodular
indistinct. The nuclei are small, hyperchromatic, and oval. regenerative hyperplasia of chief cells (arrowheads) with mild
inflammatory cell infiltration.
during the course of surgery to remove thyroid tumors or Functional disturbances associated with hypocalcemia in
multifocal hyperplasia. Regeneration of adequate functional cows are related to paresis, whereas, in the bitch, they are
parenchyma and subsequent disappearance of clinical signs is primarily the result of neuromuscular tetany. The occurrence
generally possible, depending on the severity of damage to of either tetany or paresis in response to hypocalcemia appears to
parathyroid glands or their vascular supply. Agenesis of both be the result of basic physiologic differences in the function of the
pairs of parathyroids is a rare cause of congenital hypopara- neuromuscular junction of the cow and the bitch. The release of
thyroidism in pups. acetylcholine and transmission of nerve impulses across neu-
romuscular junctions are blocked by hypocalcemia in cows
Parathyroid stimulation associated with acute (but not in the bitch), leading to muscle paresis. Excitation-
hypocalcemia near parturition secretion coupling is maintained at the neuromuscular junc-
Parturient paresis is a complex metabolic disease characterized tion in the bitch with hypocalcemia, and tetany occurs as a
by the development of severe hypocalcemia and hypophosphate- result of spontaneous repetitive firing of motor nerve fibers.
mia near parturition and the initiation of lactation in dairy cattle.
Lactation requires high levels of calcium, exceeding the ani- Parathyroid hyperplasia
mal’s ability to mobilize sufficient calcium, and disease inci- Focal (nodular) hyperplasia. Chief cell hyperplasia may affect
dence is higher in older cows. In parturient paresis (also called the parathyroids in a distinctly focal or multifocal distribution
milk fever), the serum calcium (total and ionized) concentra- (Fig. 3-36A, B). In focal parathyroid hyperplasia, there are
tion falls to <50% of normal in spite of increased secretion of single or multiple nodules in one or both glands in which there
parathyroid hormone. The composition of the prepartum diet is an increased number of chief cells, often with an expanded
is a significant factor in the pathogenesis of parturient hypo- cytoplasmic area. The foci of chief cell hyperplasia are not
calcemia. High-calcium diets increase the incidence of the encapsulated and are poorly demarcated from adjacent
disease, and low-calcium diets or prepartum diets supple-
mented with pharmacologic doses of vitamin D reduce the
incidence of the disease. Calcium homeostasis in pregnant
cows fed a high-calcium diet appears to be maintained prin-
cipally by intestinal calcium absorption. This greater reliance
on intestinal absorption than on PTH-stimulated bone resorp-
tion is a significant factor in the more frequent development
of profound hypocalcemia near parturition. The parathyroid
glands respond to the acute hypocalcemia by increased syn-
thesis and secretion of PTH, and there are increased serum
PTH concentrations. The increased rate of hormone secretion
exceeds the rate of synthesis by the gland.
Cows fed a high-calcium diet have higher blood calcium levels
prepartum, but are less able to maintain serum calcium near the
critical time of parturition. Plasma PTH levels are lower pre-
partum than in cows fed a balanced diet, and decline further
at 48 hours postpartum. Inactive chief cells predominate in
cows fed high-calcium diets, whereas actively synthesizing A
chief cells are most numerous in parathyroids of cows fed
balanced prepartum diets. In response to the elevated blood
calcium in cows fed high-calcium prepartum diets, the C cells
are stimulated to secrete calcitonin, which decreases bone
turnover and osteoclast numbers prior to parturition.
Calcium homeostasis in cows fed balanced or relatively low-
calcium diets prepartum appears to be more under the fine control
of PTH secretion with the approach of parturition. The higher
levels of PTH secreted during the prepartum period by an
expanded population of actively synthesizing chief cells results
in a larger pool of active osteoclasts to fulfill the increased
needs for calcium mobilization at the critical time near par-
turition and the initiation of lactation.
Less is known about the development of hypocalcemic
syndromes in animal species other than in the cow. In dogs,
puerperal tetany (eclampsia) is most frequently encountered B
in the small, hyperexcitable breeds. The clinical course is rapid
and the bitch may proceed from premonitory signs of restless- Figure 3-36 Multinodular chief cell hyperplasia in a dog with
ness, panting, and nervousness to ataxia, trembling, muscular primary hyperparathyroidism. A. Note the multifocal, poorly
tetany, and convulsive seizures in 8-12 hours. There is no demarcated nodules of chief cell hyperplasia (arrowheads) that
evidence to suggest that puerperal tetany in heavily lactating are paler because of hypertrophy of the cytoplasm. B. Focal
bitches is the result of interference in PTH secretion. Supple- nodular hyperplasia (left), with hypertrophied chief cells contain-
mental dietary calcium and vitamin D have proven useful in ing abundant eosinophilic cytoplasm. The atrophied normal chief
preventing relapses in certain bitches with puerperal tetany. cells are on the right.
300 CHAPTER 3 • Endocrine Glands Calcium-Regulating Hormones
↑ FGF23
↓ PO4
excretion
A
↑ PTH ↓ Calcitriol
B
eosinophilic with occasional distinct vacuoles. A more promi-
Figure 3-37 Diffuse chief cell hyperplasia. A. Enlargement of the nent fibrovascular stroma in some diffusely hyperplastic para-
external and internal parathyroid glands in a cat with chronic thyroids may result in a lobulated appearance, and in others,
kidney disease. Bar = 5 mm. B. Hypertrophied and hyperplastic chief cells form distinct acinus-like structures.
chief cells from a dog are closely packed with narrow perivascular
spaces and abundant cytoplasm. Hyperparathyroidism secondary to renal disease
Secondary hyperparathyroidism as a complication of chronic
kidney disease (CKD) is characterized by excessive production
parenchyma. Chief cells within the nodules have a relatively of PTH. When renal disease reaches the point at which there
uniform composition with a high cytoplasm to nucleus ratio is a significant reduction in glomerular filtration rate, phos-
and a slightly more hyperchromatic nucleus than adjacent phate is retained. Early increases in serum fibroblast growth
normal chief cells. There may be slight compression of adja- factor-23 (FGF23) concentrations from osteoblasts and osteo-
cent chief cells around larger areas of focal hyperplasia. Focal cytes are a compensatory reaction and often occur before
chief cell hyperplasia often is difficult to separate from a chief hyperphosphatemia develops (Fig. 3-38). Initially, elevated
cell adenoma by using only morphologic criteria. The presence blood FGF23 depresses the renal 1-α-hydroxylase activity. In
of multiple nodules of various sizes and uniform cellularity in one the later stage of CKD, there are also decreased numbers of
or both parathyroids with minimal compression and no fibrous renal tubular epithelial cells that contain the 1-α-hydroxylase
encapsulation is more compatible with focal hyperplasia than to form the active form of vitamin D (calcitriol). Early stages
chief cell adenoma. Focal or multifocal nodular chief cell of chronic renal failure (CRF) are often associated with normal
hyperplasia is often associated with primary hyperparathy- concentrations of circulating calcitriol (even with the loss of
roidism and may require surgical removal of multiple or all nephrons) resulting from the effects of increased PTH on
parathyroid glands to control the clinical syndrome. renal 1-α-hydroxylase to enhance renal tubular synthesis of
Diffuse hyperplasia. Parathyroid hyperplasia, such as seen calcitriol. Animals with advanced CRF have decreased circu-
with chronic renal failure and long-term dietary imbalances, lating concentrations of calcitriol because of decreased renal
results in uniform enlargement of all parathyroid glands as a synthesis. Calcitriol is an important regulator of parathyroid
result of both hypertrophy and hyperplasia of chief cells (Fig. chief cell function and decreases PTH mRNA expression
3-37A). There is not a peripheral rim of compressed atrophic and increases expression of the vitamin D receptor (VDR).
parathyroid parenchyma as occurs around a functional Decreased circulating levels of calcitriol in animals with CKD
adenoma, but rather a uniform population of hyperplastic chief result in chief cell hyperplasia and increased secretion of intact
cells extending to the capsule of the gland. The chief cells often PTH. In an experimental model of CKD, anti-FGF23 antibod-
are packed together with indistinct cell boundaries, and peri- ies reversed these effects; however, this resulted in hyperphos-
vascular spaces are narrow (Fig. 3-37B). The expanded cyto- phatemia. Although increased serum FGF23 is a potential
plasmic area of chronically stimulated chief cells is lightly indicator of early renal disease, the presence of increased PTH
Calcium-Regulating Hormones 301
Hyperparathyroidism secondary to
nutritional imbalances
Nutritional secondary hyperparathyroidism occurs in cats,
dogs, certain nonhuman primates, horses, domestic, wild and
captive birds, and reptiles. The increased secretion of parathy-
roid hormone is a compensatory mechanism directed against
a disturbance in mineral homeostasis induced by diets with
either low calcium or excessive oxalate content, or high phosphate
with normal or low calcium content. Inadequate vitamin D3, Figure 3-39 Vitamin D intoxication from Solanum glaucophyl-
besides causing rickets, also causes lesions of secondary hyper- lum (Enteque seco in Argentina). Contraction of tendons and
parathyroidism in some species. The significant result of these kyphosis in affected cow. Inset: Kneeling stance caused by inabil-
imbalances is hypocalcemia, which results in parathyroid ity to straighten the front legs. (Courtesy E.J. Gimeno, La Plata
stimulation. In response to the diet-induced hypocalcemia, University, Argentina.)
chief cells undergo hypertrophy and eventually hyperplasia
(see Fig. 3-37A). The expanded cytoplasmic area is lightly
eosinophilic and vacuolated compared with chief cells in dried leaves of Solanum glaucophyllum contain a steroid-
normal animals. Perivascular spaces are narrow, and there are glycoside conjugate in which the steroidal component is iden-
few fat cells in the interstitium. The skeletal lesions of nutri- tical to 1,25(OH)2D3. The leaves are not palatable when
tional hyperparathyroidism are discussed in Vol. 1, Bones and green, but are eaten readily when dry. The calcinogenic plants
joints. appear to produce disease only in herbivores after ingestion
of leaves. Intoxication produces rapid wasting and marked
Primary parathyroid hyperplasia elevations of the calcium and phosphate levels in the blood.
Primary parathyroid hyperplasia has been described in German The patterns of these elevations of blood electrolytes as well as the
Shepherd pups associated with hypercalcemia, hypophospha- soft tissue mineralization are comparable to those produced by
temia, increased serum parathyroid hormone, and increased intoxication by vitamin D. The leaves of S. glaucophyllum are
fractional clearance of inorganic phosphate in the urine. remarkably potent, with as little as 2 g being capable of pro-
Clinical signs included stunted growth, muscular weakness, ducing elevations of calcium and phosphate in the blood of
polyuria, polydipsia, and diffuse reduction in bone density. adult cattle. The typical wasting syndrome is seen clinically
Intravenous infusion of calcium failed to suppress the autono- when animals are forced to eat large quantities of the leaves.
mous secretion of parathyroid hormone by the diffuse hyper- The animals develop kyphosis with contraction of the tendons
plasia of chief cells in all parathyroids. Lesions included and ligaments, resulting in an inability to completely straighten
nodular hyperplasia of thyroid C cells and widespread miner- their front limbs and a kneeling posture (Fig. 3-39). Contrac-
alization of lungs, kidney, and gastric mucosa. The disease is tion of the abdominal aponeurosis gives a unique tucked-up
inherited as an autosomal recessive trait. line to the abdomen, resulting in affected animals having a
racehorse-like appearance. Many animals develop severe vas-
Parathyroid suppression associated with cular and pulmonary disease as a result of irregular or occa-
vitamin D intoxication from calcinogenic sional exposure to the plant because of mineralization and
plants and rodenticides ossification of interalveolar septa in the lung.
Livestock grazing on various calcinogenic plants develop a pro- Diseases associated with the ingestion of calcinogenic plants
gressive debilitating disease with widespread mineralization of are not restricted to cattle but also occur in goats, sheep, and
soft tissues. Cestrum diurnum (day-blooming jessamine) in horses, although with lesser frequency and severity. Adult
Florida and elsewhere in the southern United States, and animals are most commonly affected, usually producing pro-
Trisetum flavescens in the Bavarian and Austrian Alps cause gressive debility. The earliest signs are those of stiffness and
calcinosis in horses, cattle, and sheep. Solanum glaucophyllum wasting. There is subtle progression to permanent lameness
(formerly malacoxylon) in Argentina and Brazil produces the resulting from contraction of the tendons. At this stage,
disease enteque seco or espichamento in cattle, which is char- affected animals often are excitable, tire easily if made to
acterized by the development of hypercalcemia, hyperphos- exercise, and may show signs of acute cardiac insufficiency. If
phatemia, and severe soft tissue mineralization. Morphologically they are removed from affected areas, the stiffness and defor-
similar diseases occur in Jamaica (Manchester wasting disease) mity are not lessened, but the wasting is stopped, and the
and Hawaii (Naalehu disease). Other plants that contain animals gain weight if good pasture is available.
calcitriol-like activity are Solanum torvum, S. verbascifolium, Autopsy reveals widespread mineralization of tissues, particu-
Dactylis glomerata, and Medicago sativa. Sporadic cases of larly the aorta, heart, and lungs, often with areas of ossification
extensive mineralization occur in cattle throughout the world. (Fig. 3-40A, B). Small mineralized blood vessels are encoun-
The leaves of these calcinogenic plants contain a tered in the subcutis, and mineralized plaques are present on
substance(s) possessing calcitriol-like biologic activity. The the parietal and visceral pleura. Portions of the lungs fail to
302 CHAPTER 3 • Endocrine Glands Calcium-Regulating Hormones
A B
Figure 3-40 Mineralization in poisoning by Solanum glaucophyllum. A. Cow heart and aorta.
B. Goat aorta. (Courtesy E.J. Gimeno, La Plata University, Argentina).
collapse, and these represent areas of mineralization in which amounts of the 25-hydroxyvitamin D are converted to cal-
the parenchyma is disrupted and emphysematous. The pul- citriol, which is present in the circulation at normal to
monary lesions primarily involve the caudal lobes and consist subnormal levels. This is because of inhibition of renal 1-α-
of irregular thickening of alveolar septa resulting from miner- hydroxylase by low serum PTH, hypercalcemia, hyperphos-
alization and collagen deposition. The opened heart often phatemia, and negative feedback from 25-hydroxyvitamin D
reveals mineralization of the right atrium but not of the right that binds to the vitamin D receptor. The hypercalcemia of
ventricle. The endocardial mineralization is most severe in the hypervitaminosis D is usually accompanied by hyperphospha-
atrium and ventricle (chiefly the basal portion of the latter) temia (because vitamin D also increases intestinal absorption
also involving the semilunar cusps, the bicuspid valve, and of phosphate in addition to calcium) and normal serum alka-
chordae tendineae, and extending into the aorta. The aortic line phosphatase activity. Skeletal disease is not a consistent
mineralization in early cases is restricted to the areas around feature, because the increased concentrations of blood calcium
orifices of large branches, but in advanced cases, it is more and phosphate are derived principally from augmented intes-
diffuse. In advanced cases of intoxication, many small arteries, tinal absorption; however, widespread mineralization of soft
especially the coronary and mesenteric arteries, are mineral- tissue occurs similar to animals ingesting calcinogenic plants.
ized severely but irregularly. The arterial mineralization begins
in the intima and, with continuous accretion, extends to the Neoplasms of the parathyroid glands
media disrupting the elastic laminae of the vessels. Histologi- Functional adenomas and carcinomas of parathyroid glands
cally, areas of mineralization are localized to the mucosa of secrete parathyroid hormone in excess of normal, causing a syn-
the abomasal fundus as well as in other fibroelastic tissues. drome of primary hyperparathyroidism. The normal control
Mineralization of ligaments and of the fibrocartilaginous por- mechanism for parathyroid hormone is lost, and hormone
tions of tendons is responsible for the stiffness, along with the secretion is excessive in spite of an increased level of blood
degenerative arthropathy that usually is present in affected calcium. Cells of the renal tubules are sensitive to alterations
animals. in the amount of circulating parathyroid hormone. The
In chronic cases, the bones become extremely dense as new excretion of phosphate and retention of calcium initially are
trabeculae are formed in the marrow spaces. These trabeculae enhanced. A prolonged increased secretion of parathyroid
appear to develop in an atypical basophilic matrix similar to hormone accelerates osteoclastic bone resorption and results
that deposited in vitamin D poisoning (see Vol. 1, Bones and in generalized fibrous osteodystrophy.
joints). Parathyroid chief cells appear initially to accumulate Adenomas of parathyroid glands are encountered in older
secretory granules after feeding S. glaucophyllum and later to animals, particularly dogs, occasionally cats, and rarely in
undergo involution and atrophy. horses. Keeshonds appear to have a genetic predisposition to
The incidence of hypercalcemia resulting from vitamin D the development of chief cell adenomas. Tumors of parathy-
intoxication in small animals has increased because of use of roid chief cells in animals are not sequelae of long-standing
vitamin D (cholecalciferol) as a pesticide and rodenticide. The secondary hyperparathyroidism of renal or nutritional origin.
ingested vitamin D is converted to 25-hydroxyvitamin D in Chief cell adenomas usually result in considerable enlarge-
the liver and is the major toxic metabolite. 25-Hydroxyvitamin ment of a single parathyroid gland (Fig. 3-41A). They are light
D has a much reduced binding affinity for the vitamin D brown to red and are located either in the cervical region close
receptor (500- to 1,000-fold) than calcitriol, but is present to the thyroids or infrequently within the thoracic cavity near
at such high concentrations that it stimulates hypercalcemia the base of the heart. Parathyroid neoplasms in the precardiac
by increasing intestinal absorption of calcium. Only small mediastinum are derived from ectopic parathyroid tissue,
Calcium-Regulating Hormones 303
A B
C D
Figure 3-41 Functional chief cell adenoma. A. Adenoma from a dog (left) that is well demarcated
and encapsulated. The thyroid gland is on the right. B. The chief cells of the adenoma (bottom)
are large with karyomegaly and abundant cytoplasm. There is a fibrous capsule with a dilated
venule. There is a thin rim of atrophied, normal chief cells with small nuclei and minimal cytoplasm
(top). C. The neoplastic chief cells have variable sized nuclei with karyomegaly. There are thin
bands of fibrous connective tissue that separate the chief cells. D. Adenoma from a horse with
primary hyperparathyroidism. The neoplasm is composed predominantly of water-clear chief cells.
displaced into the thorax with the expanding thymus during may be distributed throughout the adenoma. Some parathy-
embryonic development. Parathyroid adenomas are sharply roid adenomas are composed predominantly of large eosino-
demarcated and encapsulated from the adjacent thyroid gland. philic oxyphil cells or water clear cells (Fig. 3-41D). Adipose
Multiple white foci may be seen in the thyroids of dogs with cells and mast cells often are present in the stroma of
functional parathyroid tumors. These represent areas of C-cell adenomas.
hyperplasia in response to the long-term hypercalcemia. A Adenomas may compress the adjacent thyroid gland. A rim
parathyroid adenoma will enlarge a single gland to a great of compressed and atrophic parathyroid parenchyma usually
degree, and the remaining parathyroids will be atrophic. In is present outside the capsule of a small adenoma (see Fig.
comparison, all 4 parathyroids are enlarged 2-5 times normal 3-40B). In an animal with a functional parathyroid adenoma,
size in secondary hyperparathyroidism. Histologic demonstra- the remaining, non-neoplastic parathyroid tissue is chronically
tion of a compressed rim of parathyroid parenchyma and a suppressed by the elevated serum calcium. The atrophic chief
partial-to-complete fibrous capsule in an enlarged gland points cells are small, irregular in shape, have a small amount of
to the diagnosis of adenoma rather than chief cell hyperplasia densely eosinophilic cytoplasm and basophilic nuclei, and may
(Fig. 3-41B). contain cytoplasmic lipofuscin or lipid (see Fig. 3-41D). The
Parathyroid adenomas are composed of closely packed adenomas and the atrophied chief cells will stain immunohis-
chief cells subdivided into small groups by fine connective tochemically positive for cytoplasmic PTH 1-34 or 1-84 and
tissue septa with many capillaries. Neoplastic cells may pali- chromogranin A.
sade around small blood vessels. The chief cells are cuboidal Parathyroid adenomas usually are slow growing and can be
or polyhedral, and the cytoplasm stains lightly eosinophilic surgically excised without difficulty. Successful removal of a
(Fig. 3-41B, C). Some neoplastic chief cells may have functional parathyroid adenoma results in a rapid decrease in
karyomegaly, but this is not an indicator of malignancy. Occa- circulating parathyroid hormone levels, because the half-life
sional oxyphil cells, water clear cells, and transitional forms of parathyroid hormone in plasma is short (~5 minutes).
304 CHAPTER 3 • Endocrine Glands Calcium-Regulating Hormones
A B
C D
Figure 3-42 Parathyroid carcinoma in a cat. A. The carcinoma (in multiple nodules, at arrow-
heads) has invaded the thyroid gland and its capsule with formation of a large cyst (C). The thyroid
gland contains a central thyroid adenoma (T). The normal external parathyroid gland is also
present (arrow). B. The carcinoma is poorly demarcated and invasive into the normal thyroid
parenchyma. C. The parathyroid carcinoma and normal parathyroid gland (arrowhead) are immu-
nohistochemically positive for parathyroid hormone (PTH) 1-34. Note that some regions of the
carcinoma are negative for PTH. D. The parathyroid carcinoma is immunohistochemically negative
for thyroglobulin. The normal thyroid follicles and thyroid follicular adenoma are immunohisto-
chemically positive for thyroglobulin.
Plasma calcium levels in animals may decrease rapidly following periglandular connective tissues. Parathyroid carcinomas will
surgical removal and reach subnormal levels within 12-24 stain immunohistochemically positive for PTH and chromo-
hours, resulting in life-threatening hypocalcemic tetany. Infu- granin A and negative for thyroglobulin (Fig. 3-42C, D).
sion of calcium gluconate, feeding a high-calcium diet, and Primary hyperparathyroidism. The clinical disturbances
supplemental vitamin D therapy will correct this postopera- observed with functional parathyroid tumors primarily are
tive complication. the result of the persistent hypercalcemia and a weakening of
Parathyroid carcinomas are larger than adenomas and bones caused by excessive resorption. Hypercalcemia results
invade the capsule and adjacent structures (e.g., thyroid glands in anorexia, vomiting, constipation, depression, polyuria,
and cervical muscles) (Fig. 3-42A-D). Metastasis to regional polydipsia, and generalized muscular weakness because of
lymph nodes and lung is possible, but rare. Parathyroid carci- decreased neuromuscular excitability. Cortical bone in long-
nomas are uncommon in animals but have been observed in standing cases is thinned as a result of increased resorption by
dogs and cats. Parathyroid carcinomas are composed of chief osteoclasts stimulated by the autonomous secretion of PTH.
cells with a highly variable development of cytoplasmic organ- Lameness caused by fractures of long bones may occur after
elles, and the malignant chief cells may form follicles. Large relatively minor physical trauma. Compression fractures of
cystic spaces lined by cuboidal to flattened chief cells may be vertebral bodies can exert pressure on the spinal cord and
seen in cats, which may be identified by ultrasound examina- nerves, resulting in motor or sensory dysfunction, or both.
tion of the neoplasms prior to surgery (see Fig. 3-42A). Altera- Facial hyperostosis resulting from extensive osteoblastic pro-
tions of the nuclear morphology are present. There is usually liferation and deposition of poorly mineralized osteoid, and
a greater degree of cellular pleomorphism than in chief cell loosening or loss of teeth from alveolar sockets, has been
adenomas with more frequent mitotic figures and microscopic observed in dogs with primary hyperparathyroidism (Fig.
evidence of invasion into the adjacent parathyroid, thyroid, or 3-43A, B). They usually have a history of multiple fractures
Calcium-Regulating Hormones 305
Metastatic Hematologic
tumors malignancies
Ca
Ca
Cancer-associated
Ca hypercalcemia Ca
Humoral hypercalcemia
of malignancy
Ca
Tumor
Ca
Humoral factors
(Fig. 3-45). Many of the humoral factors produced by tumor neoplasms secrete parathyroid hormone (PTH) or PTH-like
cells that alter calcium metabolism and bone resorption can substances; however, native PTH is not produced by the vast
also be produced by osteogenic cells, such as osteoblasts. majority of neoplasms associated with HHM. Immunoreactive
The clinical syndrome of HHM in animals mimics primary PTH levels are normal or low in patients with HHM, and the
hyperparathyroidism, and a term used previously to describe tumors do not produce PTH mRNA. There are well-validated
HHM was “pseudohyperparathyroidism.” However, HHM does reports of ectopic production of PTH by some tumors, but
not mimic hyperparathyroidism in all aspects, as there are these occurrences are uncommon.
distinct differences in bone remodeling and vitamin D metab- Purification of the responsible factor from neoplasms asso-
olism between patients with HHM or with primary hyper- ciated with HHM resulted in the discovery of the hormone
parathyroidism. The most consistent feature of HHM in animals PTHrP. PTHrP plays a central role in the pathogenesis of
is increased osteoclastic bone resorption distant to the site of the HHM because it is a consistent feature of HHM and shares
neoplasm (Fig. 3-46). Other features include hypercalciuria, most or all of the biological activities of PTH. PTHrP acts
decreased fractional excretion of calcium, increased nephrog- alone in some forms of HHM but may act synergistically or
enous 3′,5′-cyclic adenosine monophosphate (cAMP), hypo- additively with other humoral factors in the pathogenesis of
phosphatemia, and hyperphosphaturia. hypercalcemia (see Fig. 3-45).
The similarities of these clinicopathologic alterations to Humoral hypercalcemia of malignancy occurs as a sponta-
hyperparathyroidism initially led to the hypothesis that the neous disease in domestic and laboratory animals. Malignant
neoplasms that are commonly associated with HHM in
animals include the adenocarcinoma derived from apocrine
glands of the anal sac in dogs (Fig. 3-47A-C), some T-cell lym-
Humoral factors and HHM phomas of dogs, multiple myeloma, and miscellaneous carcinomas
that sporadically induce HHM in various species, such as cats
Humoral factors Ca and horses (gastric squamous cell carcinoma). The dog is most
(ILs, TNFs, TGFs, etc.) often affected. HHM occurs in ~30% of dogs with T-cell lym-
Ca
phoma (usually thymic or multicentric forms) and in the
Synergy majority of dogs with adenocarcinomas derived from apocrine
Tumor or glands of the anal sac. Cats also infrequently develop apocrine
additivity
gland carcinomas of the anal sac, but HHM does not occur.
Lymphoma is a relatively common tumor in older, large-breed
PTHrP dogs, whereas the apocrine adenocarcinoma is less common.
Ca
There are 3 primary mechanisms by which humoral factors
can induce hypercalcemia:
Figure 3-45 Multiple humoral factors can act additively or syn- 1. Stimulation of osteoclastic bone resorption.
ergistically to induce hypercalcemia associated with humoral 2. Increase in calcium reabsorption from the kidney.
hypercalcemia of malignancy (HHM). ILs, interleukins; PTHrP, 3. Increase in calcium absorption from the intestine.
parathyroid hormone–related protein; TGFs, transforming growth Increased osteoclastic bone resorption is a fundamental
factors; TNFs, tumor necrosis factor. (From Rosol TJ, Capen CC. component of the pathogenesis of hypercalcemia and is a
Lab Invest 1992;67:680-702.) consistent feature of HHM. The kidney also plays a central
Na Ca
GFR
Ca Ca cAMP
R PTHrP
Osteoblasts
Osteoclastic
bone resorption
Ob
Ob
Figure 3-49 Atrophic parathyroid gland from a dog with humoral Figure 3-50 Hypercalcemic dog with lymphoma of bone marrow
hypercalcemia of malignancy. Narrow cords of atrophic chief cells (von Kossa tetrachrome stain). Several osteoclasts are present in
are separated by interstitial spaces with increased connective lacunae (arrowheads). Hyperplastic osteoblasts (Ob) and promi-
tissue. nent osteoid seams (light blue) are present adjacent to eroded
trabecular surfaces. (From Meuten DJ, et al. Lab Invest
1983;49:553-562.)
fetal and adult parathyroid glands, adenohypophysis, thyroid
C cells); skeletal, cardiac, and smooth muscle; kidney; bone;
lactating mammary gland; lymphocytes; macrophages; lung; Hypercalcemia with tumors metastatic to bone. Solid
skin; brain; pancreatic islets; testis; prostate; urinary bladder; tumors that metastasize widely to bone can produce hypercalce-
gastrointestinal tract; blood vessels; ovary; uterus; placenta; mia by the induction of local bone resorption associated with
and avian oviduct. Present evidence suggests that PTHrP acts as tumor growth. This is not common in animals, but is an impor-
an autocrine or paracrine regulator in normal tissues, having an tant cause of cancer-associated hypercalcemia in human
important role in development, differentiation, and cell function. beings. Tumors that often metastasize to bone and induce
PTHrP is involved in normal longitudinal bone growth and hypercalcemia in human patients include breast and lung
tooth eruption in addition to its role of transferring calcium carcinomas. The pathogenesis of enhanced bone resorption is
across the placental membranes. PTHrP is expressed by renal not completely understood, but the 2 primary mechanisms
glomeruli, where it may influence blood flow, and overexpres- include (1) secretion of cytokines or factors that stimulate
sion plays a role in the development of renal hypertrophy. local bone resorption, and (2) indirect stimulation of bone
PTHrP may be involved in the promotion of renal fibrosis as resorption by tumor-induced cytokine secretion from local
a result of epithelial-mesenchymal transition. In humans with immune or bone cells. Cytokines or factors that may be
diabetes mellitus type 2, serum PTHrP levels are increased, secreted by tumor cells and stimulate local bone resorption
but the physiologic significance is uncertain. PTHrP is impor- include PTHrP, transforming growth factor-α and -β, and pros-
tant in the embryonic development of the mammary glands, taglandins (especially PGE2). In some cases, bone-resorbing
lactation, and calcium levels in milk. Milk contains very high activity (see Fig. 3-40) can be inhibited by indomethacin,
concentrations of PTHrP (10-100 nM). PTHrP is produced by which suggests that prostaglandins are either directly or indi-
keratinocytes and is necessary for normal hair follicle differ- rectly associated with the stimulation of bone resorption. The
entiation. In general, PTHrP expression is increased when cytokines most often implicated in indirect stimulation of
smooth muscle is stretched, and PTHrP induces relaxation of bone resorption by local immune cells include interleukin-1
smooth muscle and attenuation of contraction. and tumor necrosis factor.
Lymphoma is the most common neoplasm associated
with hypercalcemia in dogs and cats. Peripheral lymph node
enlargement may or may not be detected, but there usually is Further reading
evidence of cranial mediastinal or visceral involvement. Most Ardura JA, et al. Parathyroid hormone-related protein promotes
lymphomas associated with HHM in dogs are of the T-cell subset. epithelial-mesenchymal transition. J Am Soc Nephrol 2010;21:
Most dogs with lymphoma and hypercalcemia have increased 237-248.
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NFκB ligand (RANKL) are also produced in some of these metabolism and beyond. Cytokine Growth Factor Rev 2012;23:
tumors. Dogs with lymphoma in the bone marrow have 37-46.
increased numbers of osteoclasts on trabecular bone surfaces Finch NC, et al. Fibroblast growth factor 23 (FGF-23) concentrations in
opposite a surface lined by osteoid and large columnar osteo- cats with early nonazotemic chronic kidney disease (CKD) and in
blasts (Fig. 3-50). healthy geriatric cats. J Vet Intern Med 2013;27:227-233.
309.e1
The principal blood supply to each lobe in the dog is from successively monoiodotyrosine (MIT) and diiodotyrosine
the cranial thyroid artery (a branch of common carotid), and (DIT). These biologically inactive iodothyronines subse-
the major venous drainage is via the caudal thyroid vein that quently are coupled together under the influence of thyroper-
enters the internal jugular vein. Lymph drainage from the oxidase to form the 2 biologically active iodothyronines—
cranial pole of the thyroid lobes in dogs is to the retropharyn- thyroxine (T4) and triiodothyronine (T3)—secreted by the
geal lymph nodes. Lymph flow from the caudal aspect of each thyroid gland.
thyroid lobe is variable, but it often bypasses any lymph nodes The functionally important thyroperoxidase enzyme in the
before entering the brachiocephalic trunk. Efferent lymphat- thyroid hormone synthetic pathway is present in the apical
ics usually enter directly into the cervical lymphatic trunk or plasma membrane and microvilli as well as in other membra-
internal jugular vein. This explains the frequent occurrence of nous structures of the follicular cells. Thyroperoxidase is a
pulmonary metastases from thyroid carcinoma in dogs prior to membrane-bound, heme-containing glycoprotein composed
development of secondary foci in regional lymph nodes. Small of 933 amino acids with a transmembrane domain. This
efferent lymphatics may pass through the caudal cervical important enzyme oxidizes (in the presence of hydrogen per-
lymph nodes along the ventral surface of the trachea before oxidase) iodide ion (I−) taken up by follicular cells through
entering the cranial mediastinum. These vascular arrange- the function of the sodium iodide symporter (NIS) into reac-
ments are significant for the spread of thyroid carcinomas. tive iodine (I2), which binds to the tyrosine residues in thyro-
The thyroid gland is the largest of the endocrine organs that globulin. Iodine is incorporated not only into newly synthesized
functions exclusively as an endocrine gland. The basic histologic thyroglobulin recently delivered to the follicular lumen, but
structure of the thyroid is unique for endocrine glands, con- also into molecules already stored in the lumen. Thyroperoxi-
sisting of follicles of various sizes (20-250 µm) that contain dase also functions as a coupling enzyme to combine MIT and
colloid produced by the follicular cells (thyrocytes). The fol- DIT to form T3, or 2 DITs to form T4.
licular cells are cuboidal to low columnar (under conditions The mechanism of active transport of iodide has been
of normal iodine intake), and their secretory polarity is shown to be associated with a NIS present in the basolateral
directed toward the lumen of the follicles. An extensive membrane of thyroid follicular cells (Fig. 3-53). Transport of
network of interfollicular capillaries provides the follicular iodide ion across the thyroid cell membrane is linked to the
cells with an abundant blood supply. Follicular cells have transport of Na+. The ion gradient generated by the Na+-K+
extensive profiles of rough endoplasmic reticulum and a large ATPase is the driving force for the active cotransport of iodide.
Golgi apparatus in their cytoplasm for synthesis and packaging The transporter protein is present in the basolateral mem-
substantial amounts of protein (e.g., thyroglobulin) that is brane of thyroid follicular cells and is a large protein contain-
then transported into the follicular lumen. The interface ing 643 amino acids with 13 transmembrane domains.
between the luminal side of follicular cells and the colloid is Other tissues, such as salivary gland, gastric mucosa,
modified by numerous microvilli. choroid plexus, ciliary body of the eye, and lactating mammary
Various numbers of lysosomes, which contain enzymes gland, also have the capacity to actively transport iodide, albeit
such as acid phosphatase, are found in the apical portion of at a much lower level than the thyroid. In the salivary glands,
follicular cells. Soon after stimulation of follicular cells by NIS protein has been detected in ductal cells but not in acinar
TSH, intracellular droplets of ingested colloid (phagosomes), cells. Only the thyroid follicular cells accumulate iodide in a
corresponding to those demonstrated by light microscopy TSH-dependent manner. The NIS gene is complex (15 exons,
with the PAS reaction, are more numerous than in the resting 14 introns), and its expression in the thyroid is upregulated
state. Some of these form phagolysosomes in follicular cells by TSH. The functionally active iodine transport system in the
by fusion with lysosomes. thyroid gland has important clinical applications in the evalua-
tion, diagnosis, and treatment of several thyroid disorders, includ-
Biosynthesis of thyroid hormones ing cancer. The NIS and active transport of iodide can be
The synthesis of thyroid hormones is unique among endocrine selectively inhibited by competitive anion inhibitors (e.g., per-
glands because the final assembly of hormone occurs extracellu- chlorate, thiocyanate), thereby effectively blocking the ability
larly within the follicular lumen. Essential raw materials, such of the gland to iodinate tyrosine residues in thyroglobulin and
as iodide ion (I−), are trapped by follicular cells from plasma, synthesize thyroid hormones.
transported rapidly against a concentration gradient to the The ability of NIS to concentrate iodide holds clinical rele-
lumen of the follicle, and oxidized by a peroxidase enzyme in vance, in addition to its physiologic importance, by providing the
the microvillus membranes to iodine (I2). basis for using radioactive iodine in the treatment and manage-
The assembly of thyroid hormones within the follicular ment of various thyroid diseases. Radioactive iodine is com-
lumen is made possible by a unique protein, thyroglobulin, monly used to destroy overactive thyrocytes in patients with
synthesized by follicular cells (Fig. 3-52). Thyroglobulin is a thyrotoxicosis (such as cats with hyperthyroidism), to ablate
high-molecular-weight glycoprotein synthesized in successive normal and malignant thyroid tissues in patients who have
subunits on the ribosomes of the endoplasmic reticulum in undergone total thyroidectomy for thyroid carcinoma, and to
follicular cells. The constituent amino acids (tyrosine and perform whole-body scans for the detection of recurrent and
others) and carbohydrates (mannose, fructose, galactose) are metastatic thyroid cancer.
derived from the circulation. Recently synthesized thyroglob- Once within the thyrocyte, iodide ion is passively trans-
ulin leaving the Golgi apparatus is packaged into apical vesi- ported via pendrin into the follicular lumen. Pendrin, a
cles that are extruded into the follicular lumen. ~86-kDa chloride/iodide transport protein, is located at the
The amino acid tyrosine, an essential component of thyroid apical membrane of thyrocytes, and is responsible for
hormones, is incorporated within the molecular structure of the transport of iodide ion into the follicular lumen. It is the
thyroglobulin. Iodine is bound to the tyrosyl residues in thy- product of the gene responsible for Pendred syndrome, a
roglobulin at the apical surface of follicular cells to form genetic disorder in human patients characterized clinically by
312 CHAPTER 3 • Endocrine Glands Thyroid Gland
I– Thg Mf Mf
AV (17S)
AV M
Mt CD CD
Mt
Ly Ly PL
GA CHO
Ly
Ly
Nucleus
DNA RNA Mt
Nucleus
mRNA 12S
Thg
mRNA M
cAMP T3,T4
Thg ATP
TSH-R
I– Carbohydrates (CHO) Amino acids TBG
– Glucose – Tyrosine T3,T4
TTR
– Mannose – Others
– Galactose
– Others ECF
Hormone synthesis Hormone secretion
Figure 3-52 Thyroid follicular cells illustrating 2-way traffic of molecules from capillaries to fol-
licular lumen. Raw materials, such as iodide ion (I−), are concentrated and rapidly transported into
the follicular lumen (left side of drawing). Amino acids (e.g., tyrosine) and sugars are assembled
by follicular cells into thyroglobulin (Thg), packaged into apical vesicles (AV), and released into
lumen. Iodination of tyrosyl residues occurs within the thyroglobulin molecule to form thyroid
hormones (iodothyronines) in the follicular lumen. Elongation of microvilli (MV) and endocytosis
of colloid by follicular cells occurs in response to thyroid-stimulating hormone (TSH) stimulation
(right side of drawing). Intracellular colloid droplets (CD) fuse with lysosomal bodies (Ly), and
active thyroid hormones (T4 and T3) are enzymatically cleaved from thyroglobulin, and free T4
and T3 are released into circulation. ECF, extracellular fluid GA, Golgi apparatus; M, mitochondria;
Mf, microfilaments; Mt, microtubules; PL, phagolysosome; T3, triiodothyronine; T4, thyroxine;
TBG, thyroxine-binding globulin; TSHR, thyroid-stimulating hormone receptor; TTR, transthyre-
tin. (Modified and redrawn from Good RA, et al. Molecular Pathology, Springfield, 1975, C.C.
Thomas Publishers.)
sensorineural hearing loss and goiter. Pendrin is closely related biologically inactive iodotyrosines (MIT, DIT), simultaneously
to a family of sulfate transport proteins; however, pendrin does released from the colloid droplets, are deiodinated enzymati-
not transport sulfate and unlike NIS does not require sodium cally, and the iodide generated is either recycled to the follicu-
for its transport of iodide. lar lumen to iodinate new tyrosyl residues or released into
the circulation under normal conditions. Thyroxine is rapidly
Thyroid hormone secretion bound in plasma to low-affinity albumin, moderate-affinity
The secretion of thyroid hormones from stores within luminal prealbumin (transthyretin [TTR]), and high-affinity thyroxine-
colloid is initiated by elongation of microvilli on follicular cells binding globulin (TBG); T3 is bound to albumin and TBG in
and formation of pseudopodia. These elongated cytoplasmic dogs. TBG has a greater affinity for T4 than for T3.
projections are increased by pituitary TSH, extend into the Negative feedback control of thyroid hormone secretion is
follicular lumen, and phagocytize a portion of adjacent colloid. accomplished by the coordinated response of the adenohypophysis
Colloid droplets within follicular cells subsequently fuse with and specific hypothalamic nuclei to circulating levels of thyroxine,
lysosomes that contain proteolytic enzymes. Triiodothyronine which is converted to T3 in target cells. A decrease in thyroid
(T3) and thyroxine (T4) are released from the thyroglobulin hormone concentration in plasma is sensed by groups of neu-
molecule and, because of their hydrophobic nature, diffuse rosecretory neurons in the hypothalamus that synthesize and
out of follicular cells into the adjacent capillaries. The secrete a small peptide (3 amino acids), thyrotropin-releasing
Thyroid Gland 313
2Na
2Na
NIS TRH Somatostatin
I I I I
TG TG
TSH TSHR TG
TPO H2O2 Pituitary
G I
cAMP TG-T3 T4 T3
L TG-T4
T3 (20%)
T3 T4 (80%)
T4 TSH
P
T
Figure 3-56 Colloid mineralization in a dog. Figure 3-58 Idiopathic follicular atrophy in a dog. Thyroid (T)
is reduced in size compared to adjacent parathyroids (P) and
lighter in color because of increased adipose connective tissue.
Thyroid arteries (arrows) are thickened and prominent because
of atherosclerosis. Scale = 5 mm.
A B
Figure 3-60 Hypertrophy and hyperplasia of thyrotrophic basophils in the pars distalis. A. Region
of the pars distalis composed predominantly of hypertrophied and basophilic thyrotrophs, with
few acidophils and chromophobic pituitary cells. B. Adjacent region of the pars distalis with mostly
acidophils and chromophobes and few basophils.
A
A
B
Figure 3-61 Lymphoplasmacytic thyroiditis in the dog. A. Early-
stage thyroiditis with infiltration of the interstitium and follicles
with lymphocytes and plasma cells and formation of lymphoid
nodules. B. Late-stage thyroiditis with lack of thyroid follicles. The
thyroid gland is composed of fibrous tissue, C cells, and foci of
lymphoplasmacytic inflammation. The normal parathyroid glands
are present adjacent to the thyroid glands. B
Figure 3-62 Lymphoplasmacytic thyroiditis in the dog. A. Thy-
roiditis with infiltration of the interstitium and follicles with
lymphocytes and plasma cells. The thyroid follicles are indistinct,
with a lack of colloid and disruption of the follicular cells. B. The
remaining degenerate follicular cells still stain immunohistochem-
ically for thyroglobulin.
318 CHAPTER 3 • Endocrine Glands Thyroid Gland
Hyperplasia of the thyroid gland thyroid hormone synthesis and decreased blood levels of T4
Non-neoplastic and noninflammatory clinical enlargements and T3. The low blood levels are detected by the hypothala-
(“goiter”) of the thyroid develop in all domestic mammals, mus and pituitary to increase the secretion of TSH, which
birds, and submammalian vertebrates. The major pathogenic results in hypertrophy and hyperplasia of follicular cells.
mechanisms responsible for the development of thyroid Diffuse hyperplastic and colloid goiter. Iodine deficiency
hyperplasia include iodine-deficient diets, goitrogenic compounds that resulted in diffuse thyroid hyperplasia was common in
that interfere with thyroid hormone synthesis, dietary iodide many goitrogenic areas throughout the world before the wide-
excess, and genetic enzyme defects in the biosynthesis of thyroid spread addition of iodized salt to animal diets. Although
hormones (Fig. 3-67). All of these factors result in inadequate iodine-deficient goiter still occurs in large areas of the world
Mechanisms of goitrogenesis
Increased Decreased
Thyroxine Demand Blood T4/T3
• Young animal
• Pregnancy
• Stress (↑) Hypothalamic TRH
• Severe infection (Releasing Hormone)
• Puberty
Defective
homeostasis LATS Thyroid gland -
(exophthalmic hypertrophy and hyperplasia
goiter) (H) of follicular cells
Clinical status
Figure 3-70 Colloid goiter with distended follicles lined by low Figure 3-71 Nodular goiter with multiple hyperplastic nodules
cuboidal and inactive follicular cells. in a horse.
because an extensive interfollicular capillary network devel- Nodular goiter in most animals is endocrinologically inactive and
ops under the influence of long-term TSH stimulation. encountered as an incidental lesion at autopsy; however, multi-
Colloid goiter represents the involutionary phase of diffuse nodular follicular cell hyperplasia is typically functional in cats.
hyperplastic goiter and is usually seen in young adult and adult Nodular goiter consists of multiple foci of hyperplastic
animals. The markedly hyperplastic follicular cells continue to follicular cells that are sharply demarcated, but not encapsu-
produce colloid, but endocytosis of colloid is decreased lated, and result in minimal compression of adjacent thyroid
because of diminished pituitary TSH levels in response to the parenchyma. The microscopic appearance within a nodule is
return of blood T4 and T3 to normal. Both thyroid lobes are variable. Some hyperplastic cells form small follicles with little
diffusely enlarged but are more translucent and lighter in color or no colloid. Other nodules are formed by larger irregularly
than with hyperplastic goiter. The differences in macroscopic shaped follicles lined by one or more layers of columnar cells
appearance are the result of reduced vascularity in colloid that form papillary projections into the lumen. Some of the
goiter and development of macrofollicles distended with follicles are involuted and filled with densely eosinophilic
colloid (Fig. 3-70). colloid. These changes appear to be the result of alternating
The changes in diffuse hyperplastic and colloid goiters are periods of hyperplasia and colloid involution. The areas of
consistent throughout the enlarged thyroid lobes. The follicles are nodular hyperplasia may be microscopic or grossly visible
irregular in size and shape in hyperplastic goiter because of causing enlargement of the thyroid, as in old horses (see
variable amounts of lightly eosinophilic and vacuolated colloid Fig. 3-71).
in the lumen. Some follicles are collapsed due to lack of There are no absolute morphologic criteria for distinguishing
colloid (see Fig. 3-69). The lining epithelial cells are columnar hyperplastic nodules and adenomas derived from thyroid follicu-
with a deeply eosinophilic cytoplasm and small hyperchro- lar cells. As a general rule, hyperplastic nodules are multiple,
matic nuclei that often are situated in the basilar part of the poorly or not encapsulated, variable in their histologic struc-
cell. The follicles are lined by single or multiple layers of ture, and do not cause compression of adjacent thyroid paren-
hyperplastic follicular cells, which in some follicles may form chyma. Adenomas tend to be well demarcated and partially
papillary projections into the lumen. Similar proliferative or fully encapsulated, uniform in histologic structure, and
changes are present in ectopic thyroid parenchyma in the neck cause compression of the surrounding parenchyma as a result
or mediastinum. of expansile growth (Fig. 3-72). Endocrinologically active
Colloid goiter may develop either after sufficient amounts thyroid adenomas result in colloid involution of follicles in the
of iodide have been added to the diet of animals with iodine- rim of surrounding thyroid because of inhibition of TSH
deficient hyperplastic goiter or after the requirements for secretion.
thyroid hormones have diminished in an older animal. Blood Inherited dyshormonogenic goiter. An inability to synthe-
thyroid hormone levels return toward normal, and the secre- size and secrete adequate amounts of thyroid hormones begin-
tion of TSH by the pituitary gland is correspondingly ning before or at birth has been documented in human infants
decreased. Follicles are progressively distended with densely and in several animal species. Congenital dyshormonogenic
eosinophilic colloid because of diminished TSH-induced goiter is inherited as an autosomal recessive trait in Corriedale,
endocytosis. The follicular cells lining the macrofollicles are Dorset Horn, Merino, and Romney sheep; Afrikaner cattle;
flattened and atrophic. The interface between the colloid and and Saanen dwarf goats. The subnormal growth rate, absence
luminal surface of follicular cells is smooth (see Fig. 3-70). of normal wool development or a rough sparse hair coat,
Some involuted follicles in colloid goiter have remnants of the myxedematous swellings of the subcutis, weakness, and slug-
papillary projections of follicular cells extending into their gish behavior indicate that the affected young are clinically
lumen. hypothyroid. Most lambs with congenital goiter either die
Nodular hyperplasia. Nodular hyperplasia (goiter) in shortly after birth or are highly sensitive to the effects of
thyroid glands of old horses, cats, and dogs appears as multiple adverse environmental conditions.
white to tan nodules of variable size (Fig. 3-71). The affected Thyroid glands are symmetrically enlarged at birth because of
lobes are moderately enlarged and irregular in contour. intense diffuse hyperplasia of follicular cells (Fig. 3-73A). Thyroid
Thyroid Gland 323
follicles are lined by tall columnar cells, but often are collapsed A
because of lack of colloid resulting from the markedly
increased endocytotic activity and diminished ability to syn-
thesize thyroglobulin (Fig. 3-73B).
Although thyroidal uptake and turnover of 131I are greatly
increased, levels of circulating T4 and T3 are consistently low. The
absence of a defect in the iodide transport mechanism and
organification or dehalogenation, together with an absence of
normal 19-S thyroglobulin in goitrous thyroids is consistent
with impairment in thyroglobulin biosynthesis. A closely related
or similar defect occurs in inherited congenital goiter in sheep,
cattle, and goats, in which the protein-bound iodine levels are
markedly elevated. This appears to be the result of iodination
of albumin and other plasma proteins by the thyroid gland
under long-term TSH stimulation. Hypothyroid goats with
congenital goiter can be returned to a state of euthyroidism B
by the addition of iodide (1.0 mg/day) to the diet. Although
Figure 3-73 A. Congenital dyshormonogenic goiter in a Cor-
the goats remain unable to synthesize thyroglobulin, supple-
riedale lamb. B. Congenital goiter in a lamb with severe diffuse
mentation with excess iodide results in sufficient formation of
thyroid-stimulating hormone-mediated follicular cell hypertro-
T3 and T4 in the abnormal iodoproteins to make the animals
phy and hyperplasia. Thyroid follicles have collapsed and have
euthyroid. Although thyroglobulin mRNA is present in the
slit-like lumens, given a lack of colloid. Immunohistochemistry
goitrous tissue, the concentration is reduced by 90-97% of
for thyroglobulin demonstrates minimal thyroglobulin (brown
normal, and the intracellular distribution is abnormal. The lack
material) in the follicular lumens, and lack of staining of the fol-
of thyroglobulin in these examples of congenital goiter in animals
licular cells resulting from the inability to effectively synthesize
appears to be the result of a defect in thyroglobulin mRNA,
thyroglobulin.
leading to aberrant processing of primary transcripts or trans-
port of the thyroglobulin mRNA from the nucleus to the
ribosomes of the endoplasmic reticulum.
In addition to defects in thyroglobulin processing, dyshor- Thyrotoxic effects of drugs and chemicals
monogenic goiter can occur by other mechanisms that impair Many of the significant physiologic and pathologic data in the
thyroid hormone synthesis, including impaired transport of literature on thyroid function and structure have come from
iodide, decreased or inactive TSH, decreased or impaired TSH studies in animals. Although the basic hypothalamic-pituitary-
receptor, decreased or impaired thyroperoxidase function, and thyroid axis functions in a similar manner in animals and
decreased deiodination of T4 to form T3. These are usually humans, there are differences between species in the response of
the result of sporadic debilitating mutations in the sodium the thyroid to chemical inhibition of hormone synthesis, which are
iodide symporter, TSH, TSH receptor, thyroperoxidase, or 5′- important when extrapolating animal data from toxicity and
deiodinase. Congenital goiter with hypomyelination has been carcinogenicity studies for human risk assessment. Long-term
reported in Rat Terrier dogs because of a mutation in the perturbations of the pituitary-thyroid axis by various xenobi-
thyroid peroxidase gene. Dyshormonogenic goiter with con- otics or physiologic alterations (e.g., iodine deficiency, partial
genital hyperthyroidism and goiter has been reported in indi- thyroidectomy) are more likely to predispose laboratory
vidual neonates or siblings (including dogs and cats) and likely animals to a higher incidence of proliferative lesions (e.g.,
occurs in all species, but is rare. hyperplasia and adenomas of follicular cells) than is the case
324 CHAPTER 3 • Endocrine Glands Thyroid Gland
↑TSH ()
Coupling
Thyro- Thyroglobulin
Extracellular peroxidase MIT DIT→ T3
fluids I I I2 tyrosine ↓T4 ↓T3
(O) DIT DIT→ T4
TBG TTR
NaI I I Binding
5' deiodinase (Type I)
symporter proteins
Deiodination
() ()
()
Goitrogenic • Thiocyanate • Thiourea, PTU • Iodide-excess
chemical • Perchlorate • Sulfonamides • Lithium
• Methimazole
• Aminotriazole
• Acetoacetamide
Figure 3-74 Mechanism of action of goitrogenic chemicals on thyroid hormone synthesis and
secretion. Chemicals can interfere with thyroid function by (1) blocking iodide ion trapping, (2)
inhibiting organic binding-coupling, or (3) disrupting proteolysis and release of T4 and T3 from
colloid. DIT, diiodotyrosine; MIT, monoiodotyrosine; PTU, propylthiouracil; T3, triiodothyronine;
T4, thyroxine; TBG, thyroxine-binding globulin; TRH, thyrotropin-releasing hormone; TSH,
thyroid-stimulating hormone; TTR, transthyretin.
in the human thyroid gland. This appears to be particularly The dog also is a species sensitive to the effects of sulfon-
true in male rats, in which there are higher circulating levels amides, resulting in markedly decreased serum T4 and T3
of TSH than in females. The greater sensitivity of the animal levels, hyperplasia of thyrotrophic basophils in the pituitary
thyroid to derangement by drugs, chemicals and physiologic gland, and increased thyroid weights. By comparison, the thy-
perturbations also is related to the shorter plasma half-life of roids of monkeys and human beings are resistant to the devel-
T4 (12-24 hours) than in humans (5-9 days), in part the result opment of changes that sulfonamides produce in the thyroid
of considerable differences among species in the transport gland.
proteins for T4. In humans, primates, and dogs, circulating T4 is bound
There also are marked species differences in the sensitivity primarily to thyroxine-binding globulin (TBG); however, this
of the functionally important thyroperoxidase enzyme to inhi- high-affinity binding protein is not present in rodents,
bition by xenobiotics. Thioamides (e.g., sulfonamides) and birds, amphibians, or fish. T3 is transported bound to TBG and
other chemicals can selectively inhibit thyroperoxidase and albumin in human beings, monkey, and dog, but only to
significantly interfere with the iodination of tyrosyl residues albumin in mouse, rat, and chicken. In general, T3 is bound
incorporated in the thyroglobulin molecule, thereby disrupt- less avidly to transport proteins than T4, resulting in a faster
ing the orderly synthesis of T4 and T3. Long-term administra- turnover and shorter plasma half-life in most species.
tion of sulfonamides results in the development of thyroid Xenobiotics that disrupt thyroid hormone synthesis,
“nodules” (e.g., focal hyperplasias and adenomas) frequently secretion, or peripheral metabolism often result in prompt
in the sensitive species (such as the rat, dog, and mice) but increases in circulating TSH levels. Chemical disruption of
not in species resistant (e.g., monkey, guinea pig, chicken, and thyroid hormone synthesis and secretion in animals may occur
humans) to the inhibition of peroxidase in follicular cells. at a number of different steps in thyroxinogenesis (Fig. 3-74).
Thyroid Gland 325
These include blockage of iodine uptake, organification minocycline, and administration of the antibiotic at high dose
defects, blockage of hormone release, drug-induced thyroid may result in disruption of thyroid function and development
pigmentation, inhibition of 5′-deiodinase, and induction of of goiter. The release of T4 is significantly decreased, but fol-
hepatic microsomal enzymes. licular cells retain the ability to phagocytize colloid in response
Blockage of iodine uptake. The initial step in the biosynthe- to TSH.
sis of thyroid hormones is the uptake of iodide from the circula- Other chemicals (or their metabolites) selectively localize
tion, and transport against a gradient across follicular cells to the in the thyroid colloid resulting in abnormal clumping and
lumen of the follicle. Various anions act as competitive inhibi- increased basophilia to the colloid. Brown to black pigment
tors of iodide transport in the thyroid, including perchlorate granules may be present in follicular cells, colloid, and mac-
(ClO4−), thiocyanate (SCNT−), and pertechnetate. Blockage rophages, resulting in macroscopic darkening of both thyroid
of the iodide-trapping mechanism has a disruptive effect on lobes. The physicochemically altered colloid in the lumina of
the thyroid-pituitary axis similar to iodine deficiency. The thyroid follicles is less able than normal colloid to support the
blood levels of T4 and T3 decrease, resulting in a compensatory formation of thyroid hormones. Serum T4 and T3 are decreased,
increase in the secretion of TSH by the pituitary gland (see serum TSH levels are increased, and thyroid follicular cells
Fig. 3-74). The hypertrophy and hyperplasia of follicular undergo hypertrophy and hyperplasia.
cells that follows sustained exposure results in increased Inhibition of 5′-deiodinase. Erythrosine (FD&C red no. 3)
thyroid weight and the development of thyroid enlargement is one the best characterized chemicals that acts as a 5′-
or goiter. deiodinase inhibitor and results in perturbations of thyroid
Organification defect. A wide variety of chemicals, drugs, function. It is a tetraiodinated derivative of fluorescein, with
and other xenobiotics affect the second step in thyroid iodine accounting for ~58% of the molecular weight. Eryth-
hormone biosynthesis. The stepwise binding of iodide to rosine is a red dye used widely as a color additive in foods,
the tyrosyl residues in thyroglobulin requires oxidation of cosmetics, and pharmaceuticals. Amiodarone is an organic
inorganic iodide (I−) to molecular (reactive) iodine (I2) by iodinated antiarrhythmic compound that also disrupts thyroid
thyroperoxidase present in the luminal aspect (microvillar hormone economy by inhibiting 5′-deiodinase. Iopanoic acid
membranes and apical cytoplasm) of follicular cells and adja- and flavonoids also inhibit the enzyme in hepatocytes.
cent colloid. Classes of chemicals that inhibit the organifica- Erythrosine alters the peripheral metabolism of T4. Inhibi-
tion of thyroglobulin include tion of 5′-deiodinase in the liver and kidney by erythrosine causes
1. Thioamides (e.g., thiourea, thiouracil, propylthiouracil, lower circulating T3 levels. This results in accumulation of inac-
methimazole, carbimazole, goitrin). tive reverse T3. The lowered circulating levels of T3 causes
2. Aniline derivatives and related compounds (e.g., sulfon- increased secretion of TSH from the pituitary and stimulation
amides, para-aminobenzoic acid, para-aminosalicylic acid, of thyroid follicular cells.
amphenone). Induction of hepatic microsomal enzymes. Hepatic micro-
3. Substituted phenols (e.g., resorcinol, phloroglucinol, somal enzymes play an important role in thyroid hormone
2,4-dihydroxybenzoic acid). economy because glucuronidation is the rate-limiting step in the
4. Miscellaneous inhibitors (e.g., aminotriazole, tricyanoami biliary excretion of T4, and sulfation, for the excretion of T3
nopropene, antipyrine and its iodinated derivative by phenol sulfotransferase. Long-term exposure to many
[iodopyrine]). chemicals may induce these enzyme pathways and result in
These chemicals exert their action by inhibiting thyroper- chronic stimulation of the thyroid by disrupting the
oxidase, which results in disruption both of the iodination of hypothalamic-pituitary-thyroid axis (Fig. 3-75). Xenobiotics
tyrosyl residues in thyroglobulin but also the coupling reaction that induce liver microsomal enzymes (such as cytochrome
of inactive iodotyrosines (MIT and DIT) to form active iodo- P450 isoenzymes and UDP-glucuronyl transferase) and disrupt
thyronines (T3 and T4) (see Fig. 3-74). thyroid function include central nervous system drugs (e.g.,
Blockage of thyroid hormone release. Relatively few phenobarbital, benzodiazepines), calcium channel blockers
chemicals selectively inhibit the secretion of thyroid hormone (e.g., nicardipine, bepridil), steroids (spironolactone), reti-
from the thyroid gland. Excess iodine inhibits secretion of noids, chlorinated hydrocarbons (chlordane, DDT, TCDD),
thyroid hormone and occasionally can result in goiter and and polyhalogenated biphenyls (PCB, PBB).
hypothyroidism. Several mechanisms have been suggested, In contrast to the previous categories of indirect-acting
including a decrease in lysosomal protease activity, inhibition thyrotoxic compounds, certain chemicals and irradiation have
of colloid droplet formation, and inhibition of TSH-mediated a direct effect on the thyroid gland, resulting in genetic damage
increase in cAMP. Lithium also has a striking inhibitory effect that leads to cell transformation and tumor formation in animals.
on thyroid hormone release. The widespread use of lithium Examples of thyroid initiators include 2-acetylaminofluorine
carbonate in the treatment of manic states occasionally (2-AAF), N-methyl-N-nitrosourea (MNU), N-bis(2-hydroxy
results in the development of thyroid enlargement with propyl) nitrosamine (DHPN), methylcholanthrene, dichloro-
either euthyroidism or occasionally hypothyroidism in human benzidine, and polycyclic hydrocarbons. Tumorigenicity of
patients. these chemicals can be enhanced by iodine deficiency.
Drug-induced thyroid pigmentation. The antibiotic mino- Understanding the mechanism of action of xenobiotics on
cycline produces a striking black discoloration of the thyroid the thyroid gland provides a rational basis for extrapolation of
lobes, with the formation of brown pigment granules within findings from long-term rodent studies for the assessment of
follicular cells. These pigment granules stain similarly to safety for humans (see Figs. 3-74, 3-75). Many nongenotoxic
melanin and are best visualized with the Fontana-Masson chemicals and drugs disrupt one or more steps in the synthesis
procedure. Electron-dense material first accumulates in and secretion of thyroid hormones, which results in subnormal
lysosome-like granules and in the rough endoplasmic reticu- levels of T4 and T3 and compensatory increased secretion of
lum. The pigment appears to be a metabolic derivative of pituitary TSH. When tested in highly sensitive species, such
326 CHAPTER 3 • Endocrine Glands Thyroid Gland
↑ UDP-glucuronyl
T4 transferase
Bile
Thyrotropic Hypothalamus
T4-glucuronide area
T4 → T3
T4-glucuronide TRH ()
xs TSH
Thyroid
Neoplasia Hyperplasia
gland
(late) (early)
Figure 3-75 Multiple sites of disruption of the hypothalamic-pituitary-thyroid axis by xenobiotics.
Chemicals can exert direct effects by disrupting thyroid hormone synthesis or secretion and indi-
rectly influence the thyroid through inhibition of 5′-deiodinase or by inducing hepatic microsomal
enzymes (e.g., T4-uridine diphosphate (UDP)-glucuronyl transferase). All of these mechanisms can
lower circulating levels of thyroid hormones (T4 and T3), resulting in release from negative feed-
back inhibition and increased secretion of thyroid-stimulating hormone (TSH) by the pituitary
gland. The chronic hypersecretion of TSH predisposes the sensitive rodent thyroid to develop an
increased incidence of focal hyperplastic and neoplastic (predominantly adenomas) lesions. T3,
triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; xs, excess. (From Capen CC.
Toxicol Pathol 1997;25:39-48.)
as rats and mice, these compounds result early on in follicular Fig. 3-72). Other thyroid adenomas are composed of fluctuant
cell hypertrophy/hyperplasia, and in long-term studies they thin-walled cysts filled with yellow to red fluid. The external
increase the incidence of thyroid tumors. Prolonged stimula- surface of cystadenomas is smooth and covered by an exten-
tion of the human thyroid (and likely other species, such as sive network of blood vessels. Small masses of neoplastic tissue
the dog or horse) by TSH will induce neoplasia only in excep- remain in the wall and form rugose projections into the cyst
tional circumstances, possibly by acting together with some lumen. The thyroid parenchyma of the affected lobe may be
other genetic, metabolic, or immunologic abnormality. For completely obliterated.
example, goiter, in adults is not associated with an increased Adenomas are classified into follicular and papillary types.
incidence of thyroid tumors. They are sharply demarcated and encapsulated by a partial or
complete fibrous capsule of variable thickness. Adenomas
Neoplasms of the thyroid gland derived from follicular cells that retain the ability to form follicles,
Most thyroid tumors are of follicular origin. They are common in according to one of several patterns, are considerably more
dogs and cats and distinctly rare in cattle, sheep, and swine. common than papillary adenomas in animals. Each follicular
Horses infrequently develop both thyroid follicular and C-cell adenoma tends to have a consistent growth pattern within
tumors. Tumors usually develop in animals that often are itself.
permitted to live to an advanced age, such as dogs, cats, guinea There are several different patterns of growth for follicles,
pigs, and horses. Guinea pigs occasionally develop thyroid similar to those of the normal thyroid. Microfollicular adeno-
follicular adenomas or carcinomas. mas consist of tumor cells arranged in miniature follicles with
small amounts of colloid or an absence of colloid. Macrofollicu-
Follicular cell adenoma lar adenomas are comprised of irregularly shaped large follicles
Adenomas are usually white to tan, relatively small, solid nodules that are greatly distended with colloid and lined by flattened
that are well demarcated from the adjacent thyroid parenchyma. follicular cells. There often is extensive hemorrhage and des-
The affected thyroid lobe is only moderately enlarged and quamation of follicular cells into the lumina of the distended
distorted. A distinct white fibrous capsule of variable thickness follicles.
separates the adenoma from the compressed parenchyma. Cystic adenomas consist of 1 or 2 large cavities filled with
Only a single adenoma usually is present in a thyroid lobe (see proteinaceous fluid, necrotic debris, and erythrocytes. Focal
Thyroid Gland 327
accumulations of tumor cells, forming either follicles or solid location. Studies using primary cultures of follicles from
nests, are present in the capsule of dense fibrous connective thyroid proliferative lesions from cats with hyperthyroidism
tissue. These adenomas may develop by progressive cystic have reported that organification and 3H-thymidine labeling
degeneration. Trabecular adenomas are the most poorly dif- continue in the absence of TSH, in contrast to follicles from
ferentiated of the follicular type. The tumor cells are small normal cat thyroids. These findings suggest that an intrinsic
and are arranged in narrow columns separated by an edema- alteration in follicular cell function occurs in thyroids of cats with
tous fibrous stroma. There is little evidence of follicle multinodular goiter, leading to autonomy of cell growth and per-
formation. sistent overproduction of thyroid hormones. An overexpression
Oxyphilic adenomas are composed (predominantly or of the c-ras oncogene in areas of nodular hyperplasia and
entirely) of large cells with densely eosinophilic granular cyto- adenomas derived from follicular cells in cats with hyperthy-
plasm arranged in indistinct follicles with little or no colloid roidism was reported, which suggests activating mutations in
formation. Oxyphilic (Hürthle) cells appear to be metaboli- this oncogene may play a role in the pathogenesis of these
cally altered follicular cells that accumulate abnormally large proliferative lesions. In addition, genetic mutations have been
numbers of mitochondria in their cytoplasm. found in the TSH receptor and the G protein (Gsα) in foci
Papillary adenomas of thyroid origin are recognized infre- of hyperplasia or adenomas (similar to humans with toxic
quently in most animal species. Columnar or cuboidal follicu- nodular goiter), which may be important, especially if the
lar cells are arranged in a single layer about a thin vascular TSH receptor is activated or there is increased cAMP pro-
connective tissue stalk. These papillary projections extend into duced by the modified cells. Point mutations in the human
the lumina of cystic spaces of various sizes. The cysts contain thyrotropin receptor (TSHR) gene cause 2 forms of thyrotoxi-
desquamated tumor cells, colloid, erythrocytes, and occasion- cosis, namely, autonomously functioning toxic follicular ade-
ally laminated foci of mineralization resembling psammoma nomas and hereditary (autosomal dominant) toxic thyroid
bodies. hyperplasia. The normal feline TSHR sequence between
codons 480 and 640 is highly homologous to that of other
Hyperthyroidism associated with thyroid tumors mammalian TSHRs, with 95, 92, and 90% amino acid identity
Multinodular hyperplasia and follicular cell adenomas are between the feline, canine, human, and bovine TSHRs,
common lesions in thyroid glands of adult-to-aged cats that respectively.
develop a clinical syndrome of hyperthyroidism. Follicular cell The syndrome of hyperthyroidism in aged cats can be associ-
adenomas often develop in a thyroid with multinodular ated with adenomas, multinodular hyperplasia, or adenocarcino-
hyperplasia. Thyroid carcinomas are uncommon. Adenomas mas derived from follicular cells. The most common clinical sign
and carcinomas are most likely to be encountered in aged cats, is weight loss, in spite of normal or increased appetite. Poly-
whereas nodular hyperplasia can occur at any age. The mean dipsia and polyuria, increased frequency of defecation,
age of cats with benign tumors has been reported to be 12.4 increased volume of stools, and increased activity occur. A
years, and thyroid carcinomas as 15.8 years. Guinea pigs with common functional disturbance is tachycardia accompanied
thyroid follicular adenomas or carcinomas can also develop by premature beats and/or a systolic murmur. Cardiomegaly
hyperthyroidism. resulting from left ventricular hypertrophy may be evident on
Since the late 1970s, there has been a dramatic increase in radiographs or at autopsy.
the incidence of thyroid neoplasms and other focal proliferative Thyroid adenomas in cats usually appear as well-demarcated,
lesions in cats, resulting in hyperthyroidism, and at present, it is lobulated nodules that enlarge and distort the contour of the
one of the 2 most common endocrine diseases in adult cats, dia- affected lobe (Fig. 3-76). A thin, partial fibrous capsule sepa-
betes mellitus being the other. Prior to 1980, clinical hyper- rates the adenoma from the adjacent, often compressed,
thyroidism was diagnosed infrequently in cats. The reason for thyroid parenchyma. Functional thyroid adenomas are com-
the apparent increased incidence is uncertain, but appears in posed of cuboidal to columnar follicular cells with occasional
part to be related to (1) a larger population of older cats papillary infoldings that form follicles containing variable
seeking veterinary medical care since 1980, (2) improved amounts of colloid (Fig. 3-77A,B). The follicles usually are
assays for thyroid hormones, and (3) detailed characterization partially collapsed and contain little colloid because of the
of the clinical syndrome and increased awareness of its intense endocytotic activity of neoplastic follicular cells. Long
common occurrence in adult to aged cats by veterinary clini- cytoplasmic projections extend from the follicular cells into
cians. In addition, there does appear to be a “real” increase in the lumen to endocytose colloid (Fig. 3-78). As a result of the
the incidence of feline hyperthyroidism over the last 30 years.
Potential risk factors have been reported to include a predomi-
nantly indoor environment, regular treatment with flea
powders, exposures to herbicides and fertilizers, goitrogens in
commercial foods (such as bisphenol-A [BPA], which acts as
a thyroid receptor antagonist, or polyphenolic soy isoflavones P
that inhibit conversion of T4 to T3), and non-Siamese breeds A
(10 times greater occurrence). It has been suggested that wide
variations (excessive to inadequate) in dietary iodine intake
over prolonged periods may play a role in the pathogenesis of
thyroid disorders in cats. Figure 3-76 Functional follicular cell adenoma (A) in a cat with
This important thyroid disease in cats most closely resem- hyperthyroidism. The tumor is sharply demarcated from the
bles toxic nodular goiter in humans. Hyperplastic and neoplastic normal thyroid. The hilus of the thyroid (left) contains multiple
thyroid tissue from cats is transplantable into athymic (nude) ultimobranchial cysts (arrowheads) and a small remnant of the
mice and continues to overproduce T4 and T3 in a subcuticular thymus (arrow). P, parathyroid gland.
328 CHAPTER 3 • Endocrine Glands Thyroid Gland
ER
p
B
Figure 3-77 Functional follicular cell adenoma. A. The adenoma
is composed of follicles with little stored colloid as a result of
autonomous and excessive secretion of thyroid hormones. B. Fol- P
licles in the normal thyroid tissue have undergone colloid involu-
tion and are distended with colloid and lined by low cuboidal
follicular cells as a morphologic response to suppressed thyroid-
stimulating hormone levels.
Figure 3-79 Multinodular follicular cell hyperplasia and adeno-
mas in both thyroid lobes from a cat with hyperthyroidism. P,
parathyroid gland with mild hyperplasia. Bar = 5 mm.
marked endocytotic activity, numerous colloid droplets are
present in the apical cytoplasm of follicular cells in close
proximity to the many lysosomal bodies. Follicles in the sur- Cats with hyperthyroidism usually have markedly elevated
rounding suppressed thyroid are enlarged and distended by serum thyroxine and triiodothyronine levels. Normal feline
colloid, a lesion referred to as “colloid involution.” The follicu- serum levels of T4 measured by radioimmunoassay are
lar cells are low cuboidal and atrophied with little evidence 19-64 nmol/L (~1.5-5.0 µg/dL), and serum T3 levels are
of endocytotic activity in response to the elevated levels of 0.9-3.1 nmol/L (60-200 ng/dL). The serum T4 levels in cats
thyroid hormones produced by the adenoma, resulting in sup- with hyperthyroidism range from 64-640 nmol/L (5.0 to >50
pressed levels of TSH (see Fig. 3-77B). Focal areas of necrosis, µg/dL), and serum T3 levels range from 1.5-150 nmol/L (100-
mineralization, and cystic degeneration are present in larger 1,000 ng/dL). Moderately increased liver-derived serum
adenomas. Functional follicular adenomas often develop in enzyme levels, including aspartate aminotransferase (AST
thyroids that have multinodular hyperplasia of follicular cells [SGOT]), alanine aminotransferase (ALT [SGPT]), and espe-
in both lobes. cially alkaline phosphatase, occur in hyperthyroid cats.
Hyperthyroidism in cats also occurs in association with bilat- The likelihood of developing clinical hyperthyroidism asso-
eral multinodular (“adenomatous”) hyperplasia. These multiple ciated with thyroid neoplasms in animals depends upon (1)
areas of thyroid hyperplasia usually do not appreciably enlarge the capability of tumor cells to synthesize T4 and T3, and (2)
the affected lobe(s) (Fig. 3-79). The hyperplastic nodules are the degree of elevation of circulating levels of T4 and T3. For
composed of irregularly shaped, colloid-filled follicles lined by example, dogs have a much more efficient enterohepatic excretory
cuboidal follicular cells. The multiple nodules of follicular cell mechanism for thyroid hormones than cats and infrequently have
hyperplasia eventually may coalesce or progress to form mac- clinical signs associated with functional thyroid tumors. Cats are
roscopically observable thyroid adenomas. very sensitive to phenol and phenol derivatives, and have a
Thyroid Gland 329
A
A
B
B
Figure 3-82 Thyroid follicular carcinoma in a dog with invasion
in thyroid veins. A. Note the distention of the thyroid veins by
tumor emboli growing into and down the veins (arrows). Bar =
1 cm. B. Growth of a follicular cell carcinoma tumor embolus in
a distended vein. L, lumen of the vein.
B
Figure 3-83 Compact thyroid follicular carcinoma. A. Neoplastic
cells form solid sheets of cells separated by fibrous stroma. B.
Immunohistochemistry for thyroglobulin can be used to confirm
the diagnosis of compact follicular carcinoma.
Figure 3-85 Malignant mixed thyroid carcinoma from a dog.
There are poorly differentiated thyroid follicular cells with
formation of neoplastic bone with osteoid (O), osteoblasts, and
packed within clusters separated by fibrous stroma. The scant osteocytes.
cytoplasm is eosinophilic, and the oval nucleus is densely
hyperchromatic. Mitotic figures are frequent.
Giant cell carcinoma is a highly malignant thyroid tumor carcinomas infrequently metastasize to bone and may be asso-
derived from poorly differentiated follicular cells. The anaplas- ciated with hypercalcemia.
tic tumor cells are large, pleomorphic, and often spindle shaped, Some thyroid tumors in the dog secrete sufficient thyroid
making differentiation from a fibrosarcoma difficult. Syncytial hormone to produce mild clinical signs of hyperthyroidism. It
cells may be prominent in some area of the carcinoma (Fig. 3-84). is surprising that hyperthyroidism occurs even with functional
The demonstration of identifiable epithelial structures may tumors because experimental induction of hyperthyroidism in
require multiple sections from several areas of the tumor. Fol- the dog requires daily administration of ~25 times the normal
licular remnants of transitional forms suggest that giant cell replacement dose of desiccated thyroid or L-thyroxine. The
carcinomas are derived from thyroid follicular cells. clinical signs of hyperthyroidism in dogs with functional
Malignant mixed thyroid tumors have been reported in the thyroid tumors include weight loss, polyphagia, polyuria, poly-
dog. The tumors contain both malignant thyroid follicular dipsia, weakness and fatigue with exercise, intolerance to heat,
cells and mesenchymal elements, usually osteogenic or carti- and nervousness.
laginous (Fig. 3-85). Thyroid carcinomas occur much less frequently in cats
Thyroid carcinomas often grow rapidly, invading adjacent than either adenomas or multinodular hyperplasia. They often
structures, such as the trachea, esophagus, and larynx, and result in considerable enlargement of one or both thyroid
usually are fixed in position. The earliest and most frequent site lobes and may invade adjacent structures. Thyroid carcinomas
of metastasis is the lung, because thyroid carcinomas tend to are characterized by neoplastic invasion of vessels and connec-
invade branches of the thyroid vein. Tumor cords may be tive tissue capsule. Metastases to regional lymph nodes (ret-
palpated in the thyroid or jugular veins in some animals with ropharyngeal, mandibular, deep cervical) and distant sites have
thyroid carcinoma. The retropharyngeal and caudal cervical been reported infrequently in thyroid carcinomas of cats. The
lymph nodes are less frequent sites of metastasis. Thyroid well-differentiated thyroid adenocarcinomas are composed of
332 CHAPTER 3 • Endocrine Glands Thyroid Gland
a uniform pattern of small follicles containing variable amounts reported to develop C-cell tumors (30%) or hyperplasia of C
of colloid. Strands of dense connective tissue with an abun- cells and ultimobranchial derivatives (15-20%) when they
dant capillary network and foci of lymphocytes subdivide the were fed diets with a high calcium content similar to that fed
neoplastic cells into small lobules. to cows. These frequently occurring hyperplastic and neoplastic
Thyroid carcinogenesis and radiation. Epidemiologic lesions of C cells have been observed only in bulls and not in
investigations in humans and animal studies have indicated cows. The incidence of C-cell tumors increases with advancing
that the risk of developing thyroid cancer is increased follow- age in bulls.
ing exposure to external (localized) X-rays (especially to the The syndrome of C-cell tumors in bulls shares many simi-
cervical region) or to internal 131I irradiation. larities with medullary thyroid carcinoma in humans. Multiple
endocrine tumors, especially bilateral pheochromocytomas and
Neoplasms of thyroglossal duct remnants occasionally pituitary adenomas, are detected coincidentally
Tumors arising in cystic remnants of the thyroglossal duct are in bulls and human patients with C-cell tumors. This may
rare in animals but have been reported in dogs. They appear represent a simultaneous neoplastic transformation of multi-
as well-circumscribed, fluctuant, movable enlargements ple endocrine cell populations of neural crest origin in the
(2-4 cm diameter) on the ventral midline in the cranial cervi- same individual. A high frequency of thyroid C-cell tumors
cal region. The clinical history usually indicates a slowly pro- and pheochromocytomas has been reported in a family of
gressive expansion of the cervical mass. On cross-section, Guernsey bulls, suggesting an autosomal dominant pattern of
multilocular cystic areas containing translucent proteinaceous inheritance. Diffuse or nodular hyperplasia of secretory cells
fluid alternate with white solid areas. The thyroid glands in the adrenal medulla appears to precede the development
appear to be normal in the few cases studied in dogs. These of pheochromocytoma.
tumors appear to develop from the epithelium of the thyro- The calcitonin-producing C cells were described initially
glossal duct and are not a cystic metastasis from a primary in dogs as light or gray cells and are particularly prominent in
carcinoma in the thyroid gland. this species. Nodular aggregations of C cells (C-cell clusters)
Neoplasms of thyroglossal duct remnants are well-differentiated in dogs are present either near the thyroid hilus in the peri-
papillary carcinomas. Multiple papillary outgrowths covered thyroidal connective tissues, or within the thyroid lobes along
by multiple layers of tall cuboidal to columnar epithelial cells the course of the major branches of the thyroid artery. The
extend from the cyst wall into the lumen (Fig. 3-86). The cyst ultimobranchial body (last, usually fifth pharyngeal pouch)
wall is composed of dense fibrous connective tissue with focal that delivers the neural crest–derived C cells to the postnatal
areas of hemorrhage and cholesterol clefts. Aggregations of thyroid gland fuses with each thyroid lobe at the hilus and
thyroidogenic epithelium in the form of small follicles and cell distributes C cells throughout each lobe to various degrees in
cords are present within the fibrous capsule and in surround- different species. In the dog, nodular aggregations of C cells
ing connective tissue. These follicles are lined by low cuboidal frequently persist along the course of the major vessels to the
epithelium and contain variable amounts of colloid. Carcino- thyroid; therefore C-cell hyperplasia in dogs should be diagnosed
mas of thyroglossal duct remnants appear to be well differen- only when there is a definite increase in C-cell numbers through-
tiated and slow growing, with limited evidence of local tissue out each thyroid lobe compared to age-matched controls. Both
invasion. thyroid lobes should be sectioned longitudinally in a consis-
tent manner for microscopic evaluation. This will minimize
Thyroid C-cell (parafollicular) tumors the prominent regional differences of C cells in the thyroid
Tumors derived from C cells (parafollicular cells) of the glands of normal dogs, which can result in the overinterpreta-
thyroid gland are most frequently encountered in adult-to- tion of these focal aggregations of C cells as a significant lesion.
aged bulls (ultimobranchial body origin), certain strains of The C cells in the focal aggregations have abundant, lightly
laboratory rats, adult-to-aged horses, but infrequently in dogs eosinophilic, finely granular, cytoplasm and a spherical-oval
and other species. A high percentage of aged bulls have been nucleus. There are occasional ultimobranchial-derived, colloid-
containing follicles lined by more basophilic cells within the
focal accumulations of C cells along the course of vessels
within the thyroid lobe or in the connective tissues of the
thyroid hilus in dogs.
Focal (nodular) hyperplasia of C cells often precedes the
development of C-cell neoplasms in animal and humans. The
histologic distinction between focal hyperplasia and adenoma of
C cells often is difficult and somewhat arbitrary. The diagnosis
of C-cell hyperplasia refers to a focal or diffuse increase of C
cells between thyroid follicles and/or within the follicular
basement membrane. Focal C-cell hyperplasia is a preneoplas-
tic change that occurs sporadically and may be increased in
animals with chronic hypercalcemia. Diffuse C-cell hyperpla-
sia is a physiologic response to chronic hypercalcemia (Fig.
3-87A, B). The C cells appear normal, with abundant, lightly
eosinophilic, granular cytoplasm and a round-to-oval nucleus
Figure 3-86 Papillary cystadenocarcinoma derived from thyro- with finely stippled chromatin. Cell boundaries often are
glossal duct remnants in a dog. Note the normal thyroid follicles indistinct. Focal hyperplasia of C cells forms a nodule with
in the wall of the neoplasm derived from the persistent thyroglos- an approximate diameter equal to or <5 average colloid-
sal duct. containing thyroid follicles with minimal evidence of
Thyroid Gland 333
A B
C D
Figure 3-88 Multinodular C-cell adenoma in a horse. A. The adenoma has multiple nodules that
compress the adjacent thyroid parenchyma and are surrounded by a fibrous capsule. Bar = 1 cm.
B. The adenoma is well demarcated and compresses adjacent thyroid follicles. C. The neoplastic
C cells are well differentiated and have abundant cytoplasm that is lightly eosinophilic or ampho-
philic. Note the multiple entrapped thyroid follicles that contain homogeneous or vacuolated
colloid present in the C-cell adenoma. D. Calcitonin immunohistochemistry demonstrates the
neoplastic C cells. Note that the follicular epithelial cells of the entrapped follicles are negative
for calcitonin.
tumors in bulls (Fig. 3-90A, B). Depending upon the feeding that have abundant lightly eosinophilic cytoplasm and are
regimen, adult bulls may ingest 3.5-6.0 times the amount of located either in the wall of thyroid and ultimobranchial fol-
calcium normally recommended for maintenance. The chronic licles or as larger nodules with a solid histologic structure (Fig.
stimulation of C cells by high levels of calcium absorbed from the 3-90C). This often is accompanied by multifocal hyperplasia
digestive tract is related to the pathogenesis of C-cell neoplasms. of C cells in other parts of the thyroid lobes and hilus. The
A significant decline in the incidence of C-cell tumors occurs neoplastic C cells often are embedded in an increased amount
when bulls are switched from a high-calcium intake to a of hyalinized stroma that may contain amyloid. Other areas
reduced-calcium intake. Cows do not develop proliferative of this unique thyroid neoplasm in bulls appear to be derived
lesions of C cells under similar dietary conditions, possibly from less differentiated ultimobranchial remnants and consist
because of the high physiologic requirements for calcium of follicle-like structures, cysts, and tubules composed of
imposed by pregnancy and lactation. Familial or sporadic acti- immature small basophilic cells. They closely resemble undif-
vation (gain-of-function) of the RET tyrosine kinase proto- ferentiated or stem cells of the normal ultimobranchial body
oncogene is important in humans with C-cell (medullary) in bulls and other species that have the potential to differenti-
carcinoma or multiple endocrine neoplasia (involving both C ate into both C and follicular cells. Thyroid follicles and crib-
cells and chromaffin cells of the adrenal) and may play a role riform structures with colloid-like material formed by cells
in animals. resembling differentiated follicular cells often are present
Ultimobranchial tumors in the thyroid glands of bulls in the neoplasms in close association with these more primi-
often have a more complex histologic structure than the tive ultimobranchial-derived structures. The heterogeneous
typical C-cell (medullary) neoplasms in human patients, histologic structure of ultimobranchial neoplasms in bulls
horses, dogs, and certain strains of laboratory rats. Focal areas resembles an unusual type of thyroid carcinoma of human
in the tumor are composed of more differentiated C cells patients. This variant, designated as an intermediate type of
Thyroid Gland 335
B
B
C
Figure 3-89 C-cell carcinoma in a dog. A. The neoplastic cells
are polyhedral with amphophilic, finely granular cytoplasm, and C
are separated by bands of fibrous stroma. Note the 2 residual
Figure 3-90 C-cell carcinoma in a bull. A. Enlargement of the
thyroid follicles. Most of the follicular epithelial cells have been
ventral neck because of C-cell carcinoma in the thyroid gland and
replaced by C cells, but the colloid remains. B. Immunohisto-
metastasis to multiple cervical lymph nodes (arrowheads).
chemistry for calcitonin reveals variable cytoplasmic staining for
B. C-cell carcinoma metastases to multiple cervical lymph nodes.
calcitonin. The lightly stained C cells secrete calcitonin in an
C. Neuroendocrine pattern of malignant C-cells with the forma-
unregulated manner, so they have little stored cytoplasmic calci-
tion of elongated cells with eosinophilic cytoplasm and nuclear
tonin. C. Homogeneous amyloid deposits may be seen between
palisading.
neoplastic cells in some C-cell carcinomas.
336 CHAPTER 3 • Endocrine Glands Adrenal Cortex
Further reading
Bojanic K, et al. Congenital hypothyroidism of dogs and cats: a review.
New Zealand Vet J 2011;59:115-122.
Broome MR, et al. Clinical features and treatment outcomes of 41 dogs
with sublingual ectopic thyroid neoplasia. J Vet Intern Med
2014;28:1560-1568.
Broome MR, et al. Exogenous thyrotoxicosis in dogs attributable to
consumption of all-meat commercial dog food or treats containing
excessive thyroid hormone: 14 cases (2008-2013). J Am Vet Med
Assoc 2015;246:105-111.
Campos M, et al. Immunohistochemical expression of potential
therapeutic targets in canine thyroid carcinoma. J Vet Intern Med
2014;28:564-570. Figure 3-91 Normal adrenal glands (top = right; bottom = left)
Capen CC. Toxic responses of the endocrine system. In: Klaassen CD, from a dog. The cortex is paler compared to the medulla because
editor. Casarett and Doull’s Toxicology: The Basic Science of Poisons. of the presence of cytoplasmic lipid vacuoles. The cortical to
6th ed. New York: McGraw Hill; 2001. p. 711-759. medullary ratio is approximately 1 : 1-2 : 1, depending on the area
Gaskill CL, et al. Changes in serum thyroxine and thyroid-stimulating of sectioning. The red areas are cortical congestion.
hormone concentrations in epileptic dogs receiving phenobarbital
for one year. J Vet Pharmacol Therap 2000;23:243-249.
Hilderbran AC, et al. Nonthyroidal illness syndrome in adult horses. J develops from cells of the celomic epithelium that are of
Vet Intern Med 2014;28:609-617. mesodermal origin and are related developmentally, anatomi-
Lacroix L, et al. Na+/I− symporter and Pendred syndrome gene and cally, and physiologically with steroid-producing cells of
protein expressions in human extra-thyroidal tissues. Eur J Endocri- the gonads. The coelomic epithelium transcription factors,
nol 2001;144:297-302. GATA-6 and GATA-4, direct differentiation of the steroid-
Mooney CT. Canine hypothyroidism: a review of aetiology and diag- producing cells of the adrenal and ovaries, respectively. The
nosis. New Zealand Vet J 2011;59:105-114. chromaffin tissue and sympathetic ganglion cells of the adrenal
Ozmen O, Haligur M. Immunohistochemical observations on TSH medulla are derived from ectoderm of the neural crest. It is
secreting cells in pituitary glands of goat kids with congenital goitre. not until relatively late in fetal development that a definitive
J Vet Med A 2005;52:454-459. relationship between the 2 primordia occurs.
Peeters ME, et al. Feline thyroid adenomas are in part associated with
mutations in the G(s alpha) gene and not with polymorphisms Structure of the adrenal gland
found in the thyrotropin receptor. Thyroid 2002;12:571-575. The adrenal glands are covered by a thin fibrous capsule and
Ramos-Vara JA, et al. Immunohistochemical detection of thyroid tran- are richly vascularized, receiving arterial branches either
scription factor-1, thyroglobulin, and calcitonin in canine normal, directly from the aorta or from the phrenic, renal, and lumbar
hyperplastic, and neoplastic thyroid gland. Vet Pathol 2002;39:480- arteries. The arteries form a vascular plexus in the capsule that
487. eventually supplies the entire adrenal gland through separate
Rosol TJ, et al. Endocrine System. In: Haschek WM, et al., editors. channels to the capsule, cortex, and medulla. A sinusoidal
Haschek and Rousseaux’s Handbook of Toxicologic Pathology. network is formed about the cell columns of the adrenal
Elsevier/Academic Press; 2013. p. 2391-2492. cortex that empties into the venous tree at the periphery of
Watson SG, et al. Somatic mutations of the thyroid-stimulating the medulla. The larger branches of the venous tree empty
hormone receptor gene in feline hyperthyroidism: parallels with into the adrenal vein.
human hyperthyroidism. J Endocrinol 2005;186:523-537. The adrenal cortex classically is subdivided into 3 layers or
Williams ED. Mechanisms and pathogenesis of thyroid cancer in zones, although the demarcation between zones often is not
animals and man. Mutation Res 1995;333:123-129. distinct.
Zabka TS, et al. Characterization of xenobiotic-induced hepatocellular • The zona glomerulosa (multiformis, arcuata) is composed
enzyme induction in rats: anticipated thyroid effects and unique of columns of cells that have a sigmoid arrangement
pituitary gland findings. Toxicol Pathol 2011;39:664-677. next to the capsule. It represents ~15% of the cortex
and is responsible for the secretion of mineralocorticoid
hormones.
• The secretory cells of the zona fasciculata are arranged in
ADRENAL CORTEX long anastomosing cords separated by numerous small cap-
Development, structure, and function illaries. This middle zone, which comprises ~70% of the
Embryonic development of the adrenal gland cortex, is composed of cells that contain abundant cyto-
The adrenal glands of mammals consist of 2 distinct parts that plasmic lipid and are responsible for the secretion of the
differ not only in morphology and function but also in origin. glucocorticoid hormones.
Because of their close structural relationships, the outer cortex • The zona reticularis accounts for the remaining 15% of the
and inner medulla of the adrenal gland usually have been cortex. The secretory cells are arranged in small groups
considered parts of one organ (Fig. 3-91). The adrenal cortex surrounded by capillaries. This inner layer is responsible for
336.e1
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Adrenal Cortex 337
the secretion of sex steroids by the adrenal gland. Cortical Glucocorticoids also decrease the initial inflammatory reac-
cells may project for a short distance into the medulla. tion and its classic manifestations of heat, swelling, and pain.
Growth and replacement of adrenocortical cells follows a The degree of hyperemia, extravasation, cellular migration,
distinct pattern of cell differentiation, proliferation, and migra- and infiltration at the site of injury is decreased. Especially
tion. Adrenocortical stem cells (Sf1−, Gli1+) reside in the important are the effects of glucocorticoids on the vascular
adrenal capsule and migrate to the zona glomerulosa to form responses of increased permeability, diapedesis, and extravasa-
small nests of proliferative progenitor cells (Sf1+). The pro- tion. Capillary blood flow is decreased, and there is less endo-
genitor cells replace the both the zona glomerulosa and fas- thelial swelling. In addition, a number of phagocytic mechanisms
ciculata cells (Sf1+). As the zona fasciculata cells age, they are inhibited by glucocorticoids, and clearance of particulate
migrate centrally down the cords of the adrenal cortex and substances from the blood and lymph is impaired. The accu-
eventually differentiate into reticularis cells. Cortical cells con- mulation of engulfed antigens in macrophages probably is
tinue to migrate toward the cortical-medullary junction and related to the enhanced stability of lysosomal membranes caused
undergo apoptosis at that location. This is why pigment-laden by glucocorticoids. There is a diminished capacity of lyso-
macrophages are often found at the cortical-medullary junc- somes to interact with phagocytized material and release
tion in older animals. The process of adrenocortical cell pro- hydrolytic enzymes.
liferation and migration can be followed by in vivo labeling of Glucocorticoids exert a negative effect on wound healing.
DNA synthesis, such as with bromodeoxyuridine (BrdU). Dogs receiving high therapeutic levels of adrenal corticoste-
roids or animal patients with hyperadrenocorticism may have
Biosynthesis and action of adrenal cortical hormones wound dehiscence following surgery. The basis mechanism
Mineralocorticoids are adrenal steroids that have their principal involved is inhibition of fibroblast proliferation and collagen
effects on ion transport by epithelial cells, resulting in a loss of synthesis, leading to a decrease in scar tissue formation.
potassium and conservation of sodium. The most potent and Secretion of adrenal sex hormones by cells of the zona
important naturally occurring mineralocorticoid is aldoste- reticularis occurs under normal conditions but in minute
rone. The enzymatically controlled electrolyte “pumps” in amounts that probably are of minor physiologic significance.
epithelial cells of the renal tubule and sweat glands respond Secretory cells of the inner zone of the cortex synthesize
to mineralocorticoids by conserving sodium and chloride and progesterone, estrogens, and androgens. Under pathologic con-
by excreting potassium. In the distal convoluted tubule of the ditions, excessive secretion of adrenal sex steroids infrequently
mammalian nephron, a cation exchange mechanism exists for may occur associated with an adrenocortical neoplasm. The
the resorption of sodium from the glomerular filtrate and clinical manifestations of virilism, precocious sexual develop-
secretion of potassium into the lumen. These reactions are ment, or feminization depend upon which steroid is secreted
accelerated by mineralocorticoids and proceed at a slower rate in excess, the sex of the patient, and the age of onset.
in their absence. A lack of secretion of mineralocorticoids The renin-angiotensin system is the major regulator of
(such as in idiopathic adrenal atrophy of dogs) may result in aldosterone production by the zona glomerulosa of the adrenal
a lethal retention of potassium and loss of sodium. cortex. Renin is an enzyme secreted into the circulation by
Glucocorticoid hormones secreted by the adrenal cortex cells of the juxtaglomerular apparatus in the kidney. It acts to
are involved with the intermediary metabolism of glucose. cleave the plasma globulin angiotensinogen, to form angioten-
Cortisol and lesser amounts of corticosterone are the most sin I. This decapeptide is further hydrolyzed to angiotensin II
important naturally occurring glucocorticoids secreted by the by a converting enzyme. Angiotensin II is both a potent vaso-
adrenal gland in domestic animals. In general, the actions of constrictor and a trophic hormone for the zona glomerulosa
glucocorticoids on carbohydrate, protein, and lipid metabolism of the adrenal cortex, resulting in the synthesis and secretion
result in sparing of glucose and a tendency to hyperglycemia and of aldosterone. It is a very labile peptide that is quickly inac-
increased glucose production. The acute effects of glucocorti- tivated in plasma and tissues by angiotensinases.
coids are observed 15-30 minutes before the compensatory A number of factors regulate renin secretion by the kidney.
effects of insulin become prominent. There is a decrease in The “short loop” of negative feedback control is the direct
glucose uptake in adipose tissue, skin, fibroblasts, and lym- inhibition exerted by circulating angiotensin II. The “long
phoid tissue, followed shortly by increased catabolism in these loop” is exerted by an indirect feedback inhibition by aldoste-
tissues and muscle. This provides amino acids for gluconeo- rone on renin secretion. Renin release and eventually aldoste-
genesis, which is increased mainly in the liver. In addition, rone secretion are increased by conditions that compromise
glucocorticoids decrease lipogenesis and increase lipolysis in blood flow and pressure to the kidney, severe dehydration that
adipose tissue, which results in release of glycerol and free results in decreased intravascular blood volume, and sodium
fatty acids. depletion.
Glucocorticoids also function to suppress inflammatory and Adrenocorticotropin (ACTH) secreted by the adenohy-
immunologic responses and thereby attenuate the associated pophysis is the principal regulator of adrenal cortical growth
tissue destruction and fibroplasia. However, under the influ- and secretory activity, particularly of cells in the zonae fascicu-
ence of high levels of glucocorticoids, there is enhancement lata and reticularis. The adrenal cortex secretes physiologic
of the spread of infections and reduced resistance to a number quantities of cortisol only in response to ACTH stimulation.
of bacterial, viral, and fungal diseases. Glucocorticoids may The zona glomerulosa (and its secretion of aldosterone) is
impair the immunologic response at any stage from the initial responsive to ACTH, but at a lower level compared to the
interaction and processing of antigens through the induction zonae fasciculata and reticularis. ACTH exerts its action on
and proliferation of immunocompetent lymphocytes and sub- target cells through the melanocortin 2 receptor and subse-
sequent antibody production. Inhibition of a number of lym- quent activation of adenylyl cyclase and generation of the
phoid cell functions by glucocorticoids forms part of the basis intracellular mediator, 3′,5′-adenosine monophosphate (cyclic
for suppression of the immunologic response. AMP). Cyclic AMP stimulates certain key enzymes (e.g.,
338 CHAPTER 3 • Endocrine Glands Adrenal Cortex
Lysosome
Endocytosis
SER
LDL Acetyl CoA
Steroidogenesis
Steroid
nCEH hormone
HDL Cholesterol Mitochondrion
ACAT Storage nCEH
pathway
Nucleus
A Lipid droplet CE
Lysosome
Endocytosis
SER
LDL Acetyl CoA
Steroidogenesis Steroid
nCEH hormone
HDL Cholesterol Mitochondrion
ACAT nCEH
Storage CE
pathway
CE Nucleus
B Lipid droplet CE
Figure 3-99 Cholesterol metabolism and steroid hormone biosynthesis in adrenocortical cells.
Cholesterol is the substrate for steroid hormone biosynthesis. Conversion of cholesterol to preg-
nenolone occurs in the mitochondria, and oxidative reactions catalyzed by cytochrome P450
enzymes occur in both the smooth endoplasmic reticulum (SER) and mitochondria. Sources of
cholesterol include lipoprotein (low-density lipoprotein [LDL] and high-density lipoprotein
[HDL]) uptake from serum, de novo synthesis from acetate via the acetyl coenzyme A pathway,
and hydrolysis of cholesteryl esters (CE) by neutral CE hydrolase (nCEH). The storage pool in
the form of lipid droplets is derived principally from the conversion of free cholesterol to CE,
catalyzed by acyl coenzyme A/cholesterol acyltransferase (ACAT). (From Latendresse JR, et al.
Toxicol Appl Pharmacol 1993;122:281-289.)
• Toxin activation by mitochondrial cytochrome P450 dogs are considerably more sensitive to the effects of o,p′-
(CYP450) enzymes in the cortical cells. Activation of DDD, and it has been used effectively in a dose-dependent
toxins can result in the generation of reactive oxygen manner in the medical management of pituitary-dependent
metabolites, result in membrane damage, and produce hyperadrenocorticism caused by autonomous secretion of
phospholipidosis in the cells. ACTH by pituitary (corticotroph) tumors. o,p′-DDD is a
• Exogenous steroids, which can disrupt normal function selective toxin for the zonae fasciculata and reticularis; thereby
and structure of the adrenal cortex. Agonists will induce sparing the important life-sustaining functions of the zona
negative feedback inhibition of ACTH secretion by the glomerulosa.
pituitary and will result in atrophy of the zonae fasciculata
and reticularis. Some steroids, such as the sex steroids, can Adrenal lesions associated with hypoadrenocorticism
induce proliferative lesions in the adrenal cortex. Antago- Idiopathic adrenocortical atrophy. The most frequently observed
nists will block steroid hormone action, leading to increased lesion in dogs with hypoadrenocorticism is bilateral idiopathic
ACTH secretion and diffuse hyperplasia of the cortex. adrenocortical atrophy in which all layers of the cortex are mark-
• DNA damage, by agents such as carcinogens or radiation, edly reduced in thickness (Fig. 3-100A-C). There usually is
may induce neoplasia of the adrenal cortex. deficient production of all classes of corticosteroids (mineralo-
There is considerable species variation in the response of corticoids, glucocorticoids, and adrenal sex steroids). The
the adrenal cortex to exogenous chemicals. This is because of adrenal cortex is reduced to one tenth or less its normal thick-
both inherent differences in the sensitivity to certain drugs ness and consists primarily of the adrenal capsule. The adrenal
and differences in the metabolic pathways of steroidogenesis. medulla is relatively more prominent and, with the capsule,
An interesting example is o,p′-DDD (mitotane, a derivative makes up the bulk of the remaining adrenal glands. The patho-
of DDT), which was originally developed to treat metastatic genesis of idiopathic adrenocortical atrophy is unknown, but
adrenal cortical cancer in humans. However, humans are rela- it is likely that the lesion is the result of immune-mediated inflam-
tively insensitive to the effects of o,p′-DDD, and the drug was mation similar to Addison’s disease in humans. Multiple foci
not effective in the treatment of adrenal cancer. In contrast, of lymphocytes and plasma cells are seen interspersed between
342 CHAPTER 3 • Endocrine Glands Adrenal Cortex
A
B
C D
Figure 3-100 Idiopathic adrenal cortical atrophy in a dog. A. All 3 layers of the adrenal cortex
from both glands are markedly reduced in thickness because of atrophy as a sequela of immune-
mediated adrenalitis and destruction of parenchymal cells. The arrows mark the edges of the
medulla. Bar = 5 mm. B. Chronic adrenal cortical atrophy in a dog with hypoadrenocorticism.
The medulla lies between the arrowheads, and there is congestion in the thin cortical region. The
capsule is prominent. C. Severe adrenal cortical atrophy. The adrenal capsule (top) appears thick-
ened because of collapse of the layers of the cortex. The cortex is very thin (between arrowheads)
with a few remaining vacuolated cortical cells. There is scattered lymphocytic inflammation of the
capsule and cortex. The medulla (M) is along the bottom. D. Early phase of immune-mediated
adrenalitis in a dog with infiltration of lymphocytes and plasma cells in the zona fasciculata and
loss of cortical cells.
adrenal sinusoids and groups of fibroblasts in the earlier stages infarction of the cortex, invasion and destruction of adrenal
of the disease (Fig. 3-100D). The entire 3 zones of the cortex cortex by metastatic neoplasms, hemorrhage and necrosis with
are nearly absent in dogs that die from untreated hypoadre- subsequent replacement by fibrous connective tissue, and
nocorticism. The capsule appears thickened because of col- extensive amyloid deposition along adrenal sinusoids.
lapse of the adrenal cortex plus fibroblastic proliferation. Many of the functional disturbances of hypoadrenocorticism
No obvious pituitary lesions other than compensatory associated with chronic adrenal insufficiency are not specific
hyperplasia of corticotrophs have been observed in dogs with and include recurrent episodes of gastroenteritis, slowly pro-
idiopathic adrenal cortical atrophy. All zones of the adrenal gressive loss of body condition, and failure to respond appro-
cortex are involved, including the zona glomerulosa, which is priately in stressful situations, such as minor illnesses or
not under ACTH control. In comparison, trophic atrophy of surgery. Less commonly, the dog is presented in a shock-like
the adrenal cortex secondary to a destructive pituitary lesion coma with no history of previous illness. Although hypoadre-
that decreases ACTH secretion is characterized by severe nocorticism occurs in dogs of any breed or sex and at any age,
atrophy only of the inner 2 cortical zones. These animals do idiopathic adrenocortical insufficiency occurs more frequently
not have the characteristic electrolyte abnormalities present in young adult dogs. This may be related to the immune-
in hypoadrenocorticism because the secretion of aldosterone mediated pathogenesis with the generation of autoantibodies
remains within normal limits. against cortical cells, progressive degeneration of parenchymal
Additional (less common) causes of adrenocortical insuffi- cells, and lymphoplasmacytic adrenalitis.
ciency in the dog include granulomatous inflammation that Reduction in the synthesis and secretion of mineralocorti-
destroys the cortex, thrombosis of adrenal vessels with coids, primarily aldosterone, results in marked alterations of
Adrenal Cortex 343
serum potassium, sodium, and chloride levels. Less potassium glomerulosa with fibrosis of the capsule, which consistently
is excreted by the kidney, resulting in a progressive rise in contains cells with PAS-positive cytoplasmic granules. Depend-
serum potassium levels and severe hyperkalemia. Less sodium ing on duration and severity of exposure, adrenal lesions may
and chloride are reabsorbed from renal tubules, leading to persist following removal of the drug. Plasma aldosterone and
various degrees of hypernatriuria and hyperchloruria and a sodium levels are reduced after exposure to toxic levels of
corresponding decline in blood levels. The severe hyperkale- carbadox, and potassium is increased.
mia frequently produces marked cardiovascular disturbances
that are reflected by changes in the electrocardiogram. Hyperplasia of the adrenal cortex
Although the development of clinical signs often is insidi- Accessory cortical nodules are common in the adrenal glands
ous and not readily apparent, the dog frequently is presented of adult-to-aged animals and are found in the capsule, cortex,
with acute circulatory collapse and evidence of renal failure. and medulla. Many accessory cortical nodules either arise as
Progressive decrease in blood volume contributes to hypoten- evaginations of the outer cortex into the capsule and sur-
sion, weakness, and microcardia. Peripheral circulatory col- rounding periadrenal fat, or invaginations of the cortex into
lapse may result from progressive hemoconcentration. the medulla (Fig. 3-101A).
Increased excretion of water by the kidney, resulting from Nodular hyperplasia also is common in the adrenal as well-
hyponatremia and hypochloremia, results in progressive dehy- defined spherical nodules in the cortex or attached to the
dration and hemoconcentration. Emesis, diarrhea, and anorexia capsule. Hyperplastic nodules are usually multiple and bilat-
are common in dogs with hypoadrenocorticism, and they con- eral, yellow, and may involve any of the 3 zones of the cortex
tribute to the animal’s deterioration. Weight loss is frequently or medulla (Fig. 3-101B). Histologically, the nodules near
severe. the capsule resemble zona glomerulosa, sometimes with areas
Decreased production of glucocorticoids results in several similar to zona fasciculata. The cells either are about the same
characteristic functional disturbances of hypoadrenocorticism. size as those of the adrenal cortex or hypertrophied. The lipid
Failure of gluconeogenesis and increased sensitivity to insulin content in these hyperplastic nodules is not depleted in cir-
contribute to development of moderate hypoglycemia. Hyper- cumstances that reduce the amount of lipid in the rest of the
pigmentation of the skin occurs in some dogs with long- cortex. Hyperplastic cortical nodules are most common in
standing adrenocortical insufficiency. This change results from older horses, dogs, and cats.
lack of negative feedback on the pituitary gland, increased Nodular hyperplasia of the zona reticularis may appear as
release of ACTH, and binding to melanocyte-stimulating discrete foci of cortical parenchyma extending into the
hormone (MSH) receptors on melanocytes in the skin. medulla and result in an irregular corticomedullary junction
Peripheral lymph nodes may be moderately increased in (Fig. 3-101C). This adrenal lesion has been seen in animals
size as a result of lymphoid hyperplasia. Histologically, promi- with functional disturbances suggesting androgen excess (e.g.,
nent germinal centers are observed in lymph nodes, and sub- greater muscle mass, well-developed crest, hypertrophy of
stantial numbers of eosinophils may infiltrate the peripheral clitoris, and involution of mammary glands).
lymph sinus. There often are increased numbers of eosinophils Diffuse cortical hyperplasia results in uniform, usually
and lymphocytes in the circulation as a result of the dimin- bilateral, enlargement of the adrenal cortex (Fig. 3-101D).
ished cortisol levels. There is a marked hypertrophy and hyperplasia of cells in the
Hematologic alterations that occur in hypoadrenocorticism zonae fasciculata and reticularis in response to autonomous
include hemoconcentration caused by dehydration and loss of hypersecretion of ACTH by a corticotroph adenoma of the
intravascular fluid volume. Blood urea and creatinine levels pituitary. The hyperplastic cells in the zona fasciculata are
begin to rise as renal perfusion and urine output decrease. The vacuolated (lipid rich) and arranged in straight columns sepa-
serum glucose level ranges from low normal to moderately rated by sinusoids. Cells in the outer zona glomerulosa often
subnormal in affected dogs, but this usually is not responsible are compressed by the expanded inner 2 zones. The cortico-
for functional disturbances. medullary junction is irregular in diffuse hyperplasia, and pro-
Hypercalcemia occurs in ~30% of dogs with hypoadreno- jections of cortical cells often extend into the medulla. Areas
corticism. The elevated serum calcium concentration returns of discrete nodular hyperplasia may be present in a diffusely
to normal when the adrenal cortical disease is treated with hyperplastic cortex.
adequate corticosteroid replacement therapy. The mechanism Hyperplasia of zona glomerulosa occurs as part of the
of hypercalcemia is not understood completely, but the compensatory mechanism of the body to a variety of factors
ionized fraction of serum calcium remains normal, whereas that stimulate long-term release of renin from the juxtaglo-
the nonionized fraction increases, and there is inappropriate merular apparatus of the kidney (Fig. 3-101E). Chronic
hypocalciuria for the degree of hypercalcemia. Because the sodium depletion or potassium excess, decreased blood
ionized serum calcium concentration is not increased, the volume to the kidney, or a sustained reduction in systemic
hypercalcemia is not deleterious to the animal; however, blood pressure all will increase aldosterone production by
some of the clinical signs of hypoadrenocorticism (vomiting, stimulating renin release. Renin results in the formation of
anorexia, polyuria, polydipsia) are similar to those of angiotensin II, a trophic hormone for the zona glomerulosa of
hypercalcemia. the adrenal cortex.
Carbadox and related compounds (olaquindox and
cytadox) are antibiotics and growth promotants used in young
pigs. Chronic or high exposure has been associated with Neoplasms of the adrenal cortex
lesions in the zona glomerulosa. There is disorganization of Myelolipoma
the zona glomerulosa, with loss of distinction from the zona This is a benign lesion encountered in the adrenals of cattle,
fasciculata, hydropic degeneration, and eventually atrophy, nonhuman primates, and infrequently in other animals. It is
mild fibrosis, and mononuclear cell infiltrates in the zona composed of accumulations of well-differentiated adipose
344 CHAPTER 3 • Endocrine Glands Adrenal Cortex
C D
E
Figure 3-101 Adrenal cortical hyperplasia. A. Discrete accessory adrenal cortical nodules in the
capsule and medulla in a dog. Bar = 5 mm. B. Multifocal nodular cortical hyperplasia (arrows) in
a dog. Well-demarcated cortical adenoma (A). Bar = 5 mm. C. Multifocal cortical hyperplasia
of the zona reticularis in a bovid. Bar = 5 mm. D. Bilateral diffuse adrenal cortical hyperplasia in
a dog with a functional pars distalis chromophobe adenoma that secreted adrenocorticotropic
hormone. Bar = 1 cm. E. Hypertrophy and hyperplasia of the zona glomerulosa in a dog. Note
the enlarged and columnar zona glomerulosa cells forming prominent arches.
Cortical carcinoma
Adrenal cortical carcinomas occur less often than adenomas
and have been reported most often in cattle and older dogs, but B
infrequently in other species. Carcinomas develop in adult to
older individuals, and there is no apparent breed or sex pre-
disposition. Activation of the PI3 kinase by insulin growth
factor-1 (IGF-1) may be important in the pathogenesis of
adrenal cortical carcinoma in humans and dogs.
Adrenal carcinomas are larger than adenomas and more
likely to be bilateral. In dogs, they are composed of variegated,
yellow-red, friable tissue that incorporates the affected adrenal
gland (Fig. 3-103A). They are often fixed in location because
of extensive invasion of surrounding tissues with extension into
the caudal vena cava, forming large tumor-cell thrombi. Car-
cinomas may attain considerable size in cattle (≥10 cm in
diameter) and have multiple areas of mineralization or
ossification.
Carcinomas are composed of more highly pleomorphic
cortical cells than adenomas, and are subdivided into small C
groups by fibrovascular stroma of variable thickness. The
architecture of the affected adrenal usually is completely Figure 3-102 Adrenal cortical adenoma in a dog with telangiec-
obliterated by the carcinoma. The pattern of growth varies tasis. A. Well-demarcated adenoma (between arrowheads) in the
between individual tumors and within the same carcinoma. adrenal cortex. The adenoma has large dilated sinusoids (telangi-
Tumor cells usually are large and polyhedral with prominent ectasis) with chronic hemorrhage. Normal cortex (C). B. Adrenal
nuclei and densely eosinophilic or vacuolated cytoplasm, but cortical adenoma composed of thickened cords of well differenti-
the tumor may also contain smaller cells (Fig. 3-103B). Areas ated cells. Note the clusters of hemosiderin-laden macrophages.
of hemorrhage within the tumors are common because of C. Cords of adrenal cortical adenoma cells are separated by large
rupture of thin-walled sinusoids. Metastasis occurs most fre- dilated sinusoids that mimic hemangioma.
quently to the liver and lungs. The normal adrenal cortex can
be immunohistochemically stained for steroidogenic factor-1,
calreticulin, α-inhibin, melan-A, and S-100 protein, and
346 CHAPTER 3 • Endocrine Glands Adrenal Cortex
Hyperadrenocorticism
The manifestations and lesions associated with hyperadreno-
corticism (Cushing’s syndrome), mainly in dogs, result from
long-term overproduction of cortisol by hyperactive adrenal
cortices. As a result of the cortisol excess, affected dogs develop
a spectrum of functional disturbances and lesions from the
combined gluconeogenic, lipolytic, protein catabolic, and
anti-inflammatory effects of the glucocorticoid hormones on
A many organs. The course of the disease is insidious and slowly
progressive. Cortisol excess is one of the most frequent endocri-
nopathies in adult-to-aged dogs, occurs occasionally in cats,
but is encountered infrequently in other species of domestic
animals.
The elevation in circulating cortisol levels in dogs with
hyperadrenocorticism may result from one of several different
pathogenic mechanisms. The most common mechanism (85%
of cases) is a functional corticotroph (ACTH-secreting) adenoma
of the pituitary gland (pars distalis or pars intermedia in dogs)
that causes bilateral adrenal cortical hypertrophy and hyper-
plasia (see Fig. 3-101D). Hyperadrenocorticism associated
with adrenal cortical hyperplasia occurs most frequently in
small-breed dogs, such as Poodles and other breeds.
Functional adrenal neoplasms are infrequent (15% of
B
cases) causes of the syndrome of cortisol excess (Cushing’s
Figure 3-103 Functional adrenocortical carcinoma in a dog. A. syndrome) in the dog. One third of dogs with hyperadre
Adrenocortical carcinoma with destruction of the normal adrenal nocorticism caused by an adrenal tumor have activating
gland (left) and invasion of the caudal portal vein with formation mutations in the stimulatory G protein α-subunit associated
of a tumor thrombus (right). The contralateral adrenal gland with the ACTH receptor (melanocortin 2 receptor [MC2R]),
(lower) has cortical atrophy secondary to hyperadrenocorticism. which may allow the functional tumors to be independent of
Bar = 1 cm. B. Large, polyhedral cortical carcinoma cells forming ACTH stimulation for secretion of cortisol. Many of the clini-
clusters with lack of the typical narrow cord formation seen in cal signs and lesions of naturally occurring hyperadrenocorti-
the normal adrenal cortex. There are also small carcinoma cells cism can be induced by the long-term, daily administration of
present. large doses of corticosteroids for the treatment of other
diseases.
The appetite and intake of food often are increased as a
adenomas and carcinomas will be variably positive for the direct result of either the hyperadrenocorticism or the destruc-
same antigens. tion of hypothalamic centers that control appetite by a dor-
Carcinomas and adenomas of the adrenal cortex in dogs sally expanding pituitary tumor. The muscles of the extremities
occasionally are functional and secrete excessive amounts of and abdomen are weakened and atrophied. The loss in tone
hormone, usually cortisol. Approximately 15% of dogs with of the abdominal muscles and muscles of the appendicular
hyperadrenocorticism (Cushing’s disease) are due to func- skeleton results in gradual abdominal enlargement, lordosis,
tional adrenal tumors, whereas 85% of dogs have pituitary muscle trembling, and a straight-legged, skeletal-braced
tumors that secrete ACTH. The clinical picture of adrenal posture (Fig. 3-104). Profound atrophy of the temporal
cortical carcinoma may be complicated by compression of muscles may result in obvious concave indentations and
adjacent organs by the large tumor, invasion into the aorta or readily palpable prominences of underlying skull bones. Hepa-
caudal vena cava leading to intra-abdominal hemorrhage, and tomegaly resulting from increased fat and glycogen deposition
metastases to distant sites. may contribute to the development of the distended, often
Functional cortical adenomas and carcinomas are associ- pendulous, abdomen. The muscular asthenia and wasting is
ated with atrophy of the contralateral cortex because of nega- the result of increased catabolism of structural proteins, com-
tive feedback inhibition of pituitary ACTH secretion by the bined with diminished protein synthesis, under the influence
elevated blood cortisol levels. The atrophic cortex consists of long-term cortisol excess.
primarily of the adrenal capsule and zona glomerulosa. Few Skin lesions occur in a high percentage of dogs with hyper-
secretory cells remain in the zonae fasciculata and reticularis. adrenocorticism. The initial changes in the skin often are
Similar atrophy may be present in the remnants of com- observed over points of wear, such as neck, flanks, behind the
pressed adrenal cortex around functional adenomas. The ears, and over bony prominences. These initial skin changes
adrenal medulla in the contralateral gland may appear spread in a bilaterally symmetrical pattern to involve a signifi-
expanded and more conspicuous because of the lack of corti- cant percentage of the body surface. The basic skin lesion
cal parenchyma. of cortisol is atrophy of the epidermis and pilosebaceous
Adrenal Cortex 347
B
A
C D
Figure 3-106 Adrenal hyperplasia and tumors in a ferret. A. Adrenal cortical adenoma. Note that
the adenoma consists of well differentiated, polyhedral cells with fat vacuoles and spindle-shaped
cells. Inset: Multifocal adrenocortical hyperplasia with a focal adenoma (arrowhead) replacing the
normal adrenal cortex and medulla. B. The spindle-shaped cells of the adrenal adenoma stain
immunohistochemically positive (brown cytoplasmic staining) for desmin. C. Adrenocortical
carcinoma with replacement of the normal adrenal gland, capsular invasion, and vascular invasion
(arrowhead). D. Adrenocortical carcinoma with small polyhedral cells containing small fat vacuoles
and a region of myxoid differentiation with formation of glands filled with basophilic mucin.
certain disorders characterized by overproduction of adrenal Pheochromocytomas are tumors of chromaffin cells and are
medullary hormones. This is best done on urine samples col- almost always located in the adrenal gland of animals. They can
lected over a 24-hour period as catecholamine overproduction be either unilateral or bilateral (Fig. 3-108A-C). Although size
often is episodic rather than continuous. varies considerably, they often are large (≥10 cm diameter)
and incorporate the majority of the affected adrenal gland. A
small remnant of the adrenal gland often can be found at one
Neoplasms of adrenal medullary secretory cells pole (see Fig. 3-108B). Smaller tumors are completely sur-
Pheochromocytoma and malignant rounded by a thin compressed rim of adrenal cortex. Large
pheochromocytoma pheochromocytomas are multilobular and variegated light
Pheochromocytomas are the most common neoplasms arising in brown to yellow-red as a result of areas of hemorrhage and
the adrenal medulla of animals. They develop most often in necrosis. A useful aid in macroscopic diagnosis of pheochro-
cattle and dogs, and infrequently in other domestic animals. mocytoma is the Henle chromaffin reaction with either potas-
In bulls and humans, pheochromocytomas may develop con- sium dichromate or iodate. Application of Zenker’s solution
currently with calcitonin-secreting C-cell tumors of the to the flat-cut surface of a freshly resected tumor results in
thyroid gland. In some animals, this appears to represent neo- oxidation of catecholamines, forming a dark brown pigment
plastic transformation of multiple types of endocrine cells of within 20 minutes (see Fig. 3-108C).
neuroectodermal origin in the same individual. Malignant Tumor cells in pheochromocytomas vary from small
pheochromocytoma is used to designate medullary tumors that cuboidal or polyhedral cells to large pleomorphic cells with
invade through the adrenal capsule and into adjacent struc- multiple hyperchromatic nuclei (Fig. 3-109). The cytoplasmic
tures or that metastasize to distant sites. area is lightly eosinophilic, finely granular, and plasma
350 CHAPTER 3 • Endocrine Glands Adrenal Medulla
Tyrosine OH
NH2
HO
Tyrosine Neural input
hydroxylase ACTH
O
Dihydroxy- HO
phenylalanine OH
(DOPA) NH2
HO
Aromatic L-amino acid
decarboxylase
HO NH2
Dopamine
HO
Dopamine Neural input
-hydroxylase Adrenal corticoids
OH
HO NH2
Norepinephrine
HO
Phenylethanolamine Adrenal
N-methyl transferase corticoids
(PNMT)
OH H
HO N
CH3
Epinephrine
HO
Figure 3-107 Synthesis of norepinephrine and epinephrine in chromaffin cells of the adrenal
medulla. Tyrosine hydroxylase is the rate-limiting enzyme. Enzymatic conversion of tyrosine to
L-dihydroxyphenylalanine (DOPA) and dopamine occurs in the cytoplasm. Synthesis of norepi-
nephrine occurs in the secretory granule, which is the site of dopamine β-hydroxylase. Norepi-
nephrine leaves the secretory granules and is converted to epinephrine in the cytoplasm by
phenylethanolamine-N-methyltransferase (PNMT) and then re-enters the secretory granules.
ACTH, adrenocorticotropic hormone. (From Rosol TJ, et al. Toxicol Pathol 2001;29:41-48.)
membranes often are indistinct because of early onset of cells have a coarsely granular internal core of lower density
autolysis in adrenal medullary tissue. Tumor cells are charac- and a narrow submembranous space (see Fig. 3-110).
teristically subdivided into small lobules by fine connective Small pheochromocytomas are well encapsulated and
tissue septa and capillaries. remain confined to the affected adrenal gland. Larger malig-
Pheochromocytomas are composed of epinephrine-secreting nant pheochromocytomas may exert pressure on and invade
cells, norepinephrine-secreting cells, or both. The principal distin- adjacent tissues, particularly the caudal vena cava and aorta
guishing morphologic feature of these 2 populations of cells is in (Fig. 3-111A). Tumor cells often invade the capsule and pen-
the fine structure of their secretory granules. Pheochromocyto- etrate through the wall of the caudal vena cava, forming a
mas from which norepinephrine is the principal catechol- large thrombus that partially occludes the venous return from
amine are composed of cells with secretory granules that have the caudal extremities (Fig. 3-112B). Metastasis occurs to the
an eccentrically situated electron-dense core surrounded by a liver, regional lymph nodes, spleen, and lungs in ~50% of dogs
wide submembranous space (Fig. 3-110). When epinephrine with malignant pheochromocytomas. Growth of tumor cells
is the principal catecholamine, the secretion granules in tumor in a subendothelial location along vascular sinusoids and arti-
factual displacement of clusters of tumor cells into the lumen
of thin-walled veins during sectioning and forced through the
capsule should not be misinterpreted as evidence of malig-
nancy in adrenal medullary neoplasms.
Functional pheochromocytomas with clinical signs related to
catecholamine overproduction occur infrequently in animals.
Tachycardia, edema, and cardiac hypertrophy observed in
dogs and horses with pheochromocytomas have been attrib-
uted to excessive catecholamine secretion. Arteriolar sclerosis
and widespread medial hyperplasia of arterioles have been
reported in dogs with pheochromocytomas that were associ-
ated with clinical signs suggestive of paroxysmal hypertension.
The catecholamine content in pheochromocytomas from
bulls with concurrent C-cell tumors of the thyroid gland is
higher than in the normal bovine adrenal medulla. Urinary
excretion of vanillylmandelic acid and free unconjugated cat-
echolamines is elevated in bulls with pheochromocytomas.
Figure 3-109 Pheochromocytoma in a dog. The neoplastic chro- Mechanisms of adrenal medullary tumor
maffin cells are polyhedral with finely granular cytoplasm and development
form cords or packets separated by fine connective tissue stroma. The cause of pheochromocytomas in domestic animals
The neoplastic cells are similar to normal chromaffin cells. is unknown. Most tumors are sporadic, but a familial
Figure 3-110 Pheochromocytomas from a bull. Left panel: Pheochromocytoma composed pre-
dominantly of cells with ultrastructural characteristics of epinephrine-secreting cells of the adrenal
medulla. Medullary cells contain many secretory granules(s) of low electron density and a narrow
submembranous space. Right panel: Pheochromocytoma composed predominantly of cells with
norepinephrine-secreting cells of the adrenal medulla. Secretory granules(s) have an eccentric
electron-dense core surrounded by a prominent submembranous space.
352 CHAPTER 3 • Endocrine Glands Adrenal Medulla
B
Figure 3-111 Malignant pheochromocytoma in dogs. A. The
malignant pheochromocytoma has invaded through the adrenal
capsule (arrowheads) into the surrounding tissues and around
major regional arteries. Bar = 5 mm. B. A malignant pheochromo-
cytoma (top) has invaded through the caudal vena cava to form
a large intravascular tumor embolus. Bar = 1 cm.
Ganglioneuroma
Ganglioneuromas are benign tumors in the medulla composed of
multipolar ganglion cells and neurofibrils with a prominent
fibrous connective tissue stroma. They usually are well-
differentiated small tumors that, in cattle, often contain
melanin pigment. The surrounding adrenal cortex is com-
pressed to various degrees, depending upon the size of the
tumors. Neoplastic cells in medullary tumors occasionally may
differentiate in 2 directions, resulting in adjacent pheochro-
mocytomas and ganglioneuromas in the same adrenal gland.
Further reading Peterson RA, et al. Adrenal cortical carcinomas with myxoid differen-
Altman NH, et al. Castration and its relationship to tumors of the tiation in the domestic ferret (Mustela putorius furo). Vet Pathol
adrenal gland in the goat. Am J Vet Res 1969;30:583-589. 2003;40:136-142.
Bielinska M, et al. Gonadectomy-induced adrenocortical neoplasia in Power SB, et al. Accidental carbadox overdosage in pigs in an Irish
the domestic ferret (Mustela putorius furo) and laboratory mouse. weaner-producing herd. Vet Rec 1989;124:367-370.
Vet Pathol 2006;43:97-117. Richter WR. Tubular adenomata of the adrenal of the goat. Cornell Vet
Couëtil L, et al. Plasma adrenocorticotropin concentration in healthy 1957;47:558-577.
horses and in horses with clinical signs of hyperadrenocorticism. J Rosenthal KL, Peterson ME. Evaluation of plasma androgen and estro-
Vet Intern Med 1996;10:1-6. gen concentrations in ferrets with hyperadrenocorticism. J Am Vet
Doss JC, et al. Immunohistochemical localization of chromogranin A in Med Assoc 1996;209:1097-1102.
endocrine tissues and endocrine tumors of dogs. Vet Pathol Ross MA, Innes JRM. Dystrophic calcification in the adrenal glands of
1998;35:312-315. monkeys, cats, and dogs. Arch Pathol 1955;60:655-662.
Duckett WM, et al. Functional pheochromocytoma in a horse. Rossmeisl JH, et al. Hyperadrenocorticism and hyperprogesteronemia
Compend Contin Educ Pract Vet 1987;9:1118-1121. in a cat with an adrenocortical adenocarcinoma. J Am Anim Hosp
Favier J, et al. Paraganglioma and phaeochromocytoma: from genetics Assoc 2000;36:512-517.
to personalized medicine. Nat Rev Endocrinol 2015;11:101-111. Shoemaker NJ, et al. Correlation between age at neutering and age at
Fernandez LP, et al. Thyroid transcription factors in development, dif- onset of hyperadrenocorticism in ferrets. J Am Vet Med Assoc
ferentiation and disease. Nat Rev Endocrinol 2015;11:29-42. 2000;216:195-197.
Fox RR, Crary DD. Genetics and pathology of hereditary adrenal hyper- Smallwood LJ, Barsanti JA. Hypoadrenocorticism in a family of Leon-
plasia in the rabbit. J Hered 1978;69:251-254. bergers. J Am Anim Hosp Assoc 1995;31:301-305.
Galac S, et al. Urinary corticoid/creatinine ratios in the differentiation Sponenberg DP, McEntee K. Pheochromocytomas and ultimobranchial
between pituitary-dependent hyperadrenocorticism and hyperadre- (C-cell) neoplasms in the bull: evidence of autosomal dominant
nocorticism due to adrenocortical tumour in the dog. Vet Quart inheritance in the Guernsey breed. Vet Pathol 1983;20:396-400.
1997;19:17-20. Van Der Molen EJ. Toxicological Pathology of Quinoxaline-Di-N-Oxide
Gliatto JM, et al. A light microscopical, ultrastructural and immunohis- Feed Additives for Young Pigs. Utrecht, The Netherlands: Drukkerij
tochemical study of spindle-cell adrenocortical tumours of ferrets. Elinkwijk; 1989.
J Comp Pathol 1995;113:175-183. Weiss CA, Scott MV. Clinical aspects and surgical treatment of hyper-
Gould WJ, et al. Evaluation of urinary cortisol:creatinine ratios for the adrenocorticism in the domestic ferret: 94 Cases (1994-1996). J Am
diagnosis of hyperadrenocorticism associated with adrenal gland Anim Hosp Assoc 1997;33:487-493.
tumors in ferrets. J Am Vet Med Assoc 1995;206:42-46. West JL. Bovine pheochromocytoma: case report and review of litera-
Howell JM, Pickering CM. Calcium deposits in the adrenal glands of ture. Am J Vet Res 1975;36:1371-1373.
dogs and cats. J Comp Pathol 1964;74:280-285. Williams B, Heffess C. Proliferative lesions of the ferret adrenal cortex.
Hullinger RL. Adrenal cortex of the dog (Canis familiaris). Histomorpho- Vet Pathol 1994;31:5.
logical changes during growth, maturity, and aging. Zentralbl Vet- Williams BH, et al. Adrenal teratoma in four domestic ferrets (Mustela
erinaermed C 1978;7:1-27. putorius furo). Vet Pathol 2001;38:328-331.
Kelly DF. Neuroblastoma in the dog. J Pathol 1975;116:209-212. Wright BJ, Conner GH. Adrenal neoplasms in slaughtered cattle.
Kool MMJ, et al. Activating mutations of GNAS in canine cortisol- Cancer Res 1968;28:251-263.
secreting adrenocortical tumors. J Vet Intern Med 2013;27:1486- Yarrington JT, Capen CC. Ultrastructural and biochemical evaluation of
1492. adrenal medullary hyperplasia and pheochromocytoma in aged
Latendresse JR, et al. Pathogenesis of cholesteryl lipidosis of adreno- bulls. Vet Pathol 1981;18:316-325.
cortical and ovarian interstitial cells in F344 rats caused by tricresyl
phosphate and butylated triphenyl phosphate. Toxicol Appl Phar-
macol 1993;122:281-289.
Li X, et al. Neoplastic diseases in ferrets: 574 cases (1968-1997). J Am
Vet Med Assoc 1998;212:1402-1406.
Lo AJ, et al. Treatment of aldosterone-secreting adrenocortical tumors
in cats by unilateral adrenalectomy: 10 cases (2002-2012). J Vet
Intern Med 2013;28:137-143.
Miller CC, et al. Lactation associated with acidophilic pituitary adenoma,
pheochromocytoma, and cystic endometrial hyperplasia in two
goats. J Am Vet Med Assoc 1997;210:378-381.
Newman SJ, et al. Characterization of spindle cell component of ferret
(Mustela putorius furo) adrenal cortical neoplasms—correlation to
clinical parameters and prognosis. Vet Comp Oncol 2004;2:113-
124.
Parnell NK, et al. Hypoadrenocorticism as the primary manifestation of
lymphoma in two cats. J Am Vet Med Assoc 1999;214:1208-1211.
Peterson ME, Feinman JM. Hypercalcemia associated with hypoadre-
nocorticism in sixteen dogs. J Am Vet Med Assoc 1982;181:802-
804.
354 CHAPTER 3 • Endocrine Glands Paragangliomas (Chemodectomas)
Bielinska M, et al. Review paper: origin and molecular pathology of between the ascending aorta and pulmonary artery near the
adrenocortical neoplasms. Vet Pathol 2009;46:194-210. left coronary artery, and scattered in the wall of the pulmonary
Edwards JF, Ralston KE. Adrenal cortex carcinomas with distant metas- artery. Although chemoreceptor tissue appears to be widely
tases in beef cattle at slaughter. J Comp Pathol 2013;149:1-9. distributed in the body, tumors develop principally in the aortic
Galac S, et al. Expression of steroidogenic factor 1 in canine cortisol- and carotid bodies of animals. The genetic pathogenesis of
secreting adrenocortical tumors and normal adrenals. Dom An paragangliomas is similar to pheochromocytoma (see Pheo-
Endocrinol 2014;49:1-5. chromocytoma and malignant pheochromocytoma).
Grossi AB, et al. Histologic and immunohistochemical classification of
41 bovine adrenal gland neoplasms. Vet Pathol 2013;50:534-542. Aortic body adenoma and carcinoma
Kool MMJ, et al. Insulin-like growth factor—phosphatidylinositol 3 Aortic body neoplasms are encountered more frequently than
kinase signaling in canine cortisol-secreting adrenocortical tumors. neoplasms of the carotid body in animals, but the reverse is
J Vet Intern Med 2015;29:214-224. true for humans. These tumors develop primarily in dogs, and
Labelle P. Metastatic tumors to the adrenal glands in domestic animals. infrequently in cats and cattle. Brachycephalic breeds of dogs,
Vet Pathol 2005;42:52-58. such as the Boxer and Boston Terrier, are highly predisposed
Marino G, et al. Ectopic adrenal tissue in equine gonads: morphofunc- to develop tumors of the aortic and carotid bodies.
tional features. Turk J Vet Anim Sci 2012;36:560-565. Aortic body tumors appear most frequently either as single
Reusch CE, et al. Histological evaluation of the adrenal glands of seven masses or as multiple nodules within the pericardial sac near the
dogs with hyperadrenocorticism treated with trilostane. Vet Rec base of the heart (Fig. 3-115A). They vary considerably in size
2007;160:219-224. (0.5-12 cm) with carcinomas, in general, being larger than
Rosol TJ, et al. Disorders of calcium. Hypercalcemia and hypocalcemia. adenomas. Solitary small aortic body adenomas either are
In: DiBartola SP, editor. Fluid Therapy in Small Animal Practice. 2nd attached to the adventitia of the pulmonary artery and ascend-
ed. Philadelphia: WB Saunders; 2000. p. 108-162. ing aorta or are embedded in the adipose connective tissue
Rosol TJ, et al. Adrenal gland: structure, function, and mechanisms of
toxicity. Toxicol Pathol 2001;29:41-48.
Salesov E, et al. Urinary and plasma catecholamines and metaneph-
rines in dogs with pheochromocytoma, hypercortisolism, nonadre-
nal disease and in healthy dogs. J Vet Intern Med 2015;29:597-602.
Walczak EM, Hammer GD. Regulation of the adrenocortical stem cell
niche: implications for disease. Nat Rev Endocrinol 2015;11: a
14-28.
PARAGANGLIOMAS (CHEMODECTOMAS)
Development, structure, and function
Paragangliomas are neuroendocrine tumors derived from cells
of the neural crest and occur in association with sympathetic
or parasympathetic ganglia in the body (head, neck, thorax,
and abdomen). Synonyms include chemodectoma and glomus
tumors. They usually are benign. In domestic animals, most A
paragangliomas occur in dogs and are derived from the che-
moreceptor organs (nonchromaffin extra-adrenal paraganglia),
which are sensitive to changes in the blood carbon dioxide
content, pH, and oxygen tension, thereby aiding in the regula-
tion of respiration and circulation. Carotid and aortic bodies
can initiate an increase in the depth, minute volume, and rate
of respiration by way of parasympathetic nerves, and result in
an increased heart rate and elevated arterial blood pressure by
way of the sympathetic nervous system. They are composed
normally of parenchymal (chemoreceptor, glomus) cells and stel-
late (sustentacular) cells. Nerve endings with synaptic vesicles
as well as nerve fibers are seen in close association with the
chemoreceptor cells.
Chemoreceptor tissue is present at several sites in the body,
including the carotid body, aortic bodies, nodose ganglion of B
the vagus nerve, ciliary ganglion in the orbit, pancreas, bodies
on the internal jugular vein below the middle ear, and glomus Figure 3-115 Aortic body tumor in dogs. A. Aortic body tumor
jugulare along the recurrent branch of the glossopharyngeal (arrowheads) at the base of the heart of a dog, adjacent to the
nerve. Aortic bodies of dogs normally consist of clusters of aorta (a). Bar = 1 cm. B. Aortic body tumors consist of sheets or
cells embedded in adventitia at multiple sites, including the clusters of polyhedral cells with eosinophilic or vacuolated cyto-
innominate artery immediately below the origin of the right plasm separated by fine fibrous stroma. Most tumors contain
subclavian artery, on the cranial surface of the aortic arch, scattered hypertrophic giant cells with lobulated karyomegalic
beneath the arch between the aorta and pulmonary artery, nuclei (arrow).
Paragangliomas (Chemodectomas) 355
between these major vascular trunks. They have a smooth reported cases of carotid body tumors also had aortic body
external surface and on cross-section are white, mottled tumors.
with red to brown areas. Larger adenomas may indent the atria The histologic characteristics of chemoreceptor tumors
or displace the trachea, are multilobular, and partially sur- (“chemodectomas”) are essentially similar whether they are
round the major arterial trunks at the base of the heart. derived from the carotid or aortic body. The neoplastic che-
Although the vessels may be completely surrounded by neo- moreceptor cells are subdivided into lobules by prominent
plastic tissue, there usually is little evidence of vascular branching trabeculae of connective tissue that originate from
constriction. the fibrous capsule. They are further subdivided into small
Aortic body carcinomas occur less frequently in dogs than compartments by fine septa that contain collagen and reticulin
adenomas. Carcinomas may infiltrate the wall of the pulmo- fibers plus small capillaries. Tumor cells are commonly aligned
nary artery to form papillary projections into the lumen or along and around small capillaries. Most tumors contain a
invade through the wall into the lumen of the atria. Although variable number of large hypertrophied giant cells with irregu-
tumor cells often invade blood vessels, metastases to the lung lar or lobated karyomegalic nuclei (Fig. 3-115B).
and liver occur infrequently. The tumor cells of chemodectomas are discrete, cuboidal
Aortic body tumors in animals tend to be more benign than to polyhedral, and closely packed. The cytoplasm is lightly
tumors of the carotid body. They grow slowly by expansion eosinophilic, finely granular, and often vacuolated. Cells
and exert pressure on the vena cava and atria. Aortic body comprising chemodectomas rapidly undergo autolysis. Cell
carcinomas may invade locally into the atria, pericardium, and boundaries become indistinct, and the cytoplasm appears
adjacent large thin-walled vessels. When they metastasize, sec- clear if the postmortem interval is prolonged. Chromaffin gran-
ondary foci of growth are found most frequently in the lung ules cannot be demonstrated in the cytoplasm of cells comprising
and liver. chemodectomas, in contrast to pheochromocytomas of the
Tumors of the aortic bodies in animals are not functional adrenal medulla. However, the tumor cells contain variable
(i.e., they do not secrete excess hormone into the circulation), numbers of endocrine secretory granules that can be demon-
but may result in a variety of functional disturbances as space- strated by electron microscopy and will stain immunohisto-
occupying lesions. These include manifestations of cardiac chemically positive for chromogranin A. The tumor cells may
decompensation caused by pressure on the atria, vena cava, or also be positive for neuron-specific enolase, synaptophysin,
both, associated with larger aortic body adenomas and carci- and S-100 protein, but not all cases will be positive for these
nomas. There may be dyspnea, coughing, vomiting, cyanosis, markers.
hydrothorax, hydropericardium, ascites, edema of the subcu- Cells of aortic and carotid body tumors in the dog resemble
taneous tissue (involving head, neck, and forelimbs), and those in normal chemoreceptor tissue, but lack the normal
passive congestion of the liver. The accumulation of serous, relationship to sustentacular, neural, and vascular elements.
often blood-tinged, fluid in the pericardial sac, results from The large polyhedral chemoreceptor or parenchymal cells are
the invasion of tumor cells into lymphatics at the base of the arranged in small clusters. The cytoplasmic density of the
heart or the compression of small pericardial veins. neoplastic cell varies from light to dark, depending on the
development of secretory organelles and numbers of storage
Carotid body adenoma and carcinoma granules.
Carotid body neoplasms arise near the bifurcation of the common Carotid body tumors are very vascular and have numerous
carotid artery in the cranial cervical area. They usually appear muscular arterioles, large thin-walled veins, and an abundant
as a unilateral slow-growing mass and only rarely develop on network of capillaries in the connective tissue septa. There are
both sides in the same animal. focal areas of hemorrhage from disruption of thin-walled
Carotid body adenomas are well encapsulated, have a vessels and areas of coagulative necrosis. Several layers of
smooth external surface, and are 1-4 cm in diameter. The tumor cells may radiate along fine connective tissue septa
bifurcation of the carotid artery is incorporated in the mass, from the thin-walled vessels. Tumor cells frequently invade
and tumor cells adhere firmly to the tunica adventitia. A blood vessels and lymphatics with the formation of emboli.
branch of the glossopharyngeal nerve may be traced into the Carcinomas have evidence of tumor cell invasion through the
capsule of the tumor by careful dissection. Adenomas are firm, capsule and into the walls of large muscular arteries and adja-
white with scattered areas of hemorrhage, and extremely vas- cent structures.
cular. Complete surgical excision or biopsy often is difficult Dogs with carotid body tumors usually are presented with
due to the high degree of vascularity and intimate relationship a palpable, slowly enlarging mass in the craniolateral cervical
with major arterial trunks in the neck. region near the angle of the mandible. Larger neoplasms inter-
Carotid body carcinomas are larger (up to 12 cm in diam- fere with swallowing because of pressure on the esophagus
eter) and more coarsely multinodular than adenomas. and result in circulatory disturbances from compression of the
Although malignant carotid body tumors appear to be encap- larger veins in the neck. Other functional disturbances may
sulated, tumor cells invade the capsule and penetrate into the be related to the presence of an aortic body tumor in the same
walls of adjacent vessels and lymphatics. The external jugular animal.
vein and several cranial nerves (in addition to the carotid Carotid body tumors tend to be more malignant than aortic
bifurcation) may be incorporated by the neoplasm. Larger body tumors, and metastases are present in about 13 of reported
tumors can result in extensive dorsolateral deviation of the cases. The presence of tumor cell emboli in vascular or lym-
trachea. Metastases of carotid body tumors occur in about 13 phatic spaces in a biopsy of a primary chemodectoma does
of cases and have been found in the lung, bronchial and medi- not necessarily indicate that metastases are present in distant
astinal lymph nodes, liver, pancreas, and kidney. Multicentric organs.
neoplastic transformation of chemoreceptor tissue occurs fre- The etiology of carotid and aortic body tumors is unknown,
quently in brachycephalic breeds of dogs. About 2 3 of the but it appears that a genetic predisposition aggravated by chronic
356 CHAPTER 3 • Endocrine Glands Multiple Endocrine Neoplasia (MEN)
hypoxia may account for the higher risk of certain brachyce- and finely granular, often with indistinct individual cell bound-
phalic breeds, such as the Boxer and Boston Terrier. Carotid aries. The neoplastic cells stain positive by immunohistochem-
bodies of several mammalian species, including dogs, undergo ical methods for chromogranin A and neuron-specific enolase.
hyperplasia when subjected to chronic hypoxia by living in a Ultrastructurally, neoplastic cells of orbital paragangliomas in
high-altitude environment. People and cattle living at high horses are similar to those in canine aortic and carotid body
altitudes have a higher frequency of chemodectomas com- tumors, with typical membrane-bound secretory granules and
pared to those living at sea level. prominent arrays of rough endoplasmic reticulum.
Surgical removal of the tumors by transpalpebral orbital
Heart-base tumors derived from exenteration has been performed with variable success,
ectopic thyroid depending upon the degree of local tissue invasion of the
Adenomas and carcinomas derived from ectopic thyroid tissue tumor beyond the orbit. Manipulation of the tumors during
account for ~5-10% of “heart-base” tumors in dogs. They often surgery may result in hypotension.
compress or invade structures in the cranial mediastinum near
the base of the heart. Areas of ectopic thyroid tumors with a
compact cellular (solid) pattern of arrangement are difficult Further reading
to distinguish histologically from aortic body tumors. Cells Aupperle H, et al. Primary and secondary heart tumours in dogs and
comprising ectopic thyroid tumors generally are smaller than in cats. J Comp Pathol 2007;136:18-26.
aortic body tumors, with more hyperchromatic nuclei and eosino- Brown PJ, et al. Immunohistochemical characteristics of canine aortic
philic cytoplasm. and carotid body tumours. J Vet Med A Physiol Pathol Clin Med
Neoplastic thyroid follicular cells are not consistently sub- 2003;50:140-144.
divided into small packets by fine strands of connective tissue. Ilha MRS, Styer EL. Extra-adrenal retroperitoneal paraganglioma in a
Tumor giant cells are infrequent in ectopic thyroid tumors, dog. J Vet Diagn Invest 2013;25:803-806.
and the stroma is less prominent. Multiple sections usually Miesner T, et al. Extra-adrenal paraganglioma of the equine orbit: six
reveal the formation of primitive follicular structures or colloid- cases. Vet Ophthalmol 2009;12:263-268.
containing follicles by neoplastic follicular cells in ectopic Paltrinieri S, et al. Pathologic and immunohistochemical findings in a
thyroid tumors but not in aortic body tumors. Thyroglobulin feline aortic body tumor. Vet Pathol 2004;41:195-198.
immunohistochemistry can be used to confirm a diagnosis of Rizzo SA, et al. Malignant mediastinal extra-adrenal paraganglioma
ectopic thyroid tumor if typical follicle structures and colloid with spinal cord invasion in a dog. J Vet Diagn Invest 2008;20:272-
are not present. Ectopic thyroid carcinomas arising at the base 275.
of the heart in dogs either remain localized and enlarge in the Uchida K, et al. Glomus tumor in the digit of a cat. Vet Pathol
cranial mediastinum or occasionally metastasize to extratho- 2002;39:590-592.
racic sites.
Extra-adrenal paragangliomas
MULTIPLE ENDOCRINE NEOPLASIA (MEN)
Benign and malignant extra-adrenal paragangliomas in the
mediastinum or retroperitoneum are occasionally reported in Multiple endocrine neoplasia (MEN) occurs in humans who
the horse, dog, cat, or other species. The tumors originate from have a genetic predisposition to developing endocrine tumors
chromaffin or nonchromaffin paraganglia. The chromaffin in multiple organs. There are different subtypes of MEN,
paraganglia are ganglia of the sympathetic truck, such as the depending on the genetic pathogenesis, which include MEN1,
aortic-sympathetic ganglion (organ of Zuckerkandl) near the MEN2A, MEN2B, and familial medullary thyroid carcinoma
adrenal gland. Tumors of chromaffin paraganglia are con (FMTC). Medullary thyroid carcinoma is the term used for
sidered extra-adrenal pheochromocytomas. The tumor cell C-cell carcinoma in humans.
morphology and pattern of paragangliomas are typical of neu- • MEN1 patients have islet cell tumors, pituitary adenoma,
roendocrine tumors or chemodectomas and may stain immu- and parathyroid hyperplasia caused by mutation of the
nohistochemically positive for chromogranin A, neuron-specific MEN1 gene that encodes for menin, which is a tumor
enolase, or synaptophysin. Metastases of the malignant neo- suppressor.
plasms are reported to occur to the brain, lung, kidney, spleen, • MEN2A patients have parathyroid hyperplasia, C-cell
or thyroid gland. tumors or hyperplasia, and pheochromocytoma as the
result of a gain-of-function rearrangement of the RET
Orbital (extra-adrenal) paragangliomas proto-oncogene, which is a cell membrane tyrosine kinase.
A unique extra-adrenal paraganglioma occurs in horses, result- • MEN2B patients have C-cell tumor or hyperplasia, and
ing primarily in clinical signs related to exophthalmos. The pheochromocytoma, also because of activation of RET.
lesion appears to be derived from cells of neural crest origin, • FMTC patients have familial C-cell tumors caused by acti-
most likely nonchromaffin paraganglia near the ciliary gan- vation of RET and the NTRK gene (receptor tyrosine
glion. The neoplastic cells usually invade locally in the retro- kinase for nerve growth factor).
bulbar space but may infiltrate more aggressively through the Sporadic MEN has been reported in animals, such as dogs,
optic canal into the cranial vault, resulting in lysis of bone and cats, horses, cattle, and rarely in other species. The genetic
extension into the nasal cavity. pathogenesis has not been discovered in most cases, which
The tumors are densely cellular with nests or packets of may differ from the conditions described in humans, because
neoplastic cells subdivided by a fine fibrovascular (reticulin- the spectrum of neoplasia is variable. Rats have a high back-
positive) stroma characteristic of neuroectodermal-derived ground incidence of C-cell tumors, but it appears that the RET
tumors. The cytoplasmic area is abundant, lightly eosinophilic, proto-oncogene does not play a role in the pathogenesis.
356.e1
Further reading
Arias-Stella J, Bustos F. Chronic hypoxia and chemodectomas in bovines
at high altitudes. Arch Pathol Lab Med 1976;12:636-639.
Cheville NF. Ultrastructure of canine carotid body and aortic body
tumors: comparison with tissues of thyroid and parathyroid origin.
Vet Pathol 1972;9:166-189.
Cho K-O, et al. Metastatic intracavitary cardiac aortic body tumor in a
dog. J Vet Med Sci 1998;60:1251-1253.
Chou C-L, et al. Electrophysiological and immunocytological demon-
stration of cell-type specific responses to hypoxia in the adult cat
carotid body. Brain Res 1998;789:229-238.
Edwards C, et al. The carotid body in animals at high altitude. J Pathol
1971;104:231-238.
Hardcastle MR, et al. Carotid and aortic body carcinomas (chemodec-
tomas) in a dog. J Am Vet Med Assoc 2013;242:175-177.
Hayes HM, Sass B. Chemoreceptor neoplasia: a study of the epidemio-
logical features of 357 canine cases. J Vet Med (A) 1988;35:401-
408.
Herbach N, et al. Metastatic extra-adrenal sympathetic paraganglioma
in a horse. J Comp Pathol 2010;143:199-202.
Hoglund R. An ultrastructural study of the carotid body of horse and
dog. Z Zellforsch Mikrosk Anat 1967;76:568-576.
Kameda Y. The accessory thyroid glands of the dog around the intra-
pericardial aorta. Arch Histol Jpn 1972;34:375-391.
Kumamoto K, et al. Malignant aortic body tumor in a Holstein cow.
J Vet Med Sci 1997;59:383-385.
Levy M, et al. Chemodectoma in a horse. Can Vet J 1990;31:776-777.
Obradovich JE, et al. Carotid body tumors in the dog. Eleven cases
(1978-1988). J Vet Intern Med 1992;6:96-101.
Patnaik AK, et al. Extra-adrenal pheochromocytoma (paraganglioma)
in a cat. J Am Vet Med Assoc 1990;197:104-106.
Sander CH, Whitenack DI. Canine malignant carotid body tumor. J Am
Vet Med Assoc 1970;156:606-610.
Shinya K, et al. Glomus tumor in a dog. J Vet Med Sci 1997;59:949-
950.
Smith P, et al. The earliest histopathological response to hypobaric
hypoxia in rabbits in the Rifugio Torino (3370 M) on Monte Bianco.
J Pathol 1993;170:485-491.
van Maanen C, et al. Three cases of carcinoid in the equine nasal cavity
and maxillary sinuses: histologic and immunohistochemical fea-
tures. Vet Pathol 1996;33:92-95.
van Nes JJ, et al. Glomus jugulare tumour in a dog; a case report.
Tijdschr Diergeneeskd 1978;103:1091-1098.
Willis R, et al. Aortic body chemodectoma causing pulmonary oedema
in a cat. J Small Anim Pract 2001;42:20-23.
Yates WDG, et al. Chemoreceptor tumors diagnosed at the Western
College of Veterinary Medicine 1967-1979. Can Vet J 1980;21:
124-129.
Multiple Endocrine Neoplasia (MEN) 357
Further reading
De Cock HEV, MacLachlan NJ. Simultaneous occurrence of multiple
neoplasms and hyperplasias in the adrenal and thyroid gland of
the horse resembling multiple endocrine neoplasia syndrome: case
report and retrospective identification of additional cases. Vet
Pathol 1999;36:633-636.
Kiupel M, et al. Multiple endocrine neoplasia in a dog. J Comp Pathol
2000;123:210-217.
Walker MC, et al. Multiple endocrine neoplasia type 1 in a crossbred
dog. J Small Anim Pract 2000;41:67-70.
CHAP TER 4
Female Genital System
Donald H. Schlafer • Robert A. Foster
PATHOLOGY OF THE GENITAL SYSTEM OF THE INFLAMMATORY DISEASES OF THE UTERUS 387
NONGRAVID FEMALE 359 General considerations 387
GENERAL INTRODUCTION 359 Endometritis 388
Unique challenges presented by the female Metritis 389
reproductive system 359 Chronic endometritis 389
DISORDERS OF SEXUAL DEVELOPMENT 360 Uterine abscess 390
Normal sexual differentiation 360 Parametritis and perimetritis 390
Establishment of sex chromosomes 360 Pyometra 390
Establishment of gonad phenotype 360 PATHOLOGY OF THE GRAVID UTERUS, PLACENTA,
Phenotypic sexual development 360 AND FETUS 393
Development of the tubular genitalia 360 General considerations 393
Abnormal sexual development 361 Embryonic death 395
Sex chromosome disorders of sexual development 363 Fetal death 395
XY disorders of sexual development 365 Mummification of fetus 395
XX disorders of sexual development 365 Fetal maceration and emphysema 396
Ovary—developmental anomalies 366 Embryonic death with persistence of membranes (cystic
Cysts arising from remnants of developmental structures. 366 placental mole) 396
Arrested development of the paramesonephric duct 367 Adventitial placentation (semiplacenta diffusa) 396
Vaginal anomalies 369 Hydramnios and hydrallantois 397
PATHOLOGY OF THE OVARY (NONDEVELOPMENTAL-RELATED Amniotic plaques, placental mineralization, and avascular
CONDITIONS) 370 chorion 397
Miscellaneous lesions 370 Prolonged gestation 397
Age-related degenerative changes 371 ABORTION AND STILLBIRTH 398
Equine ovarian varicosities 371 Diagnosing the infectious causes of abortion 399
Ovarian cysts 371 Bacterial causes of abortion 402
Germinal inclusion cysts of the mare 372 Brucellosis 402
Cystic follicular disease 372 Campylobacter infections of the genital tract in sheep
Cystic ovarian disease in cows 372 and cattle 406
Luteinized cyst 373 Flexispira rappini infections 408
Extra-ovarian lesions associated with cystic ovarian Listeriosis 408
degeneration in cows 373 Leptospira infections causing abortion in cattle 409
Cystic ovarian degeneration in other species 374 Leptospira infections of the pregnant uterus in swine 410
NEOPLASTIC CONDITIONS OF THE OVARY 375 Leptospira infections causing abortion or stillbirth in horses 411
Sex cord–stromal tumors 375 Leptospira infections causing abortion in sheep 411
Tumors of the surface celomic epithelium 377 Ureaplasma diversum infection 411
Tumors of germ cells 377 Trueperella pyogenes as a cause of abortion in cattle
Tumors of nongonadal tissues 378 and sheep 412
Metastatic tumors 378 Salmonella as a cause of abortion in sheep and cattle 412
Vascular hamartomas 378 Yersinia pseudotuberculosis as a cause of abortion
PATHOLOGY OF THE UTERINE (FALLOPIAN) TUBES 379 in cattle, sheep, and goats 413
Hydrosalpinx 379 Histophilus somni infections of the pregnant bovine uterus 414
Salpingitis 380 Chlamydophila (Chlamydia) infections causing abortions 414
Pyosalpinx 380 Abortion in sheep, goats, and cattle caused by
PATHOLOGY OF THE UTERUS 380 Coxiella burnetii 416
Abnormalities of position or location 380 Mare reproductive loss syndrome and late-term abortions 417
Circulatory disturbances 381 Nocardioform placentitis in mares 417
PATHOLOGY OF THE ENDOMETRIUM 382 Miscellaneous infections causing abortion in mares 417
Irregularities of endometrial growth 382 Mycotic abortion in cattle 418
Atrophy 382 Epizootic bovine abortion 419
Hyperplastic conditions of the endometrium 382 Protozoan infections causing abortions 420
Adenomyosis 385 Toxoplasmosis 420
Endometrial polyp 385 Neospora infections causing reproductive failure in cattle,
Uterine accumulation of secretory or sheep, dogs, and cats 421
inflammatory exudates 386 Sarcocystis species causing abortion in cattle, goats,
Hydrometra and mucometra 386 sheep, and pigs 423
Serosal inclusion cysts 386 Genital tritrichomoniasis 423
358
Pathology of the Genital System of the Nongravid Female General Introduction 359
Viral infections of the pregnant uterus 424 Infectious bovine cervicovaginitis and
Porcine reproductive and respiratory syndrome (PRRS) 424 epididymitis (“epivag”) 443
Classical swine fever virus infection of the pregnant Infectious pustular vulvovaginitis of cattle 443
uterus in sows 424 Contagious equine metritis 445
Bovine viral diarrhea virus infection of the pregnant uterus 425 Necrotic vaginitis and vulvitis 445
Border disease virus infection in sheep and goats 426 Dourine 445
Equine arteritis virus infection of the pregnant uterus NEOPLASTIC CONDITIONS OF THE TUBULAR GENITALIA 447
in mares 427 Smooth muscle tumors (leiomyoma, leiomyosarcoma) 447
Wesselsbron virus infection of the pregnant uterus in Canine transmissible venereal tumor 448
sheep and cattle 428 Fibropapilloma of the vulva 449
Porcine parvovirus infection of the pregnant uterus 429 Transmissible genital papilloma of the pig 449
Bovine parvovirus infection of the pregnant uterus in cattle 429 Carcinoma of the endometrium and cervix 449
Canine minute virus infection 430 Lymphosarcoma 450
Bluetongue virus infections of pregnant sheep and cattle 430 Metastatic tumors 450
Epizootic hemorrhagic disease virus infection of the PATHOLOGY OF THE MAMMAE 451
pregnant uterus in cattle, sheep, and white-tailed deer 431 Developmental biology 451
Chuzan disease of cattle 431 Inflammatory disease of the mammary glands 451
Canine herpesvirus infection in pups and pregnant bitches 431 Mechanical injury 451
Suid herpesvirus 1 infection causing abortion in swine 432 Innate and acquired resistance of mammae 451
Suid herpesvirus 2 (cytomegalovirus) infection of the Bovine Mastitis 452
pregnant uterus of the pig 433 Staphylococcal mastitis 452
Bovine herpesvirus infections of the pregnant uterus Coliform mastitis 454
in cattle, goats, sheep, and pigs 433 Streptococcal mastitis 455
Bovine herpesvirus 4 (cytomegalovirus) infection of Summer mastitis 455
the pregnant uterus in cattle 435 Mycoplasma mastitis 456
Equid herpesvirus 1 abortion in horses 435 Miscellaneous infections 456
Akabane virus infection of the pregnant uterus 437 Mastitis in swine 457
Schmallenberg virus infection of cattle, sheep, and goats 438 Mastitis in horses 457
Aino virus infection in cattle 438 Mastitis in sheep and goats 457
Cache Valley virus infection of sheep 438 Mastitis in dogs and cats 458
Rift Valley fever virus infection of cattle and sheep 439 Mastitis in camelids 458
Circovirus postweaning multisystemic wasting syndrome 440 MAMMARY MASSES INCLUDING NEOPLASIA 459
MISCELLANEOUS LESIONS OF THE POSTPARTUM UTERUS 440 Non-neoplastic mammary enlargement and masses 459
Mammary neoplasia in dogs 460
PATHOLOGY OF THE CERVIX, VAGINA, AND VULVA 441 Prognosis and grading of mammary neoplasia 460
PATHOLOGY OF THE CERVIX 441 Benign mammary neoplasms 460
PATHOLOGY OF THE VAGINA AND VULVA 442 Mammary carcinomas 460
Swelling of the vulva 442 Mammary sarcomas 463
Inflammatory diseases of the vagina and vulva 443 Mammary neoplasia in cats 463
Granular vulvitis 443 Mammary neoplasia in other species 464
Mesonephric
tubules
Developing
gonad
Paramesonephric Mesonephric
duct duct
Figure 4-1 Embryonic development of the female genital system.
Initial development of the indifferent ducts, tubules, and external
genitalia is the same in male and female embryos. Anatomically,
Figure 4-2 Abnormal external genitalia of a horse with a disor-
the internal organs in the “indifferent” stage consist of 2 bilaterally
der of sexual development. There is clitoromegaly and partial
symmetrical ductal systems—the mesonephric (Wolffian; male)
fusion of the vulvar lips. The external female genitalia were par-
and paramesonephric (Müllerian; female) ducts—and the devel-
tially masculinized from exposure to testosterone released from
oping, but uncommitted, gonad. Additionally, the mesonephric
testicular tissue (interstitial cells) present in its ovotestes during
duct develops tubular extensions at its cranial end that extend
embryonic development.
into the hilar area of the gonad. Although the uterine tubes,
uterine horns, body, cervix, and cranial vagina develop from the
paramesonephric duct, the mesonephric tubes become the rete
and contribute to the sex cords of the ovary. Normally the ducts becomes more readily available, complete classification
of the opposite sex regress; however, their embryonic remnants becomes possible.
are frequently encountered in otherwise normal adult animals, The main categories begin with the sex chromosome com-
appearing as grossly detectable cystic structures in or near the plement. Disorders are therefore either sex chromosome, XX,
ovary, uterus, cervix, or vagina. (Illustration prepared with the or XY DSD. The presence of the SRY gene is listed next. The
help of Michael Simmons.) gonadal type (ovary, testis, ovotestis, or dysgenesis) follows.
The tubular genitalia and the external appearance are listed.
In completion, a specific syndrome is included. Terms such as
Mesonephric tubules branching from the cranial segment of intersex, ambiguous development, hermaphrodite, or pseudo-
the mesonephric ducts contribute to development of the rete hermaphrodite are therefore avoided.
and sex cords. Abnormal sexual development commonly results in abnormal-
The mesonephric and paramesonephric ducts run parallel appearing external genitalia. As demonstrated in Figure 4-2, a
to one another. Both ductal systems are symmetrically paired photograph of a mare with bilateral ovotestes, the external
and extend caudally toward the urogenital sinus. The cranial genitalia have features that are partially female and partially
ends of the developing paramesonephric ducts do not close male. Testosterone produced by testicular tissues (interstitial
and open directly into the peritoneal cavity, corresponding to endocrine cells) of her ovotestes masculinized her external
the tissue that will become the fimbrial part of the uterine genitalia. The vulva is located more ventrally than in a normal
tube. In domestic animals, the paramesonephric ducts fuse at female, the vulvar lips are variably fused, and there is clitoro-
their caudal ends to form the body of the uterus, the cervix, megaly. Clitoral enlargement is an important indicator of an
and the cranial vagina, each with a single lumen. underlying disorder. The spectrum of changes ranges from
nearly normal-appearing females, with grossly normal ovaries
Abnormal sexual development and uteri, to males with small genitalia, perhaps hypospadias,
Disorders of sexual development (DSD) occur in all domestic and gonads contained in scrotal sacs that look like testes with
species. They result from abnormalities of sex chromosome epididymides, but histologically containing ovarian tissue. It is
origin or inappropriate product; hormone; or receptor upregu- not uncommon to find normal-appearing testes attached to
lation, downregulation, or exposure. The mechanisms involved complete and well-formed uterine horns (Fig. 4-3).
in the production of many abnormalities are not known, and Classification of gonads can be challenging, and patholo-
a condition cannot often be classified precisely. The classifica- gists often have difficulty in identifying ovotestes. Ovotestes
tion of DSD is now based on as complete a description of the contain both ovarian and testicular tissues (Fig. 4-4). Careful
underlying abnormality as possible, beginning with the sex examination of the connective tissue of the outer part of the
chromosome type, presence of SRY, gonad type, tubular genitalia, gonad for ovarian structures is required. Follicles can develop
and external genital phenotype. As sex chromosome typing here and can ovulate, and there may be corpora lutea in
362 CHAPTER 4 • Female Genital System Disorders of Sexual Development
C
Figure 4-4 Section of an ovotestis from a bitch. The gonad is Figure 4-5 Ovotestes from bitches. These 3 subgross photo-
contained within a bursa (visible on the left) and has both ovarian graphs show the variability in amounts of ovarian and testicular
tissue (with primary and antral follicles on the left) and lobules tissue that occur in ovotestes. Microscopically, ovarian tissues are
of hypoplastic testicular tissue in the medullary area (on the right) found in the cortex, and testicular tissues develop in the medulla.
containing seminiferous tubules. Even relatively small areas of A. The ovotestis on the left is mostly ovarian, with only a few
testicular tissue in ovotestes produce sufficient amounts of lobules of hypoplastic seminiferous tubules in the medulla. B. The
2 hormones: testosterone from the interstitial cells and anti- ovotestis is mostly testicular tissue (seminiferous tubules forming
Müllerian hormone from Sertoli cells, which act during early a lobular pattern), but also note the presence of tertiary follicles
gestation to masculinize the developing mesonephric and parame- in the ovarian tissue at the left pole. C. The ovotestis is nearly
sonephric ducts, tubules, and the external genitalia. entirely testicular and has a large epididymis attached.
gonads that also contain male (seminiferous and interstitial proper ligament of the ovary. Ovotestes composed of mostly
endocrine) tissue. Ovotestes will vary greatly in both their testicular tissue will look like hypoplastic testes, have large
gross and microscopic appearance, depending on the relative epididymides, and may be near or in the inguinal canal or
amounts of ovarian and testicular tissue present (Fig. 4-5). scrotal sac. They will, however, be attached to uterine horns.
Ovotestes composed predominantly of ovarian tissues are In dogs, ovotestes are commonly contained within a bursa
usually contained in a bursa. There may be identifiable epi- (Fig. 4-6). Associated developmental changes involving the
didymal tissues at the caudal pole, near the attachment of the tubular genitalia include persistence of variable amounts of
Pathology of the Genital System of the Nongravid Female Disorders of Sexual Development 363
B
Figure 4-10 A. Abnormal vulva from a freemartin heifer (same
animals as in Figure 4-9). Comparison of the external genitalia of
a normal newborn freemartin calf on the right and the prominent
clitoris and a long tuft of hair attached ventrally to the freemartin
calf’s vulva on the left. The vagina is shortened and not patent in
freemartins. B. A key diagnostic feature of the freemartin condition
B is the presence of paired hypoplastic vesicular glands, seen in this
photograph as paired structures extending from the nonpatent
Figure 4-9 A, B. Reproductive organs of a newborn freemartin vagina in the middle of the photograph.
calf. Note the markedly hypoplastic uterine horns, failure of the
paramesonephric ducts to fuse to form a single uterine body,
presence of paired vesicular glands, and abnormal gonads. In panel from cordlike structures without a lumen to well-developed
A, note that the gonads in this case are also hypoplastic and are uterine horns with lumen and endometrial glands. Communi-
sometimes ovotestes. cation with the vagina is always absent, no matter how well
developed the uterus may be.
Vestigial vesicular glands are always present, the vagina is
The gonad of a freemartin is usually a cordlike thickening hypoplastic or nonpatent with a complete hymen, the vulva
in the cranial border of the ovarian ligament. The rete is well and vestibule are hypoplastic, and the clitoris is enlarged.
developed, but other ovarian structures may be absent. Alter- Many freemartins have a prominent fold of skin on the median
natively, greatly reduced ovarian tissue can be present, but it plane of the body, extending from a position ventral to the
lacks the normal germ cell complement. The variation of the vulva to an area near the umbilicus. Mammary glands fail to
tubular genitalia is directly linked to the degree of gonadal develop.
development. When the gonad is predominantly ovary, there Twin ovulation is relatively common in horses. Most twins
is no epididymis and the deferent duct is poorly developed. do not survive to term, but vascular anastomoses with hema-
With increasing differentiation towards a testis, the deferent topoietic chimerism occur in equine twins, although freemar-
duct and epididymis become better developed. The uterus tinism is not proven. Large anastomoses occur between
and uterine tube, of paramesonephric duct origin, may vary chorionic sacs in swine, and freemartinism results. Because of
Pathology of the Genital System of the Nongravid Female Disorders of Sexual Development 365
Cysts arising from either the cranial or caudal segments of cysts, up to 1 cm in diameter, attached to the fimbria of the
the mesonephric tubules are thin-walled, movable cysts at uterine tube (Fig. 4-17). They may be detected by palpation
either the cranial or caudal pole of the ovary and are called or by ultrasonography, but do not reduce fertility. The dif-
cystic epoophoron or paroophoron, respectively, or just cystic ferential diagnosis is a cystic remnant of the mesonephric
mesonephric tubule remnants. Cystic rete are common in the duct, but these are found adjacent to the uterine tube or along
cat and dog and arise from the rete ovarii, which are also the lateral border of the uterine tube, uterine body, or in the
derived from the mesonephric tubules. These arise in the hilar cervix or vagina.
area of the ovary. All cystic remnants of the mesonephric Mesonephric duct remnants are frequently found as small
tubules have smooth muscle in their walls, whereas the cystic cysts lying along the lateral side of the uterine tubes, uterine
rete do not. The epithelial lining is cuboidal in small cysts, horns, uterine body, cervix, or cranial vagina. They are in or
tends to become squamous in slightly larger cysts, and is often near the attachment of the mesosalpinx or mesometrium of
absent due to pressure atrophy in larger cysts. Only the cystic the uterine tube and uterine horns, but those found in the
rete progress to compress ovarian tissues and compromise uterine body and cervix tend to be found within the myome-
ovarian function. Hyperplasia of the rete epithelium is com trium, and those in the vagina are commonly multiple or
mon, and cystic adenomas occur, most commonly in the bitch. linear cystic structures in the submucosa. Animals with disor-
Cystic apical segments of the paramesonephric duct or fim- ders of sexual development and a female phenotype often
brial cysts are common in mares. They are 1 or 2 thin-walled have remnants of mesonephric ducts located in the attach-
ment of the mesometrium and run parallel with the uterine
horns (Fig. 4-18). These have the microscopic appearance of
the deferent duct of the male and have a lumen lined by
epithelial cells and a relatively prominent smooth muscle wall.
Cystic mesonephric duct remnants are common in the cow.
The fluid they contain is usually clear, but may be opaque
(Fig. 4-19).
Duplication of the paramesonephric duct is occasionally
seen in dogs. These have a more complex endometrial type
lining, and the cells become vacuolated in the diestral phase
of the estrus cycle.
Cystic epoophoron
Developing
gonad
Cystic paroophoron
Paramesonephric Mesonephric
duct duct
Figure 4-15 Cysts in or near the ovary and along the uterus are common, but usually incidental
findings. The embryonic origin of several common cysts is shown in this drawing. Details are
provided in the text, and examples of some of these cysts as they occur in different species are
shown in the following figures. (Michael Simmon, illustrator.)
368 CHAPTER 4 • Female Genital System Disorders of Sexual Development
B
Figure 4-22 Double external cervical os. A. As viewed from the
vagina—caused by failure of the medial wall of the mesonephric
ducts to join and dissipate during embryonic development. B. This
defect is demonstrated in the dissected bovine cervix. The uterine
body is normally formed as a result of fusion of the 2 parameso-
Figure 4-21 Segmental aplasia of the left uterine horn of an adult nephric ducts); however, 2 separate cervical canals (demonstrated
cow. The uterine wall has been opened revealing soft tan concre- by the probes), are present in the distal cervix as a result of failure
tions formed from accumulated uterine secretions and sloughed of the medial wall of the joined paramesonephric ducts to fuse
cells. and dissipate. Complete division of both the uterine body and
cervix is less common and when present is called uterus
didelphys.
and uterus become distended and atonic, and severe dilation
leads to atrophy and permanent loss of tone of the walls. If
the hymen is perforated and the distension relieved early, the Dilations and diverticula of the cervix are a cause of infer-
genital tract may function normally. If the hymen is complete, tility in heifers. The malformations occur at the level of the
secretions may accumulate and subsequent bacterial infection third and fourth rugae, and the cervical canal is constricted
of the contents can produce pyometra. In cows, moderate caudal to the defect. The dilated areas are usually spherical
hypoplasia of the cervix, in which some rugae are absent and and located near the internal os. Diverticula are dorsal or
the canal widely patent, may prevent closure of the canal and dorsolateral and eventually become filled with tenacious
predispose to persistent invasion of the uterus and chronic mucus. The cause of the condition is unknown, but is assumed
endometritis. Occasionally, the cervical canal is irregular in its to be developmental.
course or even tortuous. Although this may not interfere with
conception following natural breeding, insertion of an insemi- Vaginal anomalies
nating catheter may be difficult or impossible. Repeated Vaginal stenosis is uncommon in most species, but occurs to
attempts to pass a pipette can lead to cervical trauma, occa- variable degrees in bitches. It may be congenital or acquired.
sionally complicated by formation of traumatic inclusion cysts The stenosis in Figure 4-24 was complete and had caused
or abscesses. dilation of the proximal vagina.
370 CHAPTER 4 • Female Genital System Pathology of the Ovary
Further reading
Campos M, et al. Sry-negative XX sex reversal in a French Bulldog.
Reprod Domest Anim 2011;46:185-188.
Cotinot C, et al. Molecular genetics of sex determination. Semin
Reprod Med 2002;20:157-167.
Ennis S, et al. The diagnosis of freemartinism in cattle using sex-specific
DNA sequences. Res Vet Sci 1999;67:111-112.
Kieffer NM. Male pseudohermaphroditism of the testicular feminizing
type of a horse. Equine Vet J 1976;8:38-41.
Koopman P. Sry and Sox9: mammalian testis-determining genes. Cell
Mol Life Sci 1999;55:839-856.
Koopman P, et al. Male development of chromosomally female mice
transgenic for Sry. Nature 1991;351:117-121.
Lillie FR. The freemartin; a study of the action of sex hormones in the
foetal life of cattle. J Exp Zool 1917;23:371-452.
MacLaughlin DT, Donahoe PK. Sex determination and differentiation.
N Engl J Med 2004;350:367-378.
Nielsen TD, et al. Ovarian cysts in guinea pigs: influence of age and
reproductive status on prevalence and size. J Small Anim Pract
2003;44:257-260.
O’Connor CL, et al. Trisomy-X with estrous cycle anomalies in two
female dogs. Theriogenol 2011;76:374-380.
Rota A, et al. Age dependent changes in plasma anti-Müllerian
hormone concentrations in the bovine male, female, and freemar-
tin from birth to puberty: relationship between testosterone pro-
duction and influence on sex differentiation. Gen Comp Endocrinol
2002;129:39-44.
Rota A, et al. The case of an Sry-negative XX male Pug with an inguinal
gonad. Reprod Domest Anim 2010;45:743-745.
Veitia RA, et al. Testis determination in mammals: more questions than
answers. Mol Cell Endocrinol 2001;179:3-16.
Wilker CE, et al. XX sex reversal in a llama. J Am Vet Med Assoc
1994;204:112-115.
Pathology of the Genital System of the Nongravid Female Pathology of the Ovary 371
form cysts and have a folded, papillary pattern. They are often
multifocal. Figure 4-28 Inclusion cysts of various sizes in the ovarian stroma
The incidence of cysts of the SES increases with age. They adjacent to the ovulation fossa in a mare. The cysts form from
are small, seldom larger than 5 mm in diameter, and can be small pieces of surface epithelium (modified peritoneum) that
located anywhere within the ovary, but their relationship to become entrapped after the surface is disrupted at ovulation.
the surface is usually obvious. These cysts are lined by cuboi- They are usually multiple. These persist for long periods of time
dal epithelium. They do not appear to have any effect on and slowly increase in size, with resultant atrophy of the ovary
fertility, but because the SES are hormonally sensitive, cyst when they become very large. Their location adjacent to the
formation may be associated with hormonal dysfunction. The ovulation fossa and persistence and slow increase in size are char-
lining of the cysts, like the surface epithelium and the SES, acteristic features of germinal inclusion cysts in the ovary of
expresses cytokeratin, and this allows differentiation from mares.
atretic follicular cysts.
Germinal inclusion cysts of the mare is also helpful, but disappointingly is provided inconsistently
Entrapment of small segments of peritoneum is associated in the histories accompanying clinical case submissions. The
with ovulation, and in the mare leads to the development of examining pathologist should persist and insist on receiving as
inclusion cysts that are found near the ovulation fossa (Fig. complete a reproductive history as possible.
4-28). They are also referred to as fossa cysts. Although rather It is only in cattle that the condition has received detailed
commonly encountered as one or a few small cysts lined by study. Accordingly, the major consideration here is of the
epithelial cells (small follicles are lined by granulosa cells) near bovine disease.
the ovulation fossa, they are rarely numerous or large enough
to interfere with ovulation. Occasionally, their expansion can Cystic ovarian disease in cows
lead to atrophy of compressed ovarian tissue with loss of A well-known feature of anovulatory follicular cysts is their
function. relation to nymphomania, but most ovarian cysts are not associ-
ated with signs of persistent estrus. The behavior of cows with
Cystic follicular disease cystic ovaries is variable. The majority of cows with ovarian
Anovulatory cystic ovarian disease occurs in most, if not all, cysts are anestrous. The disease arises from the failure of
species. Its importance as a disease entity varies greatly among mature follicles to ovulate. It occurs most often before the first
species; in domestic species, it is only a serious problem in cows postpartum ovulation. Approximately 45-60% of animals that
and sows. Cystic ovarian disease occurs infrequently in the develop anovulatory follicular cysts will re-establish normal
bitch and queen and rarely in the mare, ewe, doe, and ovarian cycles spontaneously. Cystic follicles may also develop
camelids. after postpartum ovarian cycles have been established, and
Diagnosis depends in part on differentiating anovulatory these cysts are more likely to persist if effective treatment is
cystic follicles from normal antral or tertiary follicles. An not instituted.
important criterion for this differentiation is size. Follicles The cause of cystic ovarian disease is not understood in any
larger than they should normally be at ovulation, persistence, species. The disease in cattle occurs more frequently after
and possible associated signs of hyperestrogenism are features parturient or postparturient disease, and there is evidence that
of cystic follicular disease. intrauterine infections play a role in the pathogenesis of the
Tertiary ovarian follicles vary greatly in size between disease. There is clearly a genetic predisposition to the disease
species, ranging from about 3 mm in the queen up to 7 cm in in certain families. The daughters of cows that have had cystic
the mare! Normal follicular diameters near ovulation are ovaries have a substantially increased risk of developing the
approximately 2 cm in the cow, 1 cm in the sheep and pig, disease as compared to the general population. The disease
and 0.75 cm in the dog. Knowledge of the stage of the cycle tends to involve primarily dairy cows, but it can occur in cattle
Pathology of the Genital System of the Nongravid Female Pathology of the Ovary 373
of any breed if they are withheld from breeding for a pro- into the cyst lumen. The oocyte also undergoes degeneration.
longed period of time. One of the factors that has made the The changes of the theca interna are variable. The theca is
understanding of the disease difficult is the definition of the partially luteinized in some cases, whereas in others it degen-
disease itself. Follicular cysts in cattle are usually defined as fol- erates and is infiltrated by fibrous tissue. The luteal tissue may
licles >2.5 cm in diameter that fail to ovulate and may persist. occur in patches or form a crescent of variable thickness.
By the time a follicle can meet the criteria to be defined as
cystic, the conditions that led to its formation have passed and Luteinized cyst
are not available for study. To offset this difficulty, anovulatory This type of cyst develops when ovulation fails to occur and the
ovarian disease has been produced by a variety of experimen- theca undergoes luteinization. There is no ovulation papilla, and
tal techniques. Unfortunately, it is not known whether any, or the luteal mass is smooth and rounded (Fig. 4-30). The cavity
all, of the experimental manipulations induces anovulatory of the cyst is spherical and lined by a layer of fibrous tissue
cystic disease by the mechanisms that operate in the natural adjacent to the zone of luteinized cells. Luteinized cysts occur
disease. more frequently in cattle and swine than in other species of
The most widely held theory of the origin of cystic ovarian domestic animals. Partial luteinization of the wall of follicular
disease has involved aberration of the preovulatory surge of cysts is a common feature in the bitch. In cattle they usually
luteinizing hormone, either the absence of the surge or the occur as single cysts. Single luteinized cysts may occur in
mistiming of the surge. This hypothesis, or some modification pregnant sows, but multiple cysts are associated with
of it, is still the most attractive. Cows that develop cystic infertility.
ovaries as the result of estrogen and progesterone treatment Anovulatory luteinized cysts should not be confused with cystic
have an increased mean basal concentration of luteinizing corpora lutea. A cystic corpus luteum is a corpus luteum that
hormone secretion, with increase in the frequency and ampli- has formed after ovulation and in which a central cavity has
tude of pulses, but the characteristic preovulatory luteinizing persisted in a mass of developing luteal tissue. Cystic corpora
hormone surge is deficient. This increase in luteinizing lutea are not evidence of ovarian malfunction. They form after
hormone secretion is thought to be due to aberrant hypotha- ovulation, and they do not affect the length of the estrous
lamic function altered experimentally by steroids or naturally cycle. If the cow has been successfully bred, the cavity will
by ovarian secretion. slowly become obliterated. Large central cysts may occasion-
The cysts may be single (Fig. 4-29) or multiple on one or ally persist for 30-40 days after conception. Cystic corpora
both ovaries. These cysts may persist, but during the course lutea can be distinguished from luteinized cysts by the ovulation
of the disease, additional cysts may be recruited, and some papilla that distorts the outline of the cyst at the point of ovula-
cysts undergo atresia. Patches of luteal tissue can be seen tion. Additionally, their size is greater reflecting their develop-
grossly in the wall of some of the cysts and can be recognized ment from cystic follicles.
histologically in about a quarter of them. The walls of the cysts Ovarian epidermoid cysts have been recognized in cattle.
show the same type of degeneration that occurs in normal These are reported to be multiple and small and have a squa-
atresia. Degeneration of the granulosa cells takes place first, mous epithelial lining that forms keratin.
the cells undergoing pyknosis and karyorrhexis and sloughing
Extra-ovarian lesions associated with cystic ovarian
degeneration in cows
Changes in other organs develop only if the ovarian cysts
persist. Because most cases are responsive to treatment,
Figure 4-29 Cystic follicle in the ovary of a cow. This condition Figure 4-30 Luteinized follicular cyst from a cow. Note the
is thought to be due to inadequate luteinizing hormone release, uniform layer of luteinized cells that line the transected cyst.
resulting in development of an anovulatory follicle, the lining of Because these develop from follicles that have not ovulated, there
which may luteinize to form a luteinized follicular cyst. is no ovulation papilla.
374 CHAPTER 4 • Female Genital System Pathology of the Ovary
Further reading
Bogh IB, et al. Ovarian function and morphology in the mare after
multiple follicular punctures. Equine Vet J 2003;35:575-580.
Cook DL, et al. Secretory patterns of LH and FSH during development
and hypothalamic and hypophysial characteristics following devel-
opment of steroid-induced ovarian follicular cysts in dairy cattle.
J Reprod Fertil 1991;91:19-28.
Edwards JE. Three cases of ovarian epidermoid cysts in cattle. Vet
Pathol 2002;39:744-746.
Gumen A, et al. A GnRH/LH surge without subsequent progesterone
exposure can induce development of follicular cysts. J Dairy Sci
2002;85:43-50.
McCue PM, Squires EL. Persistent anovulatory follicles in the mare.
Theriogenol 2002;58:541-543.
376 CHAPTER 4 • Female Genital System Neoplastic Conditions of the Ovary
Figure 4-33 Enlarged ovary from a mare that has been nearly Figure 4-34 Granulosa cell tumor from a mare. The tumor has
completely replaced by a large expanding granulosa cell tumor. been bisected and reveals a very characteristic gross appearance.
The red tissue on the surface of the mass in the center is the Neoplastic granulosa cells form follicle-like cavities lined by neo-
displaced congested fimbria. The ovulation fossa is lost due to plastic granulosa cells. Solid forms of this tumor occur less
expansion of the tumor. commonly.
Further reading
Ellenberger C, et al. Histomorphological and immunohistochemical
characterization of equine granulosa cell tumours. J Comp Pathol
2007;136:167-176.
Hsu FS. Ovarian hemangioma in swine. Vet Pathol 1983;20:401-409.
Lappohn RE, et al. Inhibin as a marker for granulosa-cell tumors. N Engl
J Med 1989;321:790-793.
Patnaik AK, Greenlee PG. Canine ovarian neoplasms: a clinicopatho-
logic study of 71 cases including histology of 12 granulosa cell
tumors. Vet Pathol 1987;24:509-514.
Scully RE. Ovarian tumors: a review. Am J Pathol 1977;87:686-720.
380 CHAPTER 4 • Female Genital System Pathology of the Uterus
is at best only partial expression of the body) is not difficult, and fusion of the mucosal folds, or chronic granulation tissue.
but because of its vascularity, there is always some hemor- The length of the tube is usually not uniformly involved
rhage, varying in extent from very slight to fatal. Small clots, by the inflammatory process; rather, there are segments in
which are usually retained in the bursa, can be completely which the reaction is more acute or more advanced so that
resorbed. Larger clots must be organized, and this results in the obstruction tends to involve irregular segments with the
the formation of adhesions within the bursa and the fimbri- intervening portions distended with exudate.
ated portion of the tube. With more extensive hemorrhage, The entire thickness of the wall of the duct is infiltrated
adhesions may form to adjacent abdominal viscera and other with neutrophils, lymphocytes, and plasma cells, and the same
genital tissues. cells collect in the lumen and in the mucosal cysts formed by
adhesions between the denuded epithelial folds. Surviving
Salpingitis epithelium may be partly squamous. Eventually, the bacteria
The uterine tube is a rather simple structure histologically, but will be destroyed and the exudate converted to a watery fluid
even minor inflammatory changes, evidenced by slight conges- (hydrosalpinx). Frequently, accompanying pyosalpinx are the
tion or the presence of a few plasma cells, appear to be bursal adhesions and local peritonitis described earlier.
important because of the readiness with which the epithelial Among the organisms that may be found in inflammatory
cells desquamate or lose their cilia. The proper function of the diseases of the uterine tube are streptococci, staphylococci,
living epithelium is necessary for the propulsion of the ovum, Escherichia coli, and Trueperella pyogenes, with the latter as the
for the dissolution of the cumulus oophorus prior to fertiliza- most common and important. Brucella suis in swine and Myco-
tion, and for the maintenance of a luminal environment suit- bacterium tuberculosis in cattle are responsible for specific
able to survival of the ovum. The salpingeal mucosa has much forms of salpingitis; the lesions are as described for these infec-
less capacity for restitution than does the endometrium. tions in the uterus.
Inflammation of the uterine (fallopian) tubes without signifi- Miscellaneous uncommon diseases of the uterine tubes
cant enlargement is the most common and most important tubal such as neoplasms are reported, for instance, leiomyoma,
lesion. It is usually bilateral; is usually not detectable macro- fibroadenoma, adenoma, and adenocarcinoma. Metastases
scopically; and may show serous, catarrhal, or fibrinous inflam- from ovarian neoplasms also implant within the uterine tubes.
mation. In the mildest forms of salpingitis, the mucosa alone Cystic remnants of mesonephric and paramesonephric duct
is affected, and changes of functional significance may be occur.
slight enough to be overlooked histologically. Congestion of
the mucosal vessels, mononuclear cell infiltration, loss of epi-
thelial cilia, and some desquamation of epithelium may be the PATHOLOGY OF THE UTERUS
only changes detectable. With more severe infections, catarrhal Abnormalities of position or location
exudate collects in the lumen, the mucosal folds are thickened Torsion of the uterus is uncommon except in the cow and mare.
by cellular infiltration and congestion, and the epithelium is In almost all cases, such twisted uteri are pregnant (Figs. 4-42,
in large part destroyed. Loss of epithelium occurs first in the 4-43), but torsion may also occur with pyometra, hydrometra,
free edges of the mucosal folds, and these denuded areas tend endometrial polyps, and endometrial neoplasia. The torsion is
to fuse and adhere to produce intramucosal cysts. Alterna- of the same nature as an intestinal volvulus and occurs about the
tively, in chronic catarrhal salpingitis, the mucosa is virtually transverse axis of the organ, with the mesovarium as one fixed
destroyed and replaced by proliferated connective tissue and point. In uniparous species (cow) in which a well-developed
cellular infiltrations with partial or complete occlusion of the intercornual ligament does not permit much independent
lumen. movement of the horns, the entire organ is involved in the
Salpingitis is a common lesion in animals, with both Myco- torsion, which is about the mesovarium and vagina or cervix
plasma and Ureaplasma infections. Nonspecific infections as fixed points. In multiparous species (bitch, cat) with long
causing salpingitis almost invariably do so following spread horns and no intercornual ligament, the torsion will involve
from the uterus. There is probably 70-75% association between part of one horn or the entire horn, the fixed points in the
uterine and salpingeal inflammation when diagnosis of the latter instance being the mesovarium and the site of
latter is based on histologic evidence. In some cases there will
be perimetritis with adhesions, pyosalpinx, or bursal abscess.
Adhesions of the infundibulum of the mare are very common.
The cause of these adhesions is unknown. Some are associated
with perimetritis, but most are not. It has been suggested that
they may develop as a result of ovulatory hemorrhage.
However, this explanation does not easily account for the
substantial predominance of adhesions of the right
infundibulum.
Granulomatous salpingitis is uncommon. When it does
occur, the uterine tube will be firm and distended.
Pyosalpinx
This is less common than hydrosalpinx and typically follows
metritis in the same manner as do other forms of salpingitis.
The significant anatomic difference is the accumulation of pus in
the tube following obstruction of the lumen. The obstruction may
be produced by inspissated exudate, inflammatory thickening, Figure 4-42 Torsion of a gravid bovine uterus.
Pathology of the Genital System of the Nongravid Female Pathology of the Uterus 381
Further reading
Azawi OI, et al. Pathological and bacteriological studies of hydrosalpinx
in buffaloes. Reprod Domest Anim 2010;45:416-420.
Beltman M. A novel twist to uterine torsion and abomasal displace-
ment in dairy cows. Vet J 2013;196:284-285.
Marino G, et al. Adenoma of the uterine tube in the bitch: two case
reports. Vet Res Commun 2007;31:173-175.
Palmieri C, et al. Congenital and acquired pathology of ovary and
tubular genital organs in ewes: a review. Theriogenol 2011;75:393-
410.
Ueno T, et al. Pathology of lethal peripartum broad ligament haema-
toma in 31 Thoroughbred mares. Equine Vet J 2010;42:529-533. A
Further reading
Aubry P, et al. A study of 55 field cases of uterine torsion in dairy cattle.
Can Vet J 2008;49:366-372.
Ellington JE, Schlafer DH. Uterine tube disease in cattle. J Am Vet Med
Assoc 1993;202:450-454.
Gelberg HB, McEntee K. Pathology of the canine and feline uterine
tube. Vet Pathol 1986;23:770-775.
Miesner MD, Anderson DE. Management of uterine and vaginal pro-
lapse in the bovine. Vet Clin North Am Food Anim Pract 2008;24:
409-419.
Pathology of the Genital System of the Nongravid Female Pathology of the Endometrium 383
B
Uterine accumulation of secretory or
inflammatory exudates Figure 4-54 A. Subgross photograph of a cross-section of a
Hydrometra and mucometra uterine horn from a normal bitch for comparison to B, the dis-
The 2 conditions are considered together as the difference is tended uterine lumen from a bitch with hydrometra. Long-
probably only in physical properties and depends on the standing hydrometra or mucometra can lead to atrophy of the
degree of hydration of the mucin, which in turn may be endometrium.
related to the relative activity of estrogenic hormones. The
accumulation of thin or viscid fluid in the uterus is concurrent the ovaries are normal. If affected uteri become infected,
with the development of endometrial hyperplasia or is proximal intractable pyometra results. An abnormally long and tortuous
to an obstruction of the lumen of the uterus, cervix, or vagina. cervix may result in a form of mucometra caused by the reten-
Grossly, there is uniform or segmental distension of the uterus tion of uterine secretions.
(Fig. 4-53). If hydrometra or mucometra persists for a long
time, the endometrium becomes markedly attenuated and will Serosal inclusion cysts
atrophy (Fig. 4-54). Uterine serosal inclusion cysts are thought to arise by pinch-
In cases of congenital or acquired obstruction of the lumen ing off of surface epithelial indentations. They are occasionally
of the tubular genitalia, the volume of fluid that accumulates observed in the aged pluriparous bitch and less commonly in
proximal to the obstruction depends on the site of the obstruc- ruminants, and appear as thin-walled cysts containing clear
tion. In uterus unicornis in cattle, there may be 500 mL; in watery fluid. Serosal inclusion cysts form from small folds of
imperforate hymen, there may be 10 L or more. The fluid is peritoneum that adhere and form entrapped pieces of serosal
slightly cloudy and watery, but in some cases of segmental epithelium that slowly accumulate secreted fluids. They tend
aplasia where the volume of retained secretion is not great, it to occur either during uterine involution or in association with
may be very viscid, ocher colored, and sometimes inspissated perimetritis; however, inflammatory cellular infiltrates are not
to rubbery masses of mucin and cellular detritus. In these cows usually present in or near these cysts.
Pathology of the Genital System of the Nongravid Female Inflammatory Diseases of the Uterus 387
INFLAMMATORY DISEASES OF
THE UTERUS
General considerations
Inflammation limited in extent to the endometrium is termed
endometritis; involvement of the entire thickness of the wall
is metritis; of the serosa, perimetritis; and of the mesome-
trium, parametritis. The classification is to some extent a
A useful index of the severity of reaction and of the pathogen-
esis. The great majority of inflammatory conditions of the
uterus begin in the endometrium and are in some manner
associated with the reproductive process. The predisposing
factors are to be sought then at either end of the gestation
period.
The normal nonpregnant uterus is endowed with a high degree
of resistance to infection, and even in the case of the specific
genital diseases, brucellosis, trichomoniasis, and campylobac-
teriosis, is incapable of supporting bacterial growth or even
the persistence of bacteria for any extended period. Some-
thing is known of factors that render the uterus susceptible,
B at least temporarily, to infection, and more and more is being
Figure 4-55 A. Serosal inclusion cysts on the surface of a canine discovered about innate mechanisms of resistance. The self-
uterus. These cysts develop following adhesion of the serosa to limiting nature of most infections, other than those associated
itself in areas of linear folds. B. Subgross photomicrograph reveal- with pyometra, has long been recognized and formed the basis
ing both the superficial location and very thin walls that are key for the recommendation of a period of sexual rest for animals
features of this condition. with uterine infections. Even the specific genital infections are
self-limited in duration; active infection of a uterus with Cam-
pylobacter fetus or Tritrichomonas foetus, in the absence of
pregnancy, survives only for 2-3 estrus cycles. Brucella abortus
The gross appearance of these cysts can be striking. Most causes infection of the pregnant uterus but does not persist
appear to lie on the surface of the uterus (Fig. 4-55). They well in the nonpregnant uterus, although it is apparently
contain clear fluid and have thin translucent walls. They may capable of persisting in the mammary gland and lymph nodes
vary from a few millimeters to 2 cm or more in diameter. of infected cows.
Serosal inclusion cysts can be distinguished from paraovarian Uterine resistance varies during the estrous cycle, susceptibility
cysts by their location. Similarly, although a differential diag- being greatest during the luteal phase of the cycle. Several factors
nosis would also include mesonephric duct cyst, the latter are may be involved. Uterine motility is increased during estrus,
located along the mesometrium, tend not to be multiple, are and this aids in the physical clearance of microorganisms.
not as superficially located, and microscopically would have Innate immune mechanisms, including pathogen-associated
smooth muscle in their wall. molecular patterns such as Toll-like receptors and defensins,
operate in the endometrium. The epithelium has a cytokine
profile that varies with the cycle and exposure to infectious
Further reading agents. Adaptive immune mechanisms include uterine synthesis
Chambers B, et al. Unilateral uterine torsion secondary to an inflam- and secretion of immunoglobulin G (IgG) and IgA; these vary
matory endometrial polyp in the bitch. Aust Vet J 2011;89:380- during the cycle, but the variations are not great, and the
384. timing varies between species. The functional activity of the
Gifford AT, et al. Histopathologic findings in uterine biopsy samples neutrophils migrating into the uterus may also be affected by
from subfertile bitches: 399 cases (1990-2005). J Am Vet Med the stage of the cycle, being more active during estrus than
Assoc 2014;244:180-186. diestrus, but much of the reduced uterine resistance during
Marino G, et al. Endometrial polyps in the bitch: a retrospective study diestrus and pregnancy is related to secretion into the uterine
of 21 cases. J Comp Pathol 2013;149:410-416. lumen of progesterone-induced immunosuppressants that are
Mir F, et al. Findings in uterine biopsies obtained by laparotomy from capable of inhibiting lymphocyte proliferation. It has been
bitches with unexplained infertility or pregnancy loss: an observa- well demonstrated that the uterus that is under the influence of
tional study. Theriogenol 2013;79:312-322. progesterone (which includes the pregnant uterus) is very suscep-
Nomura K, Funahashi H. Histological characteristics of canine decidu- tible to many nonspecific bacteria and that a uterus not under
oma induced by intrauterine inoculation of E. coli suspension. J Vet the influence of progesterone is remarkably resistant to the
Med Sci 1999;61:433-438. same organism, even when its expulsion is prevented by liga-
Schlafer D, Gifford AT. Cystic endometrial hyperplasia, pseudo- tion of the cervix. This comparison can be carried a step
placentational endometrial hyperplasia, and other cystic conditions further to show that even greater susceptibility to infection is
of the canine and feline uterus. Theriogenol 2008;70:349-358. present at the implantation sites in the pregnant uterus. The
387.e1
Further reading
Adams NR. Pathological changes in the tissues of infertile ewes with
clover disease. J Comp Pathol 1976;86:29-35.
Adams NR. Measurement of histologic changes in the cervix of ewes
after prolonged exposure to oestrogenic clover or oestradiol-17β.
Aust Vet J 1986;63:279-282.
Bellenger CR, Chen JC. Effect of megestrol acetate on the endome-
trium of pre-pubertaly ovariectomised kitten. Res Vet Sci 1990;
48:112-118.
Brodey RS, Fidler IJ. Clinical and pathological findings in bitches treated
with progestational compounds. J Am Vet Med Assoc
1966;149:1406-1415.
Lightfoot RJ, Adams NR. Changes in cervical histology in ewes follow-
ing prolonged grazing on oestrogenic subterranean clover. J Comp
Pathol 1979;89:367-373.
Schlafer D, et al. Theriogenology question of the month: canine endo-
metrial polyp. J Am Vet Med Assoc 1997;210:759-761.
388 CHAPTER 4 • Female Genital System Inflammatory Diseases of the Uterus
uterus after ovariectomy is resistant to infection but does not Mild endometritis may not be overtly evident clinically. A
clear infections as promptly as does the uterus under the influ- slight opacity of the normally crystal-clear estral mucus may
ence of estrogens. These factors of susceptibility and resistance be all that is seen. Histologically, the changes are not striking
provide some insight into the pathogenesis of postcoital and consist for the most part of a diffuse but light infiltration
uterine infections and pyometra in the dog and cat. of neutrophils with slight desquamation of the superficial
A different set of influences operates on the puerperium. epithelium and no significant vascular changes. Involvement
It is well recognized that uterine infections are likely to follow any of the glands is minimal. The significance of a few leukocytes
abnormal parturition, such as an abortion, retained placenta, in the stroma is always equivocal in cattle; they follow within
twin births, dystocia, and traumatic lacerations of the genital 2-3 days of parturition and are present during estrus. However,
canal. Of the specific abortive agents in the cow, C. fetus the presence of neutrophils in the stroma of the endometrium
and T. foetus typically cause early death of the conceptus is evidence of inflammation in the mare. The best indication of
that is not complicated by placental retention or metritis. But endometritis in all species consists of accumulations of plasma
with other causes, B. abortus especially, abortion may occur cells and foci of lymphocytes in the stroma. Resolution of this
later in pregnancy, at which time the well-developed and type of endometritis may occur with no more residue than a
manifold interdigitations of the cotyledons favor retention of few cystic glands with periglandular fibrosis (Fig. 4-56),
the placenta and the development of acute metritis. But in although during its course, it may be responsible for early
these instances, much of the uterine disease is the result of embryonic mortality. If the endometritis is more severe or
secondary invasion by bacteria that gain access to the uterus persists for a longer time, the cumulative damage to the endo-
as the result of an abnormal delivery of a dead or diseased metrium may render the mare sterile.
fetus. Contagious equine metritis is a venereal disease of mares
Some cases of postpartum metritis are a continuation and caused by T. equigenitalis, a gram-negative, microaerophilic
exaggeration of a gestational uterine infection, but most puer- coccobacillus. The disease produced by this organism does not
peral infections of the uterus can be viewed as analogous to wound appear to be significantly different from other common infect-
infections, with the organisms entering via the cervix. Probably ing organisms of the mare’s genitalia. The interest in this
all mares have uterine infections by streptococci within 1-3 disease stems from its apparently abrupt appearance in
days of parturition, but these do not persist for more than 2-3
days. In the cow, too, it has been observed that 25-30% are
infected in the normal puerperium but that most recover
spontaneously from these infections with T. pyogenes, E. coli,
and other bacteria. Clearly, the outcome will be determined
as much by the number and virulence of invading organisms
as by the environment within the uterus. The recognized
predisposing causes outlined previously will all be associated
with retarded uterine involution, as will most cases of metritis.
With the more virulent anaerobic bacteria, such predisposi-
tion is not essential.
The period necessary for normal involution varies with the
species and is determined by the nature of placentation (depth
and nature of invasion—deciduate versus adeciduate) and the
rate of endometrial repair. It is well advanced in the mare
within 9 days, as judged by the capacity for fertile mating at
that time, in contrast to the involutionary process in the bitch,
which involves deposition of material and extensive, slowly A
progressive remodeling. In the latter case, abnormalities of
involution are common and termed subinvolution of placental
sites. Most of these are probably never recognized clinically
and spontaneously regress.
Endometritis
In endometritis, the endometrium or uterine mucosa is mainly
involved. Almost all uterine infections begin as endometritis,
and many such cases progress to involve the myometrium,
becoming metritis. The mildest forms are seen postcoitus. In
the mare, semen is ejaculated directly into the uterus and
induces a transient postcoital endometritis. Such postmating
endometritis is recognized in most species. Infectious agents
tropic for the uterus include T. foetus and C. fetus or pyogenic B
cocci and coliforms of low pathogenicity.
Uterine infection by α-hemolytic streptococci, Klebsiella Figure 4-56 A. Endometrial tissue from a mare with marked
pneumoniae, E. coli, and Taylorella equigenitalis (the contagious lymphocytic endometritis. B. Glandular nesting caused by peri-
equine metritis organism) frequently occurs in mares both glandular fibrosis. Inflammation, gland loss, lymphatic distention,
following foaling and after coitus. The endometritis is usually and fibrosis are histologic features assessed during evaluation of
mild, but the impact on fertility can be substantial. equine endometrial biopsies for categorization.
Pathology of the Genital System of the Nongravid Female Inflammatory Diseases of the Uterus 389
horse-breeding establishments in England in 1977 and its traumatic rupture, perforation with secondary peritonitis is
rapid spread to equine studs around the world. Strict control not common except in anaerobic infections; death in untreated
measures seem to have limited its spread, and the clinical cases usually occurs first from toxemia or septicemia.
disease is now rare. The secretion may be scant or abundant, is fetid, and is
The disease causes temporary infertility in mares and a dirty yellow to red-black. The microscopic picture is that of
mucopurulent discharge that lasts 2-3 weeks. The organism purulent inflammation. Subserosal connective tissues are
can persist in infected mares for several months, and recovered edematous and filled with neutrophils, and the same process
mares represent an important reservoir of infection. Stallions surrounds the blood vessels of the myometrium and perme-
transmit the organism by genital contact but do not develop ates bundles of, and individual, muscle fibers, which them-
clinical disease. selves undergo granular degeneration. In metritis, as in acute
The temporary infertility that is the clinical hallmark of the endometritis, neutrophils are in large numbers on the mucosal
disease is the result of mild to moderate inflammation of the surface, and there is extensive hemorrhage, necrosis, and
endometrium and adjacent structures. After experimental intro- sloughing. Invasion of blood vessels, both arteriolar and venous,
duction of the organism into the uterus, and presumably after intensifies the lesion. Thrombosis may extend to the vessels
natural infection, the bacteria can be regularly demonstrated of mesometrium with the usual sequelae of hemorrhage and
in the uterine tubes, endometrium, cervix, and vagina for a infarction.
2-3 week period, during which time the organism elicits a
mild to moderate inflammatory response. The endometrial Chronic endometritis
folds are turgid and swollen and covered by a small amount Recovery from the acute phase of the infection often results
of cloudy viscid exudate. At this stage, the endometrium is in chronic endometrial involvement. With greater or lesser
edematous and the inflammatory infiltrate consists mainly of degrees of endometrial destruction and replacement by granu-
neutrophils. As the reaction subsides, the edema disappears lation and scar tissue, the uterus takes on the nature of a fis-
and plasma cells predominate. Changes in the cervix parallel tulous tract. The changes depend on the duration and severity
those of the endometrium. Salpingitis develops in some cases of the inflammation, but consist essentially of productive fibrosis
but is a less regular feature of the infection. Infection produces and leukocytosis in which lymphocytes and plasma cells predomi-
no gross changes in the vagina or vaginal vestibule, and histo- nate. Thickening of the endometrium is by inflammatory
logic changes are mild. No lesions develop in the clitoral fossa tissue; the glands are depleted; those that survive are atrophic,
or sinus, but the organism can be recovered from these sites flattened, and attenuated, or cystic because of periglandular
after it has disappeared elsewhere. fibrosis. The lining mucosa may be intact, denuded in places,
More severe grades of endometritis are common to the puer- or show foci of polypoid hyperplasia or squamous metaplasia,
perium in cattle. Nothing of significance may be visible on the as do any chronically irritated mucous membranes. The
serosal surface, but the organ is enlarged and flabby, and col- exudate in the lumen is not copious and may be serous,
lapsed rather than firm and contracted. The lumen contains catarrhal, or frankly purulent. Much of the endometrial
chocolate-colored lochia that is slightly tenacious and often stroma, especially that of caruncles, may be replaced by scar
without foul odor. With the admixture of inflammatory tissue, and dystrophic mineralization of necrotic portions of
exudate and placental detritus, the uterine content becomes the endometrium may sometimes be extensive enough that
progressively dirty gray-yellow. The endometrium is red and the lining of the uterus feels gritty.
swollen, and the intercotyledonary areas are ragged and tat- It is estimated that 20% of cows with generalized tubercu-
tered with shreds of mucosa free in the lumen. Small hemor- losis and 4% of all tuberculous cows have involvement of the
rhages are common in the mucosa, and neutrophils are endometrium. There are 3 routes of infection, namely, hema-
prominent at the surface involving all mucosal elements, togenous, via the uterine (fallopian) tubes from the perito-
including the glands. Where suppuration and superficial neum, and coital; of these, the last is exceptional. As in
necrosis produce the tattered mucosa, the surface is compa- tuberculous lesions generally in cattle, there are 2 anatomic
rable to a pyogenic membrane. The remainder of the genital forms of the lesion—miliary tuberculosis and diffuse caseating
canal may show nothing more than the traumatic lesions tuberculosis, although transitional forms do exist. It is generally
incident to parturition. If the uterus is paretic, there may be accepted that the disseminated miliary lesion is of hematog-
no discharge in the vagina. enous origin during the phase of early dissemination.
Sporadic outbreaks of suppurative endometritis associated In miliary tuberculosis, the uterus may appear normal exter-
with bovine herpesvirus 4 have been reported. The histopa- nally. In the early stages, there may be no exudate in the
thology is typical for herpesvirus infections, with focal necro- lumen, but later, as the granulomas enlarge and ulcerate, the
sis, ulceration, and common secondary bacterial infections. uterus will contain yellow purulent exudate. The granulomas
Intranuclear viral inclusion bodies are found in endometrial are visible as few or many nodules in the mucosa, usually the
epithelial and endothelial cells. more superficial portions, and microscopically are of typical
tuberculoid structure. A common site is near the bifurcation
Metritis of the uterus or in the caruncles of the pregnant uterus.
The distinction drawn here between endometritis and metritis Caseous tuberculosis causes thickening and rigidity of the
for purposes of description is that, in metritis, all layers of the horns with serofibrinous or purulent fluid in the lumen. The
uterine wall show evidence of acute inflammation. The uterus is endometrium is thickened, dry, and extensively caseous (see
paretic, and there may be little or no vaginal discharge. The Fig. 4-59). There may be intense leukocytic infiltration and
wall of the uterus is thickened with suffused blood and edema marked exudation. The caseated area is usually demarcated by
fluid and is very friable. The serosa is dull and finely granular a zone of epithelioid cells from a margin of connective tissue.
with “paintbrush” hemorrhages and a thin deposition of fibrin, In association with the uterine lesion in tuberculosis, there
or the subserosal vessels may be very prominent. Other than is often involvement of other portions of the genital tract.
390 CHAPTER 4 • Female Genital System Inflammatory Diseases of the Uterus
Uterine abscess
The formation of single or multiple abscesses is not common.
The localization of an infection to one part of the uterine wall
is thought to follow severe metritis, localized traumatic injury
to the infected endometrium, or adenomyosis. Such an abscess
may reach 15 cm in diameter and is usually well encapsulated,
although there may be some perimetrial adhesion and, in a
few instances, rupture into the peritoneal cavity or an adjacent
hollow viscus.
Uterine abscesses are observed more frequently in cattle
than in other species. There appears to be a relationship
between the frequency of abscesses and uterine manipulations
involving the use of instruments. In cattle, most large abscesses
are located in the dorsal wall of the uterine body. This is the area Figure 4-57 Perimetritis of the uterus of a cow with postparturi-
most subject to trauma during the passage of insemination ent metritis.
pipettes and uterine catheters. Abscesses that develop follow-
ing severe metritis or pyometra are usually small (1-3 cm) and
do not have preferential sites.
Pyometra
Pyometra is acute or chronic suppurative infection of the uterus
with accumulation of pus in the uterine lumen. The escape of
the pus is usually prevented by a functionally closed cervix. Figure 4-58 Pyometra in a bitch. Note the spiraling of the uterine
Drainage from the uterus may also be prevented by an horns, a change that occurs when the canine uterus is under the
acquired or congenital cervical stenosis, and in mares the influence of progesterone. Both horns are mildly distended by
gravitational pull of the flaccid, distended uterus over the brim purulent exudate. Cystic endometrial hyperplasia is a common
of the pelvis may limit the discharge of pus. Pyometra may pre-existing lesion.
occur as a sequel to uterine infections of the types described
in the previous sections, but as it is a pathologic entity with
a number of factors unique in its pathogenesis, it is considered a few weeks after estrus. Affected animals may be depressed
separately here. Pyometra is an uncommon condition in the and anorexic, frequently vomit, and have polyuria and poly-
sow, ewe, and camelids. It is relatively common in the bitch and dipsia, usually accompanied by a vaginal discharge. The patho-
cow, but less so in the mare and queen. Circumstances under logic findings vary with the stage of the disease. In less
which the disease develops in these species vary. advanced cases, the uterus may be only slightly enlarged, with
Pyometra in the bitch and queen. Pyometra in the bitch mild endometrial hyperplasia and inflammation (Fig. 4-58). In
is a disease that characteristically affects older animals, espe- the more advanced stages, there is a remarkable distension of
cially those that are not bred. The condition most often develops the uterine horns (Fig. 4-59), which may occupy most of the
Pathology of the Genital System of the Nongravid Female Inflammatory Diseases of the Uterus 391
peritoneal cavity. In contrast, pyometra in cattle most com- Figure 4-62 Marked cystic endometrial hyperplasia in a bitch.
monly develops in the postpartum period and is frequently This uterine horn is opened, exposing the endometrial surface.
associated with retention of fetal membranes (Fig. 4-60). If The endometrium is thickened, and there is massive uniform
the purulent exudate does not drain from the uterus, it can cystic distention of endometrial gland lumens.
become dehydrated with time, and the inspissated material is
found as soft concretions in the uterine lumen (Fig. 4-61).
Distension of the cornua may be symmetric or asymmetric, obviously hyperplastic, dull-white, and dry in appearance,
uniform or ampulla-like dilations, as in the uterus of mid- with small cysts visible in these hyperplastic areas.
pregnancy. The cervix is completely or almost completely Microscopically, the most significant feature is the remarkable
closed as a functional response to luteal hormones. The serosal endometrial hyperplasia and progestational proliferation in
surface of the uterus is dark, and the vessels are prominent. almost all cases (Figs. 4-62, 4-63). The cells of such progesta-
The wall is friable, and either rupture or perforation with tional epithelium are enlarged, columnar, vacuolated, and have
secondary peritonitis is common. There may be obvious small pyknotic nuclei. In some cases the normal single layer
inflammation of the peritoneal serosa and mesometrium, but of cells piles up to produce pseudostratification or localized
this is unusual. The nature of the uterine content is variable. papillary proliferations. Whatever remains of the endometrial
In the more severe cases, usually those infected with E. coli lining may show this development, or it may be patchy and
and Proteus spp., the exudate is thick, viscid, tenacious, opaque, alternating with normal epithelium.
red-brown, and with a characteristic fetid odor. In other cases, These changes are produced by the luteal hormones that
usually those infected with streptococci and staphylococci, inevitably pave the way for the development of this disease.
the exudate is more typically suppurative. The mucosa is The histologic changes caused by infection vary with the bacterial
irregular in thickness, necrotic, and ulcerated in portions with cause and time. Masses of neutrophils collect in the uterine
irregular superficial hemorrhages, and in other portions lumen and in the glands, although there is relative sparing of
392 CHAPTER 4 • Female Genital System Inflammatory Diseases of the Uterus
cow, uterine disease causes the corpus luteum to persist and release. Mares with less severe endometritis have normal or
maintain a high progesterone level. The retention of the corpus shortened cycles.
luteum appears to be due to a reduction in or inhibition of A variety of organisms may be present in pyometra in the
the synthesis and release of the luteolytic factor prostaglandin mare: Streptococcus zooepidemicus is the most common, but E.
F2α (PGF2α) by the diseased endometrium. coli, Actinomyces spp., Pasteurella spp., and Pseudomonas are
Broadly, there are 2 periods in which a uterine infection often present.
can lead to retention of a corpus luteum with the accompany- Endometrial biopsy. Endometrial biopsy is most firmly
ing hormonal effects that convert endometritis to pyometra. established in equine theriogenology. The evaluation system is
They are during the early postpartum period—following dysto- based on identification and scoring of 4 microscopic lesions
cia, retained placenta, and metritis—and at various times after plus consideration of the mare’s reproductive history. The
breeding, as a result of venereal infections, with early embry- microscopic features evaluated include stage of cycle, inflam-
onic death. Insemination during the luteal phase of the cycle mation, presence of fibrosis, dilation of lymphatics, and loss of
or similar operations that can introduce contamination into glands.
the uterus during the luteal phase can mimic venereal Only a small amount of information has been published
infection. on endometrial biopsy in other species. Pathologists are asked
The role of retained luteal tissue in the pathogenesis of to evaluate endometrial biopsies for cattle, bitches, and cam-
pyometra appears clear. The secreted progesterone endows elids, and as more information is gathered and evaluated,
the uterus with a high degree of susceptibility to infection, recommendations for scoring will be followed by further vali-
maintains functional closure of the cervix, and inhibits myo- dation of their prognostic value.
metrial contractility.
The amount of pus retained in the uterus of a cow with
pyometra varies from a few milliliters to more than several Further reading
liters and is thick, rather mucinous, and cream or gray-green Christensen BW, et al. Diagnostic value of transcervical endometrial
colored. The cervix has no seal of mucus, so although con- biopsies in domestic dogs compared with full-thickness uterine
tracted, there is usually escape of a small amount of pus into sections. Reprod Domest Anim 2012;47(Suppl. 6):342-346.
the cranial vagina. The wall of the uterus is thick, doughy, Gibson A, et al. A retrospective study of pyometra at five RSPCA hos-
and flaccid, but in long-standing cases, especially as complica- pitals in the UK: 1728 cases from 2006 to 2011. Vet Rec
tions of mucometra, the walls are thin or fibrosed. The histo- 2013;173:396.
logic changes do not differ significantly from those of Kenney RM. Cyclic and pathologic changes of the mare endometrium
endometritis of comparable duration and severity. The organ- as detected by biopsy, with a note on early embryonic death. J Am
isms involved are hemolytic streptococci, staphylococci, coli- Vet Med Assoc 1978;172:241-262.
forms, T. pyogenes, and Pseudomonas. The venereally transmitted Mateus L, et al. Virulence genotypes of Escherichia coli canine isolates
protozoan, T. foetus, can be the cause of pyometra after from pyometra, cystitis and fecal origin. Vet Microbiol 2013;166:590-
breeding. 594.
Rarely, the anomalous developments of the uterus that Schlafer DH, Gifford AT. Cystic endometrial hyperplasia, pseudo-
were described earlier can lead to pyometra. In the segmental placentational endometrial hyperplasia, and other cystic conditions
aplasias and with imperforate hymen, the lumen proximal to of the canine and feline uterus. Theriogenology 2008;70:349-358.
the site of obstruction becomes distended with mucus and Schlafer DH. Diseases of the canine uterus. Reprod Domest Anim
cellular detritus. These closed cavities provide a satisfactory 2013;47(Suppl. 6):318-322.
environment for bacterial growth, but this is not a frequent Smith FO. Canine pyometra. Theriogenol 2006;66:610-612.
complication. When it does occur, the source of infecting
organisms is probably hematogenous. Pyometras seldom
resolve spontaneously, and although the condition is not PATHOLOGY OF THE GRAVID UTERUS,
usually life threatening, as it is in bitches, the condition will PLACENTA, AND FETUS
persist unless cyclic activity can be reinstituted.
Pyometra in the mare. Pyometra in the mare differs from General considerations
the disease in the bitch and the cow in several particulars. It is difficult to generalize on the subject of diseases of preg-
Although some cases develop following difficult parturitions nancy because of the remarkable variation in the reproductive
with infections, as they do in cattle, many do not. Remarkably, affairs of the various species. Because the mechanisms by
most mares continue to cycle during the disease, and the which the gestation period is initiated, the pregnancy main-
hormonal influences that are so marked in the bitch, queen, tained, and the delivery triggered have such profound effects
and cow are much less important in the mare. on how diseases of the conceptus will be manifest, some
In some mares, cervical adhesions and closure may lead to review of the special features of reproductive patterns in the
pyometra, but in most instances the purulent material collects various domestic species is given here.
without demonstrable cervical closure, and in some cases the For a pregnancy to proceed, the normal cyclic lysis of the corpus
cervix is fully dilated. Copious amounts of pus can be dis- luteum must be prevented. This is achieved in cattle by secretion
charged under such circumstances, particularly during estrus. by the blastocyst of interferon-γ, which inhibits synthesis and
Pyometra in the mare seldom leads to evidence of systemic disease, release of PGF2α from the endometrium. This spares the
although some mares develop mild anemia. corpus luteum and allows it to serve as the corpus luteum of
The length of the estrous cycle appears to be related to the pregnancy, and it then provides part or all of the hormonal
severity of the endometrial damage. In rare cases, where the support of the pregnancy. In cattle, up to 40% of total embry-
endometrial damage is severe, the cycles are prolonged with onic loss probably occurs between days 8 and 17 of pregnancy.
long luteal phases resulting from delayed or inadequate PGF2α Early embryonic death will permit release of PGF2α and lysis
393.e1
Further reading
Chen YM, et al. Uropathogenic virulence factors in isolates of Esche-
richia coli from clinical cases of canine pyometra and feces of
healthy bitches. Vet Microbiol 2003;94:57-69.
Frazier K, et al. Endometritis in postparturient cattle associated with
bovine herpesvirus-4 infection: 15 cases. J Vet Diagn Invest 2001;
13:502-508.
Garoussi MT, et al. Mycoflora of cervicovaginal fluids in dairy cows with
or without reproductive disorders. Mycopathologia 2007;164:97-
100.
Gifford AT, et al. Histopathologic findings in uterine biopsy samples
from subfertile bitches: 399 cases (1990-2005). J Am Vet Med
Assoc 2014;244:180-186.
Keskin A, et al. Pathological abnormalities after long-term administra-
tion of medroxyprogesterone acetate in a queen. J Feline Med Surg
2009;11:518-521.
Maddens B, et al. Escherichia coli pyometra induces transient glo-
merular and tubular dysfunction in dogs. J Vet Intern Med
2010;24:1263-1270.
Mir F, et al. Findings in uterine biopsies obtained by laparotomy from
bitches with unexplained infertility or pregnancy loss: an observa-
tional study. Theriogenol 2013;79:312-322.
Nomura K, et al. Histological observations of canine cystic endometrial
hyperplasia induced by intrauterine scratching. Jpn J Vet Sci
1990;52:979-983.
Petit T, et al. Prevalence of potentially pathogenic bacteria as genital
pathogens in dairy cattle. Reprod Domest Anim 2009;44:88-91.
Potter K, et al. Clinical and pathologic features of endometrial hyper-
plasia, pyometra, and endometritis in cats: 79 cases (1980-1985).
J Am Vet Med Assoc 1991;198:1427-1431.
Zaragoza C, et al. Canine pyometra: a study of the urinary proteins by
SDS-PAGE and Western blot. Theriogenol 2004;61:1259-1272.
394 CHAPTER 4 • Female Genital System Pathology of the Gravid Uterus
of the corpus luteum and subsequent reinstitution of the estral and lies free between the endometrium and chorion, and then
cycles in these species. The delay between death of the con- the necrotic cup cells become contained in a pouch formed
ceptus and the return of the dam to estrus is usually sufficient by the enclosure in an area of chorioallantois. These are called
to allow complete or near-complete autolysis and dissolution chorioallantoic pouches and appear as teardrop-shaped small
of the fragile embryo. As a result, the early diseased products extensions from the allantoic surface on the inner surface of
of conception are rarely available for study. Venereal infections the chorioallantoic membrane near where the umbilical cord
cause some of the early losses, but on the basis of the few attaches.
studies that have been done, and on the experience in other This potent chorionic gonadotropin in mares stimulates
species, it is presumed that chromosomal abnormalities account ovarian corpora lutea to develop, and these maintain the
for most of these early losses. In monotocous species, embryos pregnancy until approximately 126-140 days, when the fetal
that die undergo prompt dissolution, the products are expelled, chorion takes over the production of progesterone. If the
and the disease is recognized only as infertility with slightly conceptus dies after day 35 of gestation, the cups persist
prolonged estral cycles. The death of a single embryo, or even and continue to secrete chorionic gonadotropin, accessory
several, does not interrupt the pregnancy in swine, and dead corpora lutea are produced, and the mare fails to return
embryos are resorbed or mummified. Rarely, the death of the to estrus and continues for a variable period in a state of
conceptus may be caused by organisms that convert the preg- pseudopregnancy.
nancy to a pyometra, the active infection preventing the lysis Domestic carnivores that are pregnant have corpora lutea
of the corpus luteum. Trichomoniasis of cattle is an example that persist during the gestation period. Prolonged luteal pres-
of a venereal infection that can lead to pyometra. ence is also a feature of the relatively long luteal phase of the
In the mare, gonadotropic hormone (equine chorionic cycle in bitches and queens. Corpora lutea develop after ovu-
gonadotropin) is produced in linear, slightly dome-shaped lation, spontaneously in the case of the bitch and induced by
structures within the endometrium, the endometrial cups (Fig. coitus in the cat. Once formed, their lifespan appears to be
4-64). These structures form early in pregnancy. Originally inherent and the hormone production by them to be indepen-
thought to be maternal in origin, “cup” cells are fetal in origin dent of a pregnancy until the last stages of gestation. As a
and arise from a band of specialized trophoblast cells that result, death of the embryos or death or sickness of the fetuses
form the chorionic girdle on the expanded blastocyst. These shortens the length of the gestation period only slightly. Fetal
cells become detached from the fetal chorion on about day death before the terminal stage does not usually lead to pre-
35 of gestation and burrow into the stroma of the endome- mature delivery; rather, the process of autolysis and resorption
trium. There the cells enlarge and appear as large binucleated or mummification begins, and the products are expelled at or
cells. near term. As a consequence, it is very rare to obtain diseased
The cup tissue becomes visible at about day 40 of gestation fetuses from these species in a satisfactory state for study. Most
as a horseshoe or ring-shaped band in the endometrium of the studies of fetal diseases in carnivores have been based on
pregnant horn (see Fig. 4-64). The cups increase in size until experimental investigation.
day 60 of gestation, at which time their hormone production The corpus luteum is essential for the maintenance of
is at a maximum. Hormone concentration falls after day 60, pregnancy during the entire gestation period in swine and
and the cups become pale and slough between days 75 and goats, as it is in dogs and cats, before term. The corpus luteum
100 of gestation. The degeneration of the cups resembles graft is only essential during the first half of pregnancy in the mare
rejection. The cells of the fetal chorion are surrounded by an and ewe, and during all but the end of pregnancy in the cow.
intense maternal accumulation of lymphocytes and undergo During this time, the effects of fetal death are unpredictable.
prompt coagulative necrosis. The necrotic slough is detached In some cases the corpus luteum may undergo luteolysis, and
the dead fetus or fetuses are expelled, usually severely autol-
ysed, but in some cases the corpus luteum will not be lysed
and will persist, and the fetus will be resorbed or more likely
expelled. If the fetus is older, and particularly in cattle, it may
be mummified. During the last third of gestation in these
species, the pregnancy requires hormonal support from the
fetus, and fetal death at this stage leads to expulsion within a
few days. Even a few days allow time for autolysis to be
evident; the fetal tissues are pale, the red cells lysed, and
pleural and peritoneal cavities are filled with hemoglobin-
stained fluid.
The mechanisms by which dead fetuses are expelled in
cattle and sheep are not known, but it is probable that they
share features with normal parturition. They must involve
PGF2α release, cervical compliance, and coordinated myome-
trial contraction. Chronic fetal disease in cattle and sheep
results in premature delivery of live but diseased fetuses.
Because fetal stress activates the same hypothalamic-pituitary-
Figure 4-64 Endometrial cups in the endometrium of a mare. adrenal endocrine chain used to initiate normal parturition, it
These transplanted trophoblast cells produce the hormone equine is probable that chronic fetal disease operates through the
chorionic gonadotropin. This tissue dies and becomes necrotic same chain to cause abortions of live fetuses. Equid herpesviral
about 100-120 days of gestation as a result of a marked maternal infection regularly produces abortion of live, diseased, equine
lymphocytic response. fetuses.
Pathology of the Genital System of the Nongravid Female Pathology of the Gravid Uterus 395
Embryonic death
There is little that can be said with profit of the pathology of
the ovum, zygote, or early embryo, but a brief consideration
is included here for purposes of orientation.
When fertilized ova die, they undergo progressive cytolysis
within the zona pellucida, which often remains intact after
death. The whole structure then disintegrates and is resorbed
or discharged at the next estrus. It is rare to recover abnormal
ova from the bovine uterine tube during the first 72 hours
postestrus. Presumably, in those cases in which estrus occurs
after a normal cycle, the ova die most commonly between days
4 and 10 of the cycle. Most embryonic deaths in cows, however,
are associated with prolongation of the interestral period.
In the embryonic stage, the embryonic tissue proper disap-
pears first, and the trophoblast remains for a while before
degenerating.
The incidence of zygotic and embryonic mortality is remark-
Figure 4-65 A mummified bovine fetus. Fetal and placental
ably high in the species that have been studied and probably is
tissues undergo necrosis and dehydration in the absence of
in all species. Humans and the domestic species studied suffer
bacteria.
a zygotic loss of 15-30%. The causes are presumably diverse
and may vary somewhat from species to species. However, the
demonstration of abnormal karyotypes in early bovine and have occurred at different ages, the dead fetuses being of dif-
porcine zygotes and in a high percentage of unselected spon- ferent sizes and degrees of mummification or maceration.
taneous human abortions suggest that chromosomal or other
genetic abnormalities are an important cause of this mortality. Mummification of fetus
The frequency with which chromosomal abnormalities are Mummification of a dead fetus is seen occasionally in any, but
found varies with the stage of pregnancy; they are most usually multiparous, species and most commonly in the sow.
common in the early stages of pregnancy. This is the pattern In the mare, it is typically one of twin fetuses that is mummi-
one would anticipate because some of the most severe anoma- fied. Mummification may also occur in mares receiving pro-
lies are not compatible with attachment or implantation. Most gesterone in the early stages of gestation to prevent abortion
of these chromosomal abnormalities represent numerical associated with failure of endometrial cup development and
changes such as monosomy, polysomy, polyploidy, and mixo- subsequent failure of accessory corpora lutea formation and
ploidy. Only a small percentage is structural. The monosomies thereby progesterone production. The exogenously adminis-
and polysomies are the result of nondysjunction during meiosis tered progesterone inhibits contractions of the uterus and, if
or early cleavage stages. Triploidy can be caused either by 2 the fetus dies, prevents abortion, so the fetus mummifies. A
sperm fertilizing one egg or by the suppression of the second prerequisite for mummification is that bacterial infection is not
polar body and one sperm fertilizing a diploid egg; both pos- present.
sibilities increase with increased age of the gametes. Tetra- The fluids are resorbed, and the membranes become closely
ploidy occurs as a result of suppression of the first cleavage applied to the desiccated fetus. The whole mass becomes
division of the zygote. Mixoploids develop as a consequence brown or black and rather leathery, moist on the surface with
of mitotic error during cleavage division of the zygote. Struc- sticky mucus, but without odor or exudate (Fig. 4-65). The
tural anomalies are caused by spontaneous breakage and time required for complete mummification will depend to
reunion. Viruses, drugs, and radiation are known to cause this some extent on the size of the fetus. Dehydration is advanced
type of chromosome damage. by 7 days in sheep fetuses; however, complete mummification
probably requires as long as 6-8 months in the case of a
6-month bovine fetus. All stages may be observed—from the
Fetal death earliest, of beginning separation of the placenta with hemo-
A degenerate zygote or early embryo may be resorbed or globin staining of the tissues, to the latest, when all that
expelled from the uterus. At a later stage in development, the remains is a firm and shrunken remnant consisting almost
dead fetus may be mummified, macerated, or aborted; an wholly of dried skin and bones. Until the time of expulsion,
abortion is defined as the expulsion of a fetus prior to the time which on occasion occurs spontaneously, or parturition in
of expected viability. A dead fetus delivered within the period multipara that still carry some viable fetuses, the cervix
of expected viability is arbitrarily referred to as stillborn. remains closed and sealed. In uniparous animals, the mummi-
Perinatal mortality is a natural extension and refers to death fied fetus may be retained indefinitely. Animals that have had
from causes at or about the time of birth. It should be appreci- and delivered a mummified fetus usually breed normally on
ated that these different terms might be applied to fetuses subsequent occasions, so there cannot be any serious uterine
suffering from the same basic disease. lesion accompanying the fetal death. Genetic diseases (both
In uniparous domestic animals, death of the fetus in late inherited and chromosomal abnormalities), viral and proto-
pregnancy is usually followed by abortion. In multiparous zoan infections, and placental insufficiencies have been pro-
species, if most of the fetuses die at the same time, all are posed as the causes of fetal death leading to mummification,
likely to be aborted, but it is more usual for one or several but the cause is rarely firmly established in any particular case.
dead fetuses to be retained with the remaining viable ones and Very likely all the proposed causes and others can produce
delivered at parturition. It is often apparent that the deaths fetal death at an appropriate time, and mummification can
396 CHAPTER 4 • Female Genital System Pathology of the Gravid Uterus
result. The critical features for mummification appear to be the inertia, or inadequate dilation of the cervix, it may be retained
retention of the dead fetus within the uterus through the action in the uterus. The fetus putrefies, becomes distended with foul
of a functional corpus luteum and fetal skin mature enough to gas, and crepitates. If the fetus is small, the dam may survive
resist autolysis. the initial acute episode of fetal emphysema, after which
maceration occurs in a chronic, foul purulent metritis. The
Fetal maceration and emphysema cervix is not sealed, but because of uterine paresis, the pus is
Maceration and emphysema of the fetus require the presence of retained in the flaccid, dependent organ.
an infection in the uterus. If the early embryo succumbs to Advanced uterine lesions accompany the macerated fetus.
uterine or embryonic infection, maceration is usually followed The uterine wall is thickened, and the reaction within it varies
by resorption within the uterus or expulsion along with a from the acute exudative inflammation of pyometra to more-
small amount of purulent exudate. This is the usual course of or-less complete sclerosis and replacement by granulation
events in venereal infections by Campylobacter fetus and Trit- tissue in long-standing cases. In these the uterus closes firmly
richomonas foetus in cows, but is also to be expected with any about the bones, and the bones may cause perforation.
sort of nonspecific endometrial infection. The causes of infec- Fetal emphysema, at or near term, complicating dystocia is
tious death of the conceptus during the period of the fetus fatal unless treated, and maceration is not an expected sequel.
are the same as previously, but the consequences, pyometra In some cases of uterine torsion, however, the twisted cervix
or acute endometritis, are usually more severe because of the and vagina produce an adequate seal against bacterial invasion
presence of decomposing fetal remnants. The differences of the dead fetus, and mummification, rather than maceration
between pyometra and endometritis are as discussed earlier; or emphysema, results.
in pyometra the corpus luteum may persist, the cervix remains A special form of fetal emphysema occurs in ewes, caused
sealed, and the uterus withholds its contents. If the corpus by Clostridium chauvoei, the organism responsible for blackleg.
luteum and cervical seal break down, there is purulent dis- It affects fetuses near full term, causing acute tympanitic
charge of the contents, and except for the presence of fetal distension of the uterus, typical hemorrhagic and necrotizing
remnants, this endometritis does not differ much from that of lesions of the fetus, and the accumulation of dark thin dis-
the puerperium. After about the third month of pregnancy in charge in small amounts in the uterus. The pathogenesis of
the cow, complete fetal maceration does not occur. Fetal this special infection is not entirely clear, but there is usually
bones, and to a degree, fetal hair resist maceration (Fig. 4-66). a relation to rough handling, such as at shearing.
They may be discharged or retained in the purulent exudate
(pyometra) or remain in the uterine lumen indefinitely. The Embryonic death with persistence of
uterine pus is usually intensely fetid until maceration is membranes (cystic placental mole)
complete. This is an uncommon development that can follow embryonic
The usual infectious causes of fetal death and endometritis death. In the period of the embryo, the fetal membranes are
are not potent gas-formers; the development of fetal emphy- in volume and mass the greater part of the products of con-
sema almost invariably depends on patency of the cervix and ception, and it is possible for the embryo to die and to be resorbed
on invasion of the uterus and dead fetus by putrefactive organ- while the membranes persist and continue to grow. The remaining
isms from the vagina. There are 2 common antecedents to empty cyst has been referred to as a cystic placental mole. Most
emphysema: dystocia at or near term, and incomplete abor- empty placental cysts correspond in size to fetal membranes
tion. In incomplete abortion, the cervix is open but not com- at 3-4 months of gestation. There is usually no patent lumen
pletely dilated, and the fetus may be delivered into the cervix to the cyst. It is filled with a mass of clear-gelled fluid together
or cranial vagina, or because of malpresentation, uterine with placental stroma. In those cases with placentary develop-
ment, the allantoic and amniotic epithelia may be present. The
condition may become infected and converted to a pyometra
or undergo necrosis and be discharged. Infections that result
in rapid death of the fetus (e.g., bovine herpesvirus, Trueperella
pyogenes, Histophilus somni) usually result in a severely autol-
ysed fetus, as time is required for the corpus luteum to lyse,
the cervix to dilate, and for prostaglandin to contract the
uterus and expel the fetus. In infections that are chronic and
take time to kill the fetus (e.g., B. abortus, most mycotic abor-
tions, Yersinia pseudotuberculosis), the preparations for abor-
tion may be complete by the time the fetus dies, and therefore
the fetus will be aborted in a relatively well-preserved condi-
tion. In infections that are largely confined to the amnion, such
as Ureaplasma diversum, the probable mechanism involves
macrophage activation, resulting in cytokine-induced produc-
tion of prostaglandin by the endometrium, lysis of the corpus
luteum, and premature delivery of a well-preserved or slightly
autolysed fetus, depending on how quickly death follows the
infection.
Figure 4-66 A macerated bovine fetus. The presence of bacteria
causes putrefaction of fetal and placental tissues. Soft tissues Adventitial placentation (semiplacenta diffusa)
slowly undergo fetid disintegration, which leads to loss of all soft The development of intercotyledonary placentation in cattle is
tissues, and only fetal bones remain. a mechanism of compensation for inadequate development
Pathology of the Genital System of the Nongravid Female Pathology of the Gravid Uterus 397
Further reading
Basson PA, et al. “Grootlamsiekte,” a specific syndrome of prolonged
gestation in sheep caused by a shrub Salsola tuberculata (Fenzl ex
Moq) Schinz var. tomentosa C. A. Smith ex Aellen. Onderstepoort
J Vet Res 1969;36:59-103.
Buczinski S, et al. Prolonged gestation in two Holstein cows: transab-
dominal ultrasonographic findings in late pregnancy and pathologic
findings in the fetuses. J Vet Med A Physiol Pathol Clin Med
2007;54:624-626.
Evans TJ. The endocrine disruptive effects of ergopeptine alkaloids on
pregnant mares. Vet Clin North Am Equine Pract 2011;27:
165-173.
Wintour EM, et al. Anatomy, physiology and pathology of the amniotic
and allantoic compartments in the sheep and cow. Aust Vet J
1986;63:216-221.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 399
BOX • 4-1
Infectious causes of abortion
Viral
Family Arteriviridae, genus Arterivirus—Equine arteritis virus
(EAV), Porcine reproductive and respiratory syndrome virus
(PRRSV)
characteristically result in abortion as a major manifestation in abortion include hemoconcentration, circulatory failure,
(Box 4-1). anemia, fever, endotoxemia, and respiratory disease. With these
conditions, no lesion of diagnostic value will be found in the
fetus or placenta.
Diagnosing the infectious causes of abortion Pregnant animals may contact infectious agents by many
The diagnostic rate on the causes of abortion, based on exami- routes: through the respiratory tract, vagina, mouth, or, if
nation of samples submitted to veterinary laboratories insect-derived, through the circulation. Some agents may be
throughout the world, varies from 5-90%, depending on the carried into the reproductive tract with the semen or embryo
species and geographic location. The proportion of abortions transfer fluids. In cattle, U. diversum, bovine herpesvirus 1
that are caused by infection in most species, with the excep- (BoHV-1), and bovine viral diarrhea virus (BVDV) may con-
tion of the horse, is not known; however, ~90% of those abor- taminate either of these, and being preserved by freezing and
tions in which the cause is determined are assigned to resistant to the antibiotics commonly used, they survive there.
infection. In addition, it appears that some agents, such as Leptospira
Not all of the infectious causes can be recognized by the hardjo, may be maintained in the uterus or uterine tube over
examination of fetuses and placentas. The effects of infectious the open period and infect the conceptus as it develops. The
and noninfectious causes may be manifest indirectly through role of the changing hormonal influence in the reproductive
the dam or directly through the placenta and fetus. Conditions tract on the multiplication of organisms may be substantial.
in the dam affecting the fetus and placenta and which may result Campylobacter fetus moves from the vagina to the uterus as
400 CHAPTER 4 • Female Genital System Abortion and Stillbirth
pregnancy advances, and the hormonal influence is altered. may not have a significant titer (microscopic agglutination
Some organisms may multiply in the conceptus for a very long test) at the time of abortion.
period before abortion. U. diversum, for example, may remain It is important not to eliminate a disease from the list of
in amniotic fluid for up to 117 days before abortion occurs. possibilities because of a history of vaccination. Many disease
Similarly, Aspergillus fumigatus may multiply in the placenta agents may cause abortion in spite of previous vaccination, for
for at least 25 days before producing abortion, and it is sus- instance, BVDV, BoHV-1, and equid herpesvirus 1 (EHV-1),
pected that BoHV-1 remains in the placenta for a prolonged and of course, vaccination with certain live vaccines during
period before invading the fetus. pregnancy may cause abortion. Vaccination titers may be dif-
Cooperation among all parties involved (owner, clinician, ficult to distinguish from titers resulting from infection, par-
pathologist, bacteriologist, virologist, molecular biologist) is often ticularly if exposure has followed inoculation of even a single
necessary to reach a diagnosis. Eventually, other specialists, dose of vaccine. Baseline values need to be established.
including nutritionists, toxicologists, botanists, and epidemi- Frequently, lesions pointing to the diagnosis may only be
ologists, may be consulted. present in the placenta. As the placenta is a very large organ,
Because the act of abortion rarely points to a definite cause, and much of it may be normal, the more of the placenta that
it is important to collect all information at the first contact. can be examined, the more accurate assessment of it is likely to
Although the history seldom points directly to the cause of be. It rates in importance for examination equal to both the
abortion, clues may be found that will indicate what needs to alimentary and respiratory tracts of an animal after birth.
be done to determine the diagnosis. Abortion may occur Unless the entire placenta is expelled, at least part of the
sometime after the initiating illness, and therefore health, portion retained internally should be examined as it often has
performance, and travel records become important in suggest- the most severe lesion and is less contaminated by bacteria
ing the diagnosis. from the environment. If the placenta cannot be found, endome-
As the dam, placenta, and fetus may equally be involved, each trial samples become more crucial and should be requested.
should be examined and sampled. In addition, and perhaps Samples may be divided in 4 and used for bacterial culture
more important, a representative portion of the remaining and histology, a portion frozen for virology, and for molecular
animals that have not aborted should be examined. techniques, according to the submission guide of the diagnos-
• Samples should include serum from the dam and herd tic laboratory. The optimal submission includes the fetus and
(flock, or kennel), swabs, or samples from the uterus (the placenta plus serum from the dam. Serum is best collected at
caruncle in cattle may be useful), placenta, and fetus. pregnancy diagnosis and then resampled at time of abortion.
• If the placenta and fetus cannot be quickly and suitably This method has been found of particular use in the diagnosis
transported in their entirety, samples may be removed and of leptospirosis in dairy cows on drylot, where the fetus is
one portion placed in fixative and others in plastic bags on often not discovered until trampled. Examination of a “fresh”
ice for culture and molecular techniques. fetus is 53 times more likely to contribute a diagnosis than an
• Tissues may, in addition, be frozen for future culture or autolysed one. Submissions including the entire fetus, pla-
testing for agents by using one of the many immunologi- centa, and serum are 4.28 times more likely to result in a
cally based techniques presently available. diagnosis than where pieces only of the fetus are submitted.
• Samples from the conceptus for culture should include Titers of fetal antibody may also be useful in diagnosis of
placenta, stomach content, lung, and kidney. BVDV, Neospora, or leptospiral infections.
• Tissues essential for histology are a sample of the endome- Some lesions and normal findings that may be confusing
trium (caruncle), placenta, brain, eyelid (with conjunctiva), will be described briefly. To examine the caruncle, it should
thyroid, thymus, lung, heart, liver, spleen, kidney, adrenal, be cut sagittally and the cut surface examined for infarction
and intestine. To be most useful, tissues for histology must or suppuration. Infarction is most commonly recognized in
be properly fixed or chilled (not frozen) if transport is to mycotic infections but may be caused by a variety of bacteria,
exceed 3 hours. including Brucella and Salmonella. Infarction frequently results
As with the history, it is important to maximize sample collec- in retention of caruncular material by the cotyledon. A variety
tion initially, thereby permitting the use of all the necessary diag- of bacteria, including T. pyogenes, may cause suppurative pla-
nostic aids as the cause is gradually revealed. Samples not centitis. Occasionally, fibrosis of caruncles is seen and may
required are easily discarded later. The results of serology are represent normal caruncular maturation or be the result of a
more easily interpreted on a herd basis than on an individual chronic infection caused by organisms such as Yersinia
animal and may be particularly useful when samples are col- pseudotuberculosis.
lected before pregnancy or at the time of pregnancy diagnosis To examine the chorioallantoic membranes, they should
and again at the time of abortion. This technique has proven be completely spread out and inspected carefully for lesions
very useful in the diagnosis of leptospirosis. Only a representa- on both surfaces. Lesions in the bovine placenta are commonly
tive portion of the group need be sampled to establish a observed toward the tip of the pregnant horn and should not
baseline titer. Two samples from a dam that has just aborted be confused with the normal avascular chorion in this site. On
may contribute little useful information as many agents that histologic examination of H&E-stained sections of the chori-
subsequently cause abortion have initiated production of a onic villus, a blue finely granular to amorphous material may
high antibody titer long before abortion occurs. Serum anti- be observed in the interstitium. This may be glycosaminogly-
body titers are often within the “normal” range at the time of cans, mineral, bacteria, or DNA, and special stains and even
abortion. Interpretation of the significance of antibody titers close examination will differentiate it. Glycosaminoglycans
may be further complicated in that many animals may not are considered normal, as is mineral in the early stages of
respond to the agent with the production of antibody, and yet gestation. In the later stages, however, mineral is commonly
the animal may be carrying the organism and abort because observed in areas of necrosis and feels gritty on gross
of it. Up to 22% of cows aborting because of Leptospira hardjo palpation.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 401
Trophoblasts should be thoroughly examined on high infectious causes. Lesions are most frequently observed on the
power as a variety of bacteria may be phagocytosed, or at least conjunctival surface and vary from a slight infiltrate of mono-
contained, by them. The erythrophagocytic trophoblast has nuclear cells to a severe necrotizing reaction. As in other areas,
been shown to phagocytose Brucella, and the organism has the cellular infiltrate may be determined by the duration of
been seen by electron microscopy in the rough endoplasmic the infection before death of the fetus. In cattle, Yersinia spp.,
reticulum. Coxiella burnetii is also found in the trophoblast Ureaplasma, and mycotic infections are commonly associated
and can usually be distinguished from Chlamydophila and with a heavy focal mononuclear cell infiltrate just under the
other bacteria in that the cytoplasm of the cell appears foamy conjunctiva, whereas T. pyogenes infection may result in com-
compared to the finely granular appearance of bacteria. plete loss of conjunctival epithelium, and the accumulation of
Lesions of variable intensity are usually seen in vessels of large numbers of bacteria, but few inflammatory cells, on the
the placenta. Discrete necrotizing vasculitis of the endothelial surface. Many bacteria, including T. pyogenes and Listeria, con-
cells in small vessels of the villi regularly occurs with BoHV-1 tinue to multiply after the death of the animal. BVDV infec-
infection. Mycotic infections cause very severe vasculitis, tion may initiate perivascular lymphocytes and cause injury
resulting in thrombosis and infarction of the caruncle and to hair follicles. The pattern of follicular hair growth when
cotyledon. H. somni, although perhaps uncommon as a cause compared to the age of the fetus may determine the time of
of abortion, may cause a similar lesion. Chlamydophila infec- infection. Mycotic infections cause folliculitis; however, the
tions of the placenta may also cause severe vasculitis, but lesion is very variable, not only as to its presence but also its
usually without thrombosis. The bacteria-packed vessels in severity, and although intracorneal pustules may be seen, fre-
Salmonella placentitis are so near the surface that they are quently either no lesion is observed, or traces of inflammation
easily mistaken for phagocytosed bacteria in trophoblasts. and fungi are only found in the outer sloughing keratinized
Microthrombi may be present also. debris. This material may be lost unless care is taken in
Lesions of hemorrhage, necrosis, mineralization, and fibro- sectioning.
sis may also be observed on the chorionic and allantoic sur- Examination of the brain, particularly with the discovery
faces and are commonly seen with a variety of fungi and of the importance of protozoan infections as a cause of abor-
bacteria, including U. diversum. tion in ruminants, is an essential part of any postmortem
The inner surface of the amnion may be severely stained examination. Many viral infections manifest their effects in
with meconium, particularly in chronic progressive infections the brain. Although the brain often appears soft and unworthy
of the chorion. It is frequently the site of lesions associated of fixation, and some are literally poured into the fixative,
with U. diversum infection and is there characterized by mul- interesting and informative lesions are often found only in
tifocal to confluent areas of necrosis, mineralization, and fibro- this site.
sis, with marked thickening and mild vasculitis being most The lung ranks among the most common organs in which to
common. Mycotic and Mycoplasma infections may penetrate see lesions. Aspiration of meconium into airways, with or
the chorion and allantois to the amnion and result in a similar without evidence of an agent, is seen in the terminal phases
lesion. of many bacterial, and less commonly in mycotic infections,
Discrimination must be used in interpreting the results of and is probably related to the rapidity of the development of
cultures derived from samples of fetus, placenta, or even the the lesion and the degree of impairment of placental function.
stomach contents, as organisms may move or be carried from Frequently, there will be no local reaction in the lung to the
the vagina to the conceptus when the cervix dilates during an agent, and in these the exudate present probably represents
impending abortion resulting from another cause. These aspiration of the agent and inflammatory cells from a placen-
organisms may rapidly contaminate the placenta, grow in the titis. Many of the inflammatory cells may be maternal in
fetal fluids, and may even be swallowed by a viable fetus, origin. In U. diversum and bovine parainfluenza virus 3 infec-
thereby appearing in the stomach contents. To avoid confusion, tions in bovine fetuses, airways may remain relatively clear,
vaginal samples should be taken as soon as a vulvar discharge and alveolar ducts become thickened and the lumina pave-
is seen or impending abortion is suspected. Vaginal discharges mented with many macrophages and a few neutrophils. Severe
from animals with impending abortions are much less likely necrotizing bronchitis may be seen with EHV-1 infection in
to be contaminated by extraneous organisms than are samples horses, whereas BoHV-1 in cattle usually produces only mul-
from an animal that has aborted several days previously. tifocal necrosis and no visible pneumonia.
Observing the relative state of preservation of the fetus Examination of the intestine contributes much informa-
may contribute information about the cause. Acute infections, tion in some specimens. Sections should be removed from
such as those caused by BoHV-1, usually result in the dis- the small and large intestine, with care taken to preserve the
charge of a severely autolysed fetus, as the fetus is killed content intact. Bacteria may be seen colonizing the luminal
rapidly. Chronic infections, (such as U. diversum, B. abortus, Y. content and are used as an indicator of whether or not the
pseudotuberculosis, or A. fumigatus), or other persistent stresses, bacterial isolate is significant. Terminal swallowing of an agent
however, allow the fetus to prepare itself for delivery, and may transport it to the stomach; however, finding the agent
hence it is discharged in a fresh state, perhaps small for ges- in the intestinal lumen is evidence that it has been in the
tational age, and sometimes alive. Evidence of the significance animal for at least several hours. The fetus swallows amniotic
of an isolate may only be obtained by histologic examination of fluid beginning at a very early age, and bacteria and fungi
certain tissues. can be easily seen in meconium. In one survey, lesions
A few of the less commonly examined tissues that may be were observed in association with a variety of agents in 32%
useful in making the overall decision about the cause of abor- of 50 bovine fetuses examined. Lesions varied from mild
tion will be briefly considered. Microscopic examination of with A. fumigatus to focal areas of necrosis in the mucosa
the eyelid (surface and palpebral conjunctiva) will reveal with BoHV-1, diffuse necrotizing colitis with Listeria,
lesions in about 2/3 of the bovine fetuses aborted because of cryptal necrosis and Peyer’s patch lymphocyte hyperplasia
402 CHAPTER 4 • Female Genital System Abortion and Stillbirth
with Bacillus spp., loss of crypts, and large numbers of Yorke EH, et al. Uterine torsion in mares. Compend Contin Educ Vet
lamina proprial lymphocytes and plasma cells with Y. 2012;34:E2.
pseudotuberculosis.
Isolation of different organisms concurrently from the products
of abortion makes interpretation difficult. BVDV is commonly Bacterial causes of abortion
detected along with other organisms also considered to be There are many different bacteria that infect the placenta. In
causes of abortion, and in one study was found in 3 of 16 general, the response to infection is similar and stereotyped,
fetuses with Bacillus sp., 6 of 30 with T. pyogenes, and 17 of with some variation between species. The archetype bacterial
45 with fungal infection. In these animals, immunosuppres- cause of a placentitis is Brucella, which will be described first.
sion associated with BVDV infection may permit the organ-
ism to circulate in the dam and localize in the placenta, or it Brucellosis
may be that, as just stated, the animal was aborting because Bacteria of the genus Brucella are small, gram-negative bacilli
of BVDV infection and the other organisms were contami- or coccobacilli that are strictly parasitic, prefer the intracel-
nants. In contrast, abortion may occasionally be classified as lular habitat, and produce in animals chronic infections with
infectious because of histologic lesions observed, but where persistent or recurrent bacteremias typically manifested by
no organism is identified. Failure to grow the organism may abortion.
be due to improper handling of the samples or destruction of Three classic species of Brucella were described and defined
the organism in severely autolysed fetuses. originally largely on the basis of host of origin—B. melitensis,
Portions of chilled kidney are useful for the fluorescent goats; B. abortus, cattle; and B. suis, swine—but now by bio-
antibody detection of BoHV-1, BVDV, and Leptospira. Stomach chemical and serologic reactions. The differences between the
content is useful for bacterial or fungal culture and direct species are slight and quantitative rather than qualitative, and
examination for bacteria (including Coxiella) and fungi. In the number of biotypes within each species is large. The bio-
some diagnostic laboratories, all samples of stomach content logical similarities among the various species and biotypes of
and impression smears of placenta are examined using a modi- Brucella are in keeping with the remarkable similarities in the
fied acid-fast stain. Using this stain and others, an experienced diseases produced in the different hosts by the various strains
microbiologist can distinguish a variety of organisms. Certain of the organism. Infections are initially systemic, and relapsing
organisms are extremely fragile, and care in handling samples bacteremic phases are well-established events in the persisting
becomes very important. Samples to be cultured for U. diver- infections. Localization and persistence of infection may occur
sum, for example, should be collected aseptically, chilled to 4° in many organs, perhaps to a greater extent with B. suis than
C, and delivered to the laboratory immediately. Leptospires with the other species. Some organs, however, notably the
may be equally fragile. genitalia and placenta, develop intense persistent foci of
Fetal serum or thoracic fluid samples for antibody detec- infection.
tion may be collected, but the antibody titers, as in the dam, Bovine brucellosis caused by Brucella abortus. Brucellosis
must be interpreted with caution. The fetus is capable of occurs in cattle in most parts of the world. In some countries the
responding to a variety of agents with antibody production incidence of the disease is low, either because of measures
relatively early in gestation, and the presence of specific taken to prevent its entry or to eradicate it, but where the
antibody in fetal fluids may be considered evidence of fetal disease is endemic and uncontrolled, the incidence may
infection. It has been shown, however, at least in sheep, approach 20-30%.
that placental vascular damage may allow antibodies to The usual source of infection for cattle is an aborted fetus or
cross the placenta from the dam to the fetus, thereby making placenta, or contaminated uterine discharges, and the usual route
interpretation difficult. When antibody passage occurs, con- of infection is alimentary. Infection can also occur per vaginam,
centrations in the fetus will presumably be lower than in the via the conjunctiva, or through the broken or unbroken skin.
dam. Fetal antibody detection has been useful in diagnosing The relative importance of these latter routes is not known.
fetal BVDV and leptospiral infections in third-trimester Coital infection can occur but is uncommon, especially if
fetuses. genital infection in the male is long standing, possibly because
fewer organisms are excreted in semen from chronic lesions.
Infection can be transmitted at artificial insemination if semen
Further reading from infected bulls is used. Irrespective of the route of infec-
Boger LA, Hattel AL. Additional evaluation of undiagnosed bovine tion, the development and establishment of infection are
abortion cases may reveal fetal neosporosis. Vet Parasitol 2003; probably comparable and will depend on the age and repro-
113:1-6. ductive status of the animal, its inherent resistance, and on the
Lamm CG, Njaa BL. Clinical approach to abortion, stillbirth, and neo- dose and virulence of the infecting strain of the organism.
natal death in dogs and cats. Vet Clin North Am Small Anim Pract Young cattle are relatively resistant up to about the age of
2012;42:501-513. puberty. They can be infected by the usual routes and means,
Njaa BL, editor. Kirkbride’s Diagnosis of Abortion and Neonatal Loss in including the ingestion of milk in which the organisms are
Animals. Oxford, UK: Wiley-Blackwell; 2012. intermittently excreted. Calves normally eliminate infection
Schlafer DH. Canine and feline abortion diagnostics. Theriogenol in a few months.
2008;70:327-331. Once infection is established in sexually mature animals,
Schlafer DH. Examination of the equine placenta. In: McKinnon A, females especially, it tends to persist indefinitely. Some,
et al., editors. Equine Reproduction. 2nd ed. Ames, Iowa: Wiley- perhaps many, will recover completely, but which ones will,
Blackwell; 2010. p. 99-110. and when they will, cannot be predicted. The organisms
Tibary A, et al. Infectious causes of reproductive loss in camelids. The- extend quickly to the lymph nodes regional to the point of
riogenol 2006;66:633-647. entry, and there they provoke acute lymphadenitis. The
402.e1
Further reading
Ali H, et al. Common, emerging, vector-borne and infrequent aborto-
genic virus infections of cattle. Transbound Emerg Dis 2012;59:11-
25.
Decaro N, et al. Viral reproductive pathogens of dogs and cats. Vet
Clin North Am Small Anim Pract 2012;42:583-598.
Holler LD. Ruminant abortion diagnostics. Vet Clin North Am Food
Anim Pract 2012;28:407-418.
Jamaluddin AA, et al. Dairy cattle abortion in California: evaluation of
diagnostic laboratory data. J Vet Diagn Invest 1996;8:210-218.
Miller RB, Quinn PJ. Observations on abortions in cattle: a comparison
of pathological, microbiological and immunological findings in
aborted fetuses and fetuses collected at abattoirs. Can J Comp Med
1975;39:270-290.
Ortega-Pacheco A, et al. Common lesions in the female reproductive
tract of dogs and cats. Vet Clin North Am Small Anim Pract
2012;42:547-559.
Pretzer SD. Bacterial and protozoal causes of pregnancy loss in the
bitch and queen. Theriogenol 2008;70:320-326.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 403
inflamed nodes are enlarged, often much so; hyperplastic with caruncle, where hematomas appear at the ends of maternal
no clear corticomedullary distinction; and frequently bear septa late in gestation.
small or large medullary hemorrhages. The sinuses are infil- Gross lesions in the placenta are characteristic but not
trated with neutrophils and eosinophils, germinal centers and pathognomonic; similar lesions of lesser or equal severity may
proliferative activity become obvious, and there is slow but be caused by other bacterial infections, and fungi produce
remarkable accumulation of plasma cells in the medullary similar lesions, usually of greater severity. There is considerable
sinuses. The changes in the regional nodes take some weeks variation in the severity of the placental lesions, and this is
to develop fully, and they persist for a prolonged period. There reflected to some extent in the course of the local infection.
is no fibrosis or necrosis in the nodes. If the lesion is severe, abortion or premature birth is the likely
The infection may be overcome in the regional nodes, but outcome, and if the lesion is of minor severity, the calf may
once established, it is expected to spread during the phase of be delivered normally at term and be viable or nonviable. The
acute regional lymphadenitis. Spread is chiefly hematogenous, intrauterine lesions apparently progress very slowly, because
and bacteremia may persist for several months, the duration an interval of many months may elapse between infection and
of persistence apparently depending on the susceptibility or abortion or normal birth. Abortion occurs most often in the
resistance of the host. As the infection becomes chronic, bac- seventh and eighth months of gestation. Once the infection
teremia becomes intermittent, ceases in some animals, and localizes in a pregnant uterus, it almost certainly remains there
recurs irregularly for at least 2 years in 5-10% of animals. Also, and remains active until the fetus and placenta are delivered
it tends to recur at parturition. It might be expected that the and for some time thereafter. The nonpregnant uterus is not
bacteremic episodes would result in localization and persis- particularly susceptible to B. abortus, and following abortion
tence of the organism in many tissues, but curiously, localiza- or parturition, the organism is cleared from the uterus in a
tion is largely restricted to the spleen; mammary glands; few weeks, or longer in some cases.
mammary lymph nodes; pregnant uterus of the female; and The external appearance of an infected pregnant uterus is
to the lymphoid tissues, testis, and accessory glands in the normal. Sometimes the placenta is normal. Typically, between
male, and such localizations occur in the early bacteremic the endometrium and chorion in the intercotyledonary area, there
phases. The organism has little or no predilection for the is more or less abundant exudate that is odorless, dirty yellow,
kidney (although microscopic interstitial nephritis may be slightly viscid and slimy, and which contains gray-yellow,
present), ovary, bone marrow, or mesenteric lymph nodes and pulpy floccules of detritus. The fetal membranes and the
appears not to be excreted in the urine or feces. Localization umbilical cord are saturated with clear edema fluid, and the
does occasionally occur in synovial structures to produce membranes may be 1.0 cm or more thick. The fetal fluids are
purulent tenosynovitis, arthritis, or bursitis, but whether local- usually normal, although occasionally fluid in the amnion is
ization and persistence occur in synovium that is healthy is viscid and stained with meconium as the lesion extends.
not clear; some pre-existing inflammatory changes may be The placental lesions are not uniform; some cotyledons may
necessary. appear more or less normal, and others will be extensively
Infected animals, almost without exception, excrete B. necrotic, whereas still others are diseased to intermediate
abortus in the colostrum. Thereafter excretion of the organism degrees. Similarly, the intercotyledonary placenta varies in the
in milk may cease, but frequently it continues, although inter- extent to which it is changed, lesions being most prominent
mittently, throughout the period of lactation. Organisms adjacent to the cotyledons. Affected areas of intercotyledonary
excreted in milk are an important source of infection for placenta are thickened with yellow gelatinous fluid, opaque
children and also for calves, but they recover without signifi- and tough, and the normal smooth glistening surface takes on
cant effect. It is still not clear whether, and to what extent, B. an appearance resembling yellow-to-gray Morocco leather
abortus causes anatomic changes in the mammary glands. This with, on the surface, a patchy coagulum of inflammatory
must be expected, but they must also be mild and difficult to exudate and desquamated, degenerate epithelial cells. Affected
distinguish from the focal inflammatory reactions commonly cotyledons or portions of them are necrotic, soft, yellow-gray,
present in mammary glands. Dense infiltrations of the inter- and may be covered with the sticky, odorless, brown exudate.
stitial tissue by plasma cells, lymphocytes, and histiocytes, and Histologically, the lesions produced within placental
exudation of neutrophils in acini, probably constitute the tissues by Brucella bacterial infection is very similar between
usual changes. The mastitis is focal and not attended by gross species. The chorionic epithelial cells are stuffed with bacteria
changes. The cellular content of milk is increased. (Fig. 4-67), and many of them, with their inhabitants, desqua-
B. abortus has special affinity for the pregnant endometrium mate into the intercotyledonary space. Edematous placental
and fetal placenta, to which it spreads hematogenously during the stroma contains increased numbers of leukocytes, largely
initial or later bacteremia. Experiments using B. abortus in goats mononuclear but with some neutrophils. The organisms in
have shown that the organism is carried by the bloodstream intact trophoblasts are cocci, but free in the exudates; they
to the periphery of the caruncle, where at the extremities of assume a more elongate form even while still contained within
the maternal villi, capillaries leak into the narrow space the ghosts of dead trophoblasts. Within placentomes, the same
(hemophagous organ) adjacent to the fetal erythrophagocytic sort of placentitis is present, but the infection is not so exten-
trophoblast of the chorion. Cells of the erythrophagocytic sive in the trophoblasts covering the cotyledonary villi except
chorionic trophoblast either phagocytose the Brucella organ- at their base, or in the trophoblasts lining the caruncular
isms or they invade; regardless, they multiply and spread, via crypts, although many of the syncytial trophoblastic cells may
the uterine lumen and endocytosis or by cell-to-cell transfer, be necrotic. The intervillus portions of the placenta, the
to the rough endoplasmic reticulum of the adjacent chorionic so-called placental arcades, are quite severely affected, and
trophoblast cells. They multiply here and spread to the fetus exudate accumulates between the arcades and the expanded
following ulceration of the trophoblast and invasion of the outer extremities of the maternal septa. There is normally
fetal chorionic villi. The process may be similar in the bovine some placental exudate and minor hemorrhage in these
404 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Figure 4-67 Massive proliferation of Brucella canis bacteria Figure 4-68 Fetal pneumonia in a bovine fetus aborted because
within the cytoplasm of trophoblast cells, along the deep edge of of in utero infection with Trueperella pyogenes. Fetus and placenta
a canine placental labyrinth. Vasculitis and neutrophilic placenti- infected with Trueperella typically contain large numbers of bac-
tis also are features of canine brucellosis. teria. The arrow points to an alveolar macrophage with its cyto-
plasm distended with bacteria.
spaces, but this is greatly exaggerated in placentitis and con- important differential diagnosis is Trueperella abortion, which
tains infiltrated leukocytes, epithelial debris, and bacteria. The also produces suppurative placentitis and fetal lung lesions.
maternal portions of the placentome are not much involved The pneumonia found in fetuses aborted by Trueperella infec-
except for the expanded ends of the maternal septa where tion is usually accompanied by large colonies of bacteria
these are bathed in the exudate of the placental arcades, and within airways and alveolar spaces (Fig. 4-68).
in consequence, become denuded and superficially necrotic. In bovine brucellosis, by the time the placentitis has advanced
Beneath the necrotic tips of the maternal septa, there are to an extent where abortion is inevitable, acute diffuse endome-
dense aggregates of neutrophils, with granulation and fibrosis tritis, without histologic specificity, has developed. Variable lesions
extending along the sides of the septa. Inflammatory enlarge- in the fetus include necrotizing arteritis, especially of pulmo-
ment of the terminal portions of the maternal septa produces nary vessels; focal areas of necrosis; and granulomas with giant
an increased degree of placental interlocking and probably cell formation in lymph nodes, liver, spleen, and kidney. The
contributes to retention of the placenta. Adhesions, in the organism may be identified by culture, immunofluorescence,
usual sense of connective-tissue fusion, between placenta and or immunohistochemistry.
uterus do not occur. The endometrium is relatively unscathed Brucellosis in swine, caused by Brucella suis. Pigs are
in the early infections. The zona basalis shows some increase susceptible to B. melitensis and slightly susceptible to B.
in lymphocytes and plasma cells, and there may be scattered abortus. The disease is usually caused by B. suis, and this organ-
microscopic granulomas of epithelioid cells. Even the interca- ism presents important problems in many countries. There are
runcular epithelium may not be overly disturbed. Later there some differences in the diseases produced by B. suis and B.
is severe endometritis. abortus, and these depend largely on the frequency with which
The fetus is usually autolysed and somewhat edematous B. suis in swine produces focal granulomatous lesions with
with blood-tinged subcutaneous fluid. The same fluid is coagulative necrosis, the affinity of this organism for the skel-
present in excess in the body cavities and the dorsal retroperi- eton and joints, and its tendency to remain in granulomatous
toneum. The normal abomasal content of a fetus is clear, foci in the nonpregnant endometrium.
translucent, thick, and viscid; in brucellosis, it often becomes The early stages of the pathogenesis of the infection are
very turbid, of a lemon-yellow color, and flaky. The important comparable with the early stages of bovine brucellosis. Infec-
fetal lesion in brucellosis is pneumonia, which is present to some tion can occur by the same variety of routes, but in swine,
degree in most fetuses aborted in the last half of pregnancy. The brucellosis is chiefly transmitted by coitus. Boars are as readily
lungs may appear grossly normal, but histologic examination infected as sows, and most infected boars develop lesions in
reveals scattered microscopic foci of bronchitis and broncho- the testes or accessory genitalia, from which the organisms are
pneumonia. When severely affected, the lungs are enlarged shed in the semen, often for life. They may also be shed in the
and shaped to the thoracic contour, firm on palpation, red- urine from a focus of infection in the bladder. Infected females
dened on the pleural surface or hemorrhagic, and with fine may discharge the organism from the uterus for up to 2.5
yellow-white strands of fibrin on the pleura. years. Suckling piglets can be infected, although they are less
Microscopically, there may be any stage from the minor susceptible than weaners or adults, and although most infected
changes mentioned through a well-developed catarrhal bron- piglets eliminate infection, a few carry the bacterium into
chopneumonia to the fibrinous variety. The predominant adulthood.
inflammatory cells are mononuclear, although many immature With the development of lymphadenitis regional to the
and mature neutrophils may be present in some areas. The point of entry, the infection becomes bacteremic. The bacte-
septa may be edematous and with perivascular leukocytes. An remia may be transient or persist for many months or even
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 405
for some years. Localization may occur in many organs, but lesions may develop during pregnancy to a superimposed
especially in the male and female genitalia; the skeleton, diffuse catarrhal type of endometritis with patchy congestion,
including the vertebral column; synovial structures; mammary hemorrhage, and edema and a small amount of creamy-pink
glands; lymph nodes; spleen; liver; kidney; bladder; and even catarrhal exudate that contains large numbers of organisms.
in the brain. The fetal placenta may not show conspicuous changes, but as
B. suis can grow and multiply in phagocytes, and the typical a rule, it is congested with small hemorrhages and patchy
granulomatous lesion begins with the accumulation of histio- edema. Usually too, there is a thin layer of exudate that is
cytes and epithelioid cells. Perhaps as a response to developing slimy, gray-yellow, or gray-brown, like mucopus. It is more
hypersensitivity to the organisms, as the lesion enlarges, copious than the secretion normally present in the interpla-
caseous necrosis occurs centrally and fibrous tissue forms a cental space, and smears from it show numerous free organ-
capsule. The granulomas enlarge progressively, and the necrotic isms and many epithelioid cells, presumably chorionic, that
tissue attracts neutrophils. Giant cells are absent or scarce. contain clumps of bacteria. The fetus shows autolysis with
Mineral may be deposited in the necrotic foci. subcutaneous edema and blood-stained fluid within body
Articular lesions caused by B. suis are quite common. They cavities. The stomach contents may appear normal or be slimy,
begin as synovitis and chiefly affect the compound and large turbid, or yellowish and may contain small flakes like curd.
joints of the limbs. The reaction is purulent or fibrinopurulent. Brucellosis in sheep, caused by Brucella ovis. A Brucella
Osteomyelitis in this disease is typically vertebral (or usually mutant, B. ovis, causes a specific form of epididymitis in rams
observed there). As with other causes of osteomyelitis, local- in most parts of the world in which sheep are raised. The
ization is typically in the vertebral epiphyses of the lumbar organism also causes placentitis in pregnant ewes, but epididy-
region. There is, however, an unusual tendency to involve and mitis is the more common and important manifestation of the
destroy the intervertebral cartilages. The smaller bony lesions infection, and the main discussion of the disease is included
are typically granulomatous with dry caseation necrosis, but in Vol. 3, Male genital system.
the necrotic cores of larger lesions may liquefy, and the sup- There are probably as many modes of transmission as there
purative reaction extends to the meninges or fistulae to are for the Brucella in general, but in this disease, the coital
produce paravertebral abscesses. route is important; infected rams excrete large numbers of the
In the uterus and uterine tubes, there are often conspicuous organism in the semen. There is bacteremia, but no systemic
and characteristic lesions, which are not dependent on an disease. The organism is not very virulent. Even the epididy-
association with pregnancy. They have been referred to as mitis of rams is largely an indirect effect. The epididymal
miliary uterine brucellosis and, as the name infers, there are lesion produced by the organism is modest, but it does pre-
few or very many pale yellow nodules with an average diam- dispose to spermiostasis and extravasation, which produce the
eter of 2-3 mm seeded in the mucosa. When the nodules are characteristic spermatic granulomas by which the disease is
numerous, they may coalesce to form irregular plaques and recognized. In contrast to the organism’s nonpathogenic
then are associated with thickening of the uterine wall and nature in the nonpregnant ewe, the organism readily parasit-
stricture of the lumen. The same lesion is usually also present izes the placenta and produces abortion; this is not common,
in the uterine tubes, where obstruction results in pyosalpinx. although it may be important in individual flocks. Although
Incised, a small quantity of caseous exudate can be expressed the manifestations of infection in both ewes and rams are
from the nodules. Small, red, flat, and irregular granulomas are solely genital, the organism can be cultured in large numbers
often scattered over the surface of the supporting ligaments; from other organs in which it does not, however, produce
grossly, they resemble fetal fat and are easily overlooked. lesions.
There is some stromal fibrosis and diffuse cellularity in the The placenta is grossly edematous, being thickened to
tubes and endometrium because of plasma cells and lympho- 2-5 cm by gelatinous fluid. Periarteritis and arteritis are fea-
cytes. In addition, well-developed and multiple hyperplastic tures, as in most forms of placentitis. The intercotyledonary
lymphocytic nodules are evident. There are few neutrophils placenta has plaque-like thickenings that may coalesce to
in the stroma, but with the mononuclear cells, they can be resemble yellow-white chamois leather (Fig. 4-69). Diseased
seen moving through the epithelium to collect in abundance cotyledons may become partially detached; they are firmer
in the lumen of the uterus and tube and in the more superfi-
cial glands. The glands are dilated and neutrophils are
enmeshed in strands of mucin and mixed with amorphous
globs of mucus. The deeper glands are cystically dilated with
attenuated epithelium, serous or thin mucinous content, and
few, if any, inflammatory cells. The epithelium lining the
lumen and superficial glands is in part retained, in part des-
quamated, and in part shows the development of a remarkable
degree of squamous metaplasia, even to the development of
rete pegs and intercellular bridges. The organism is not visible
in the lumen.
Abortion usually occurs between the second and third month
of pregnancy, but the incidence of abortion is relatively less
than in the bovine disease; there is also a high incidence of
stillborn and weak piglets born at term, and probably also a high
incidence of early undetected embryonic deaths. The placenta
may be retained. The specific uterine lesions of porcine bru-
cellosis are described previously. Apparently, the miliary Figure 4-69 Placentitis caused by Brucella ovis in a sheep.
406 CHAPTER 4 • Female Genital System Abortion and Stillbirth
than normal, enlarged, and pale yellow. There is extensive mucoid nature of the organism, it does not possess the smooth
necrosis of the epithelial elements of the cotyledons, with (O) antigens of B. abortus or B. melitensis. As a consequence,
edema and cellular infiltration of the stroma. Organisms in the conventional brucellosis test antigens that are used for
abundance inhabit the epithelial cells of the chorion. diagnosis of the disease in other domestic species are ineffec-
Most lambs are alive at the commencement of parturition, tive in the diagnosis of B. canis infections.
but mummification or progressive autolysis is also common. Transmission of the disease can be by ingestion of infected
As usual, the fetus tends to be autolysed with blood-stained vaginal discharge after abortion or venereally by infected
fluid within body cavities. Some may contain flecks or strands seminal fluids. The seminal fluids may remain infected for
of fibrin. When present, mineralized plaques on the walls, months. Pregnant bitches may abort after 30 days of gestation,
soles, or both, of the hooves and accessory digits occur, but but most abortions occur after 50 days. Testicular degeneration
these are not pathognomonic. The fetus shows little histologic and epididymitis are the usual manifestations of the disease in
evidence of systemic infection, even though the gastric contents male dogs. Affected dogs frequently lick the scrotal skin, pro-
may be heavily infected. Mild pneumonia and lymphadenitis ducing severe ulceration. Persistent bacteremias are common
of the tracheobronchial lymph nodes may be present together in many dogs that show no signs of disease. Bacteria have been
with the development of germinal centers and plasma cells in recovered from the blood for periods as long as a year, even
other nodes and spleen. Acute interstitial nephritis, particu- though high agglutinating titers were maintained throughout
larly about the corticomedullary junction, and inflammatory the bacteremic period. The nongenital lesions consist initially
infiltrates in portal triads are common. of nonspecific enlargement of the retropharyngeal and man-
The nonpregnant uterus is not affected by the infection. Infec- dibular lymph nodes. Later the lymph nodes throughout the
tion of the fetus may be produced experimentally at any stage, body may be enlarged because of diffuse hyperplasia of lym-
but following systemic exposure, as per conjunctiva, the phocytes and macrophages. The aborted fetuses may be dead
period of greatest susceptibility to intrauterine localization is or alive when expelled, but live fetuses usually die within a
from ~21-90 days of pregnancy. few hours or days. Pneumonia, endocarditis, and hepatitis are
Following artificial exposure, there is a lag of 2-3 weeks observed in the infected fetuses.
before bacteremia develops, and the bacteremic phase, in rams Focal necrosis is prominent in the chorionic villi and many
and probably in ewes, lasts about 2 weeks. Breeding ewes to of the trophoblastic epithelial cells are laden with bacteria (see
rams with open epididymal infection is more likely to result Fig. 4-67). In the bitch, serosanguineous to gray-green vaginal
in infertility than abortion. The routes of natural exposure of discharge may be evident for 1-6 weeks following abortion
pregnant ewes are not known. Placental localization is fol- and provides a source of infection for other dogs.
lowed by slow development of the intrauterine infection, and Brucellosis in other domestic species. Brucella abortus or
the pregnancy may survive for 2-3 months after first being B. suis is regularly found in the bursal lesions described else-
infected. where as poll evil and fistulous withers (see Vol. 1, Bones and
Brucellosis in sheep and goats, caused by Brucella meli- joints). There are other isolated reports of suppurative skeletal
tensis. B. melitensis is the principal cause of brucellosis in or synovial lesions in horses caused by these organisms.
sheep and goats, although natural infections with B. abortus Whereas cats are resistant to natural infection with Brucella
occur occasionally. Brucellosis in goats and sheep is prevalent spp., dogs are relatively resistant to the classic strains of Bru-
in countries bordering the Mediterranean, in the Near East, cella, but natural infections caused by all 3 species of the
and in South America. organism do occur. The majority of such infections are asymp-
In most respects, the caprine disease resembles bovine brucel- tomatic and detected serologically. Orchitis and epididymitis
losis, but the disease in sheep is usually less protracted, and have been observed. Other lesions described in dogs with
spontaneous recovery is fairly common in a few weeks or brucellosis, chiefly minute granulomas in liver, kidney, and
months. In the early bacteremic phases, goats may suffer lymph nodes, are neither specific nor necessarily related to the
severe illness and even die, but many infections are asymp- infection.
tomatic. The early signs of the disease may be referable to
acute mastitis with palpable nodules in the gland and a secre- Further reading
tion that is clotted and watery. The organism is excreted in
the milk, usually only for a few weeks in sheep, but often for Anderson ML. Infectious causes of bovine abortion during mid- to
several months or even some years in goats. late-gestation. Theriogenol 2007;68:474-486.
As is usual for ruminants, abortion may be the only sign Carvalho Neta AV, et al. Pathogenesis of bovine brucellosis. Vet J
observed, and it tends to occur late in pregnancy. The uterine 2010;184:146-155.
and vaginal discharges after pregnancy or parturition contain Godfroid J, et al. Diagnosis of brucellosis in livestock and wildlife. Croat
large numbers of organisms. Abortion or stillbirth may termi- Med J 2010;51:296-305.
nate successive pregnancies. Graham EM, Taylor DJ. Bacterial reproductive pathogens of cats and
Brucellosis in dogs, caused by Brucella canis. B. canis was dogs. Vet Clin North Am Small Anim Pract 2012;42:561-582.
first isolated and recognized as a cause of abortion and epi- Xavier MN, et al. Pathological, immunohistochemical and bacteriologi-
didymitis in dogs in 1966. The disease was identified in Beagle cal study of tissues and milk of cows and fetuses experimentally
colonies in North America at that time. Since then, it has been infected with Brucella abortus. J Comp Pathol 2009;140:
found in many parts of the world and in a variety of breeds. 149-157.
However, accurate incidence rates are not available; in the
United States, where the infection is widespread, the reported Campylobacter infections of the genital tract in
incidence rates are 0.5-5%. sheep and cattle
The disease is caused by a mucoid strain of Brucella that Infections caused by Campylobacter spp. are common and
shares biochemical features with B. suis. Because of the widespread in humans, cattle, sheep, swine, and chickens and
406.e1
Further reading
Díaz Aparicio E. Epidemiology of brucellosis in domestic animals caused
by Brucella melitensis, Brucella suis and Brucella abortus. Rev Sci
Tech 2013;32:43-51.
Gyuranecz M, et al. Detection of Brucella canis-induced reproductive
diseases in a kennel. J Vet Diagn Invest 2011;23:143-147.
Minten MA, et al. Effects of fertility on gene expression and function
of the bovine endometrium. PLoS ONE 2013;8:e69444.
Poester FP, et al. Pathogenesis and pathobiology of brucellosis in live-
stock. Rev Sci Tech 2013;32:105-115.
Roop RM, et al. Survival of the fittest: how Brucella strains adapt to
their intracellular niche in the host. Med Microbiol Immunol
2009;198:221-238.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 407
also occur occasionally in dogs. In sheep and cattle, diseases manifestations of these Campylobacter infections in sheep are
caused by these organisms were previously grouped under the late abortion, premature birth, and the birth of weak lambs.
title of “vibriosis,” given their classification in the genus Vibrio There is not usually retention of the placenta or sterility.
at that time. The principal patterns of disease are genital, Occasional maternal deaths occur as a result of metritis. Infec-
characterized by infertility or abortion, or intestinal, character- tion is not synonymous with abortion, as infected ewes may
ized by enteritis and diarrhea. deliver infected but clinically normal lambs. The incubation
• C. fetus subsp. venerealis causes a true genital infection period is 7-60 days, and abortion occurs at any stage of preg-
and is an important cause of infertility in cattle and can nancy. The infection cycles through the flock throughout the
cause abortion in cattle and sheep. season.
• C. fetus subsp. fetus is a common resident of the ovine and Transmission of C. jejuni most often occurs by the oral
bovine intestine and can cause abortion in both species but route, and fecal contamination of water supplies is relatively
does so more commonly in sheep. frequent. The organism is carried in the intestinal tract of
• C. jejuni is a common inhabitant of the intestinal tract in poultry, and it is a commensal of cattle, sheep, and swine. The
sheep and cattle and may cause enteritis in humans and organism is also a frequent inhabitant of the intestine in dogs
occasionally animals. It frequently causes abortion in sheep and cats and many rodents.
and less often in cattle, although heavy losses in individual When strains of C. fetus subsp. fetus isolated from feces or
cattle herds do occur. bile are given orally to susceptible sheep, there is transient
Genital infection of cattle caused by Campylobacter fetus bacteremia followed by localization in the gut and bile, and
subsp. venerealis. The disease in cattle caused by C. fetus the infection can spread by contact between sheep. In preg-
subsp. venerealis is a specific venereal disease transmitted by nant, nonimmune ewes, localization also occurs in the uterus.
coitus. Infected bulls may carry the organism indefinitely in Surface (S)-layer proteins appear to be essential for coloniza-
the preputial cavity, although some recover spontaneously. tion and/or translocation of C. fetus subsp. fetus to the pla-
Bulls do not become permanent carriers until they are at least centa. With both of these Campylobacter spp., the genital
4 years of age, and most do not become readily infected until infection is primarily an intestinal infection; transmission is by
they are 5-6 years of age. Epithelial crypts are more prominent ingestion, and uterine localization is an accidental outcome of a
in the penile mucosa with advancing age and provide a favor- brief bacteremic phase in a nonimmune sheep. The incidence of
able habitat for the bacteria. This also appears to be the abortion will depend on the number of ewes pregnant more
natural habitat for these organisms, and once the infection is than 1 month and on their experience with the infecting
established in these older animals, it tends to be retained strain. Immunity following infection or abortion usually lasts
permanently as a locally innocuous surface contaminant for 2 years; however, if other strains are introduced, they may
together with the nonpathogenic C. sputorum subsp. bubulus. cause abortion, as cross-protection between strains is incom-
The organism may also survive for long periods without plete. This also applies to vaccination strains.
producing lesions on the surface of the bovine vagina, but not The abortion rate in natural outbreaks varies from 5-70%
in the uterus. Infected cows develop immunity and control but is usually ~25%. Aborted fetuses may have only nonspecific
the infection. The outstanding feature seen with the infection is edematous changes; however, some have rather specific hepatic
not abortion but temporary sterility or repeat breeding with pro- lesions. Affected livers have few or many light tan areas, from
longation of the interestral periods. It is probable that the 1 mm up to 2 cm in diameter, and randomly distributed (Fig.
delayed return to estrus is the consequence of early embryonic 4-70). Frequently, they have a “target pattern” with a more or
death following fertilization and embryo attachment. Detect- less distinct, slightly raised white outer rim and a depressed
able abortions occur at any time but chiefly about the fourth tan inner zone. The abdomen is frequently distended with
to sixth month of gestation. The placenta is not usually fluid, fibrin, and the enlarged liver. If the lamb has lived a
retained. while before succumbing, these lesions must be differentiated
The endometrial lesions in cows that are repeat breeders from the focal necrobacillary hepatitis of umbilical origin.
are mild and consist of lymphocytic inflammation with Histologically, the lesion is multifocal necrotizing hepatitis, the
nodules and scattered cystic glands. Aborted placentas are necrotic region represented by the tan area and the outer rim
often autolysed, indicating that fetal death occurs before by cellular infiltrate and necrosis. There is frequently broncho-
expulsion. Placental lesions resemble those in brucellosis but are pneumonia with large numbers of neutrophils in major
less severe. The intercotyledonary placenta is edematous, airways and alveolar ducts. Small renal cortical hemorrhages
opaque, and may be leathery; there is diffuse inflammation, may also be present.
mainly histiocytic. Diseased cotyledons are yellow and pulpy; The cotyledons are enlarged, pale yellow to tan, dull and
many have yellow necrotic villi at the margins, and in others pulpy, and covered with brown exudate. The chorionic stroma
these are scattered throughout. There may be dense accumu- is edematous and infiltrated with leukocytes, which are mainly
lations of neutrophils among the denuded villi and in the histiocytes. There is frequently vasculitis. There is mild or
stroma. The degree of placentitis is quite variable and may be acute endometritis with rather more prominent inflammatory
inconspicuous. The parasitism of the chorionic epithelium exudation in the caruncular septa. The placental lesions are
that is characteristic of Brucella occurs but is less evident in more severe over the placentomes than in the intercotyledon-
placentitis caused by C. fetus subsp. venerealis. Lesions in the ary areas and are qualitatively similar to the lesions described
fetus are nonspecific. Blood-stained fluid in the subcutis and in the placenta in bovine brucellosis.
body cavities is common, and there may also be fibrin on the Diagnosis is based on the typical hepatic lesions and demon-
serous membranes. The normal colorless thick viscid fluid of stration of the organism. Distinctive organisms may be observed
the stomach content becomes yellow, very turbid, and flaky. in smears of abomasal content or of affected cotyledons and
Genital infection of sheep and cattle caused by Campylo- show up well with special stains. Darkfield or phase-contrast
bacter jejuni or Campylobacter fetus subsp. fetus. The chief microscopy may be used to see the characteristic darting
408 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Further reading
Bidewell CA, et al. Campylobacter fetus subspecies fetus abortion in Further reading
alpacas (Vicugna pacos). Vet Rec 2010;167:457-458. Crawshaw TR, Fuller HE. Flexispira rappini suspected in ovine abortion.
Hazlett MJ, et al. A prospective study of sheep and goat abortion using Vet Rec 1994;134:507.
real-time polymerase chain reaction and cut point estimation shows
Coxiella burnetii and Chlamydophila abortus infection concurrently
with other major pathogens. J Vet Diagn Invest 2013;25:359-368. Listeriosis
Mshelia GD, et al. Epidemiology of bovine venereal campylobacteriosis: Infections by Listeria monocytogenes occur worldwide and in
geographic distribution and recent advances in molecular diagnos- a variety of animals, including humans. In ruminants, infec-
tic techniques. Reprod Domest Anim 2010;45:221-230. tions are traditionally associated with cerebral localization and
encephalitis (for general discussion of the diseases associated
with this organism, see Vol. 1, Nervous system). However,
Flexispira rappini infections localization also occurs in the pregnant uterus, and abortion or
Flexispira rappini is a highly motile, anaerobic, rod-shaped stillbirth is then the common sign. The syndromes of encepha-
bacterium with multiple flagella at both of its tapered ends. litis and abortion may occur together in a herd or flock, but
Although F. rappini is the generally accepted name, it has not rather surprisingly, this is the exception. More commonly, one
been firmly classified. The organism is closely related to organ- or the other syndrome occurs exclusively. L. monocytogenes
isms in the genus Helicobacter but is distinguished from them varies greatly antigenically; serovars 1 and 4b are commonly
by its unusual spiral grooves visible on electron microscopic isolated from cattle and serovars 4b and 5 from sheep. Serovar
examination. Comparable organisms are frequently found in 5 (L. ivanovii) seems particularly pathogenic for sheep. L.
feces of dogs and pigs and in the stomachs and intestines of a ivanovii as a cause of abortion in sheep and cattle occurs less
variety of other species. frequently than L. monocytogenes and rarely causes other
Flexispira rappini infections in pregnant ewes result in fetal conditions.
mummification, abortion, and the birth of infected lambs born L. monocytogenes is shed in the feces of normal carriers and
weak. It is not considered to be the cause of epizootics of clinically affected animals alike and has been reported to
abortion, and because the lesions closely resemble those survive in some soils for as long as 2 years. It is most often
occurring in abortion caused by Campylobacter spp. (which do spread by ingestion of food or water contaminated by feces,
cause epizootics), it is important that it be differentiated. urine, placenta, or vaginal discharges from aborting animals.
Naturally or experimentally infected ewes usually abort in Infection by the oral and other routes has been shown experi-
the last trimester of pregnancy. The fetus is usually well pre- mentally to produce abortion. Silage is often the source of the
served; however, if it is retained in the uterus, it decomposes organism in severe outbreaks of the infection. The aerobic
408.e1
Further reading
Bulgin MS, et al. Abortion in the dog due to Campylobacter species.
Am J Vet Res 1984;45:555-556.
Chaban B, et al. Evaluation of a Campylobacter fetus subspecies vene-
realis real-time quantitative polymerase chain reaction for direct
analysis of bovine preputial samples. Can J Vet Res 2012;76:166-
173.
Grogono-Thomas R, et al. Roles of the surface layer proteins of Cam-
pylobacter fetus subsp. fetus in ovine abortion. Infect Immun
2000;68:1687-1691.
Kirkbride CA. Diagnoses in 1784 ovine abortions and stillbirths. J Vet
Diagn Invest 1993;5:398-402.
Morrell EL, et al. Histopathological, immunohistochemical, lectinhisto-
chemical and molecular findings in spontaneous bovine abortions
by Campylobacter fetus. Reprod Domest Anim 2011;46:309-315.
408.e2
Further reading
Kirkbride CA, et al. Abortion in sheep caused by a nonclassified,
anaerobic flagellated bacterium. Am J Vet Res 1986;48:259-262.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 409
Further reading
Ladds PW, et al. Pathology of listeric infection in domestic animals. Vet
Bull 1974;44:67-74.
Navarro JA, et al. Diagnosis of placental pathogens in small ruminants
by immunohistochemistry and PCR on paraffin-embedded samples.
Vet Rec 2009;165:175-178.
Rowe JH, et al. Listeria monocytogenes cytoplasmic entry induces fetal
wastage by disrupting maternal Foxp3+ regulatory T cell-sustained
fetal tolerance. PLoS Pathog 2012;8:e1002873.
Silva AP, et al. Transcription of pattern recognition receptors and abor-
tive agents induced chemokines in the bovine pregnant uterus. Vet
Immunol Immunopathol 2012;145:248-256.
410 CHAPTER 4 • Female Genital System Abortion and Stillbirth
reveal and identify the organism and routine testing of fetal cavity fluids by the time the organism has localized in the fetal
cavity fluids for antibody. It has become a relatively common kidneys. Cows aborting fetuses infected with L interrogans
diagnosis (0-40% of bovine fetuses submitted), depending on serovar hardjo may have high microscopic agglutination titers,
the geographic location. Infection of cattle by either L inter- but up to 40% are reported as not having a significant titer,
rogans serovar hardjo or L interrogans serovar pomona results and more than half of those may have no detectable titer.
in bacteremia, followed by damage in various parenchymal Prospective serology on a herd basis has been reported to be
organs (especially in the young) and eventually excretion of of considerable value in sorting out titers resulting from vac-
organisms in milk and urine. Antibody titers develop by 4-6 cination and either previous or present infections.
weeks and may stay up for a year or more. Leptospires then
may localize in the proximal renal tubules. Persistence and Leptospira infections of the pregnant uterus
intensity vary with the organism and the host. L interrogans in swine
serovar hardjo excretion in urine is usually high for 4-6 weeks Abortion is often the only evidence of leptospiral infection in a
but may persist at a lower intensity for 6-12 months or life. swine herd. There may be no relationship between return to
Cessation is usually associated with a marked increase in estrus and leptospirosis. Several serovars of Leptospira inter-
urinary antileptospiral IgG and IgA antibodies. L interrogations rogans regularly infect swine: canicola, grippotyphosa, ictero-
serovar hardjo may localize in the uterine tube and descend haemorrhagiae, sejroe, pomona, and tarassovi. The latter 2
into the uterus and placenta during pregnancy. Systemic infec- serovars, which are adapted to spread in swine, are most com-
tion may produce a febrile response and “flaccid agalactia” monly associated with fetal disease and abortion. Serologic
with the udder secretion becoming scant, yellow, and thick. testing has indicated that infection by serovar bratislava, or a
The organism may also localize in the placenta and, in some closely related serovar, is also widespread; and abortions, still-
animals, produces fetal disease and abortion. born, and weak liveborn piglets may have the organism and
Most of the abortions caused by Leptospira occur in the last antibodies to it. Serovar bratislava has also been associated
trimester of pregnancy and often follow acute infection of the with infertility without abortions. In one report, L. bratislava
dam by 1-6 weeks (serovar pomona) or 4-12 weeks (serovar was detected in samples of the uterine tube by means of
hardjo). L interrogans serovar autumnalis usually causes abor- immunofluorescence. Some of the serum samples from these
tion in the second trimester. L. hardjo may cause early embry- animals were positive for antibodies, whereas others were
onic death. Fetal infection is not invariably fatal, and weak negative. In one study, where many animals had a positive titer
calves may be born with a substantial antibody titer. Fetuses to Leptospira, failure to identify L interrogans serovar bratislava
that die in utero because of Leptospira infection are usually by immunofluorescence was believed to be associated with
expelled in an autolysed state. Abortion rates with L interrogans transient infections early in life.
serovar pomona may be as high as 50%, whereas with L. Leptospires are passed in the urine, and the organisms can
hardjo, they are generally around 3-10%, and infertility is a enter through mucous membranes or breaks in the skin. Poor
common observation in infected herds. management of effluent from piggeries may result in contami-
Gross and histologic lesions in the fetus and placenta are nation of drinking water, resulting in transmission of the
nonspecific; however, the presence of Leptospira-like organisms organism to swine and other animals, inducing leptospirosis in
in trophoblast cells, nonsuppurative meningitis, and nephritis war- cattle, sheep, horses, and dogs. Infected swine develop bacte-
rants further testing. remia before the leptospires localize in the kidneys and uterus,
The placenta may be edematous, but inflammatory changes where they may persist and can be shed for months. Systemic
are modest in spite of the fact that there may be clumps of signs, if they occur at all, develop during the stage of lepto-
leptospires in the chorionic epithelium. The fetus is often spiremia. It is also during this stage that the organism invades
autolysed, and calves in which leptospiral antigen is detected the placenta and infects the fetus. Most of the abortions result-
in the placenta weigh 6-10 kg less than calves with no antigen ing from leptospirosis occur late in gestation, but stillbirths, some-
in the placenta. Histologically, multifocal necrotizing tubular times with a few partially mummified fetuses, and births of live
necrosis or interstitial inflammatory infiltrates, usually with but weak pigs are also part of the pattern. Seropositive dams
plasma cells, can be found in the kidneys of some of the may have a greater risk of having weak newborn piglets and
fetuses. Occasionally, the fetus will have nonsuppurative also of having more weak newborn piglets per litter. Infected
meningitis. fetuses often die in utero and undergo autolysis, which
The organism may be demonstrated in smears of homog- obscures any lesions. Some aborted fetuses have elevated
enates of fetal kidney, lung, liver, and placenta; in fetal aqueous immunoglobulin levels.
humor by the indirect fluorescent antibody test; or by culture. The placentas of infected pigs may be edematous, but the
The organism can also be demonstrated in sections of fixed most severe lesions are seen in those piglets delivered alive,
fetal kidney by immunohistochemistry or in frozen sections but sick, at or near term. Some of these will be icteric, have
by using the fluorescent antibody technique. In stillborn patchy hepatic necrosis, fluid, and fibrin in the peritoneal
calves, the adrenal glands, lung, and placenta are the most cavity and inflammatory changes in multiple organs. Focal
useful organs to examine for leptospiral antigen. Cultures of aggregations of lymphocytes in the renal cortex, medulla, and
fetuses can often be misleading. Calves infected with Lepto- pelvis are characteristic but inconstant. Leptospires can be
spira spp. have been found to be more likely infected by T. demonstrated in the kidneys or lungs on section by using a
pyogenes or Bacillus spp.; the latter is probably an incidental silver stain. Special stains are much more useful on tissue sec-
finding, but more easily demonstrated than the Leptospira. tions taken from swine than cattle; however, the fluorescent
Cultures of specimens can be productive but are time con- antibody test for the organism on kidney, lung, and placenta
suming and cumbersome, with a long delay before results. homogenates gives a more definitive answer and allows visu-
Fetuses that die when the infection is generalized may not alization of the lesion with the antigen. In addition, leptospires
have formed antibody, but antibody is frequently present in may frequently be demonstrated by darkfield microscopy,
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 411
Further reading
Bolin CA, et al. Reproductive failure associated with Leptospira inter-
rogans serovar bratislava infection of swine. J Vet Diagn Invest
1991;3:152-154.
Rinehart CL, et al. Efficacy of vaccination of cattle with the Leptospira
interrogans serovar hardjo type hardjoprajitno component of a
pentavalent Leptospira bacterin against experimental challenge
with Leptospira borgpetersenii serovar hardjo type hardjo-bovis.
Am J Vet Res 2012;73:735-740.
Sebastian M, et al. Funisitis associated with leptospiral abortion in an
equine placenta. Vet Pathol 2005;42:659-662.
Shanahan LM, Slovis NM. Leptospira interrogans associated with
hydrallantois in 2 pluriparous Thoroughbred mares. J Vet Intern
Med 2011;25:158-161.
Smyth JA, et al. Stillbirth/perinatal weak calf syndrome: a study of
calves infected with Leptospira. Vet Rec 1999;145:539-542.
Whitwell KE, et al. Two cases of equine pregnancy loss associated with
Leptospira infection in England. Vet Rec 2009;165:377-378.
Wilkie IW, et al. Giant cell hepatitis in four aborted foals: a possible
leptospiral infection. Can Vet J 1988;29:1003-1004.
412 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Further reading
Argue B, et al. Presence of Ureaplasma diversum in the Australian cattle
population. Aust Vet J 2013;91:99-101.
Ruhnke HL, et al. Bovine abortion and neonatal death associated with
Ureaplasma diversum. Theriogenology 1984;21:295-301.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 413
Yersinia pseudotuberculosis as a cause of abortion in Figure 4-73 Yersinia pseudotuberculosis bovine abortion. Chronic
cattle, sheep, and goats suppurative cotyledonary placentitis and pericotyledonary fibrin.
Yersinia pseudotuberculosis is a gram-negative coccobacillus in
the family Enterobacteriaceae. The DNA of Y. pestis, the cause
of human plague, and Y. pseudotuberculosis are at least 90%
interrelated. Six serogroups of Y. pseudotuberculosis are recog-
nized based on immunoreactivity of the O antigens. Y. pseu-
dotuberculosis causes ileitis, lymphadenitis, and abscessation in
humans, and infects a wide variety of domestic, laboratory, and
native animals and birds throughout the world. The organism
is frequently isolated from the feces of normal cattle, and from
abortions in sheep, goats, and cattle. In sheep, the organism
also causes abdominal abscessation and inflammation in the
testis and epididymis.
The pathogenesis of abortion probably follows invasion of
the intestinal epithelium, transient bacteremia, and localiza-
tion in the maternal caruncle, followed by passage to the
chorioallantois and fetus. It is revealing that in the description
of the experimental production of disease in sheep that
follows, uterine, and specifically caruncular, disease was
present as in naturally occurring abortion. It is possible that
nutrients in the caruncle favor localization and growth of
Yersinia that is followed by villus infarction and invasion of
the chorion.
Lesions reported are based on limited observations that are
generally similar in aborted fetuses and stillborns from sheep,
goats, and cattle. The aborted conceptus is usually well pre-
served and contains a variety of lesions. Placentitis is largely Figure 4-74 Yersinia pseudotuberculosis infection. Nonsuppura-
confined to the cotyledons. Cotyledons are red or tan, thick- tive conjunctivitis in an aborted calf.
ened and relatively devoid of exudate on the surface. Portions
of the caruncle may remain attached. The intercotyledonary
region is usually translucent, but a frosting of fibrin and some accompanied by mononuclear cell and neutrophil infiltrates.
fibrosis may closely surround the affected cotyledons (Fig. Lesions in the attached portions of caruncle consist of throm-
4-73). The thoracic and abdominal cavities contain excess bosis of septal vessels, hemorrhage, and necrosis, with a heavy
amber fluid with some fibrin. In the fetal liver, there may be diffuse infiltration of neutrophils and mononuclear cells. In
pale tan focal areas of necrosis ranging in size from 0.1-1 cm. the lamina propria of the conjunctiva, there are focal infiltra-
No other gross lesions are observed. tions of mononuclear cells, plasma cells, and a few neutrophils
Histologically in the placenta, there is necrosis of villi and (Fig. 4-74). In the lung, there are a few mononuclear cells in
moderate infiltration of granulocytes, macrophages, and mono- airways. Hepatic lesions consist of focal areas of necrosis infil-
nuclear cells in the interstitium of the chorioallantoic arcade. trated by granulocytes and mononuclear cells. Similar foci are
In placental vessels, there is fibrinoid necrosis of the media visible on microscopic examination of myocardium and lymph
414 CHAPTER 4 • Female Genital System Abortion and Stillbirth
nodes. Peyer’s patches are precociously cellular. The lamina to the epithelium of alveolar ducts, and swirling (oat-type)
propria and submucosa of the colon are heavily populated by macrophages are numerous in these areas. Fibrin often fills
plasma cells and mononuclear cells, and within the lumen, lymphatics, distending interlobular septa.
colonies of the organism and scattered inflammatory cells can Diagnosis is based on observing the characteristic lesions in
be seen in the meconium. the placenta and lung, and isolation of the organism from the
Extensive lesions in the uterus follow the experimental stomach content or placenta.
production of abortion in sheep. They consist of thrombosis
of septal vessels, necrosis of septa, and heavy infiltrations of
granulocytes in caruncles and intercaruncular regions. Further reading
Diagnosis is based on identification of the organism or its Barkallah M, et al. Survey of infectious etiologies of bovine abortion
DNA from placenta, stomach content, or lung, and the lesions during mid- to late gestation in dairy herds. PLoS ONE 2014;
described. 9:e91549.
Madoz LV, et al. Endometrial cytology, biopsy, and bacteriology for the
Histophilus somni infections of the pregnant diagnosis of subclinical endometritis in grazing dairy cows. J Dairy
bovine uterus Sci 2014;97:195-201.
Histophilus somni is the only species of the genus Histophilus, Welsh RD, Stair EL. Yersinia pseudotuberculosis bovine abortion. J Vet
family Pasteurellaceae, and encompasses bacteria isolated from Diagn Invest 1993;5:109-111.
cattle and previously described as Haemophilus somnus, as well
as ovine isolates formerly referred to as Histophilus ovis and
Haemophilus agni. H. somni is a fastidious gram-negative coc- Chlamydophila (Chlamydia) infections
cobacillus that is considered normal flora of the male and causing abortions
female bovine genital tract. There are marked differences in Chlamydophilae (chlamydiae) are obligate intracellular para-
the ability of different isolates from the reproductive tract to sites that multiply in membrane-bound vacuoles in a variety
produce central nervous system (CNS) disease. Preliminary of cells. They have 2 distinct forms, the reticulate body, which
experiments have not shown the reverse to be true. is not infectious, and the elementary body, which is infectious
H. somni is best known for its association with CNS disease and released from the cytoplasm by a mechanism not fully
and pneumonia in cattle, and these are discussed under those understood but which involves disruption of the cell. The
sections. The organism is often associated with vaginitis, infertil- inclusions, which can be seen on light microscopy, consist of
ity, abortion, and occasionally with fatal endometritis. Usually hundreds of gram-negative Chlamydophila cells bound by a
abortions induced by H. somni involve solitary animals; membrane in a cytoplasmic vacuole. Based on DNA sequence
however, occasionally an entire herd will develop reproductive analysis, the family Chlamydiaceae is divided into 2 genera:
disease, including vaginitis and infertility attributed to this Chlamydophila and Chlamydia. The species of Chlamydophila
organism. When this occurs, predisposing factors, in the form and Chlamydia of veterinary interest include the redesignated
of malnutrition, concurrent virus infection, or stress, should forms of Chlamydia psittaci, namely, Chlamydophila abortus
be considered. (former ovine serovar [immunotype] 1), C. psittaci (former
The organism is commonly resident in the vagina of cows avian serovar), C. felis (feline serovar), C. caviae (guinea pig
(3-76% of animals sampled), and in the prepuce of bulls serovar); plus C. pecorum (mammals), and Chlamydia suis
(>75% positive). Natural breeding therefore easily spreads it. (former porcine serovar of C. trachomatis). C. suis, C. pecorum,
Most strains of the organism are sensitive to the antibiotics and C. abortus have all been associated with reproductive
used in the preparation of frozen semen. Sampling of a natu- failure and abortion. Chlamydiae have also been associated
rally infected herd revealed >50% of calves infected by 7 with abortion in horses. Of significance as human pathogens
months of age. The presence of the organism in the vagina are C. psittaci, C. pneumoniae, and C. trachomatis.
does not imply clinical disease. Chlamydophila abortion in sheep, goats, and cattle. Chla-
The pathogenesis of abortion has not been clarified. The mydophila abortus is an important cause of in utero infections
organism shows some ability to penetrate the cervical area to in sheep and goats, resulting in abortion, stillbirth, and the
infect the placenta; however, lesions in the placenta are usually birth of weak offspring, and can cause abortion in women in
in cotyledons, which suggests a hematogenous route. Bactere- close contact with these aborting ruminants. The disease in
mia following a vaginal or respiratory infection is likely. Death sheep has been known as “ovine enzootic abortion” and “enzo-
of the fetus after infection is usually rapid, resulting in the abor- otic abortion of ewes” but will be referred to here as Chla-
tion of a severely autolysed fetus. mydophila abortion. C. pecorum, a fecal organism, may cause
Lesions in the placenta are primarily confined to the cotyledon sporadic abortion, but this is rare.
and consist of acute necrotic placentitis, which does not appear The products of abortion, uterine discharge, vaginal fluids,
to penetrate to either the amnion or allantoic surface. On and semen are potential sources of the organism. On exposure
histologic examination, the most distinctive lesion in the pla- of oral, conjunctival or reproductive mucosae, sheep and goats
centa consists of severe fibrinoid necrosis and thrombosis of develop chlamydophilemia and may develop interstitial pneu-
large and small arteries. The cellular infiltrate in vessel walls monia or focal hepatitis. Weeks or months later, the organism
and adjacent villi is mainly macrophages with some neutro- appears in mononuclear cells of the pregnant uterus and then
phils. There is sparing of veins and capillaries. Colonies of is found in trophoblasts; the rest of the placenta and the fetus
bacteria are visible next to the trophoblast cells. Lesions in the may become infected. Naïve animals, including newly intro-
fetus are usually sparse; however, acute fibrinous broncho- duced sheep and females pregnant for the first time, are most
pneumonia is occasionally observed. On histology, airways are vulnerable. The incubation period is 50-90 days. If infected in
seen to contain degenerating mononuclear cells, macrophages, the early part of gestation, the ewe may abort in the final trimester
but few neutrophils. Bacteria are frequently observed adjacent of pregnancy, or infection may manifest as stillbirths or weak
414.e1
Further reading
Angen O, et al. Proposal of Histophilus somni gen. nov., sp. nov. for
the three species incertae sedis “Haemophilus somnus”, “Hae-
mophilus agni” and “Histophilus ovis”. Int J Syst Evol Microbiol
2003;53:1449-1456.
Giannitti F, et al. Yersinia pseudotuberculosis infections in goats and
other animals diagnosed at the California Animal Health and Food
Safety Laboratory System: 1990-2012. J Vet Diagn Invest 2014;
26:88-95.
Headley SA, et al. Histophilus somni-induced infections in cattle from
southern Brazil. Trop Anim Health Prod 2013;45:1579-1588.
Kaneko K, et al. Influence of Trueperella pyogenes in uterus on corpus
luteum lifespan in cycling cows. Theriogenol 2013;79:803-808.
Metzner M, et al. Trueperella abortisuis, an emerging pathogen iso-
lated from pigs in Germany. Berl Munch Tierarztl Wochenschr
2013;126:423-426.
Radke BR, et al. Salmonella Muenster infection in a dairy herd. Can
Vet J 2002;43:443-453.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 415
Further reading
Henning K, et al. Demonstration of Chlamydia from an equine abor-
tion. Dtsch Tierarztl Wochenschr 2000;107:49-52.
Henning K, et al. Neospora caninum and Waddlia chondrophila strain
2032/99 in a septic stillborn calf. Vet Microbiol 2002;85:285-292.
Longbottom D, et al. Intranasal infection with Chlamydia abortus
induces dose-dependent latency and abortion in sheep. PLoS ONE
2013;8:e57950.
Rodolakis A, et al. Chlamydia psittaci experimental abortion in goats.
Am J Vet Res 1984;45:2086-2089.
Schiller I, et al. Mixed infections with porcine Chlamydia trachomatis/
pecorum and infections with ruminant Chlamydia psittaci serovar
1 associated with abortions in swine. Vet Microbiol 1997;58:251-
260.
Thoma R, et al. Chlamydiae in porcine abortion. Vet Pathol
1997;34:467-479.
416 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Figure 4-77 Caprine Coxiella burnetii abortion. Suppurative pla- Figure 4-78 Ovine Coxiella burnetii abortion. Microcolonies of
centitis primarily involving the intercotyledonary areas of the Coxiella burnetii distend the cytoplasm of trophoblasts.
chorioallantois is shown.
Abortion in sheep, goats, and cattle caused by microcolonies can be seen in conventionally stained sections,
Coxiella burnetii but must be distinguished from similar colonies formed by
Coxiella burnetii is in the family Rickettsiaceae and is the only Chlamydophila organisms. With H&E stains, Chlamydophila
member of the genus Coxiella. The organism is well known inclusions tend to stain poorly and appear more homogeneous,
as the cause of Q (query) fever in humans. It is an obligate whereas cells containing Coxiella frequently have a character-
intracytoplasmic parasite. Dairy cows, goats, and sheep are the istic foamy appearance with multiple unstained vacuoles
common reservoirs of the organism, and cats and wildlife may within a pale blue cytoplasm. The nucleus, if visible, is usually
also carry it. Human and domestic animal infection occurs pushed against the cell wall and assumes a crescent shape.
when contaminated dust is inhaled; however, massive con- The histologic lesions in affected fetuses are usually modest.
tamination of a paddock or pasture facilitates oral transmis- Granulomatous hepatitis and nonsuppurative pneumonia
sion. Infection apparently persists indefinitely in sheep and with occasional focal lymphoid accumulations around bron-
cattle, and organisms are shed at parturition and in the milk chioles have been described. A few lymphocytes and macro-
and feces. Abortion usually follows initial exposure and may phages may infiltrate the renal medulla and surround the
be unusual in endemically infected flocks. portal vessels of the liver.
Abortion tends to occur late in the gestation period, and Bovine fetuses may also be aborted as a result of Coxiella
weak lambs and kids may be born during an outbreak. The infections. The lesion in the placenta is characteristic and
aborted fetus may be well preserved or autolysed. Gross similar to that observed in sheep and goats. Care must be
lesions are confined to the placenta, which is thickened and leath- taken in attributing the simple presence of Coxiella as suffi-
ery, with multifocal to confluent areas of mineralization. The cient evidence for the cause of abortion. Animals may carry
exudate is copious, off-white, and most obvious in the inter- the organism for a prolonged period and, although they appear
cotyledonary region. If the cotyledon is involved, the early to abort only once, there may be large numbers of organisms
lesion appears as a white outer ring with flecks of white scat- in the placenta in subsequent pregnancies. Assessment of the
tered in the central region. extent of the placental lesion may be helpful.
Histologically, there is trophoblast hyperplasia and or acute Diagnosis is routinely based on the characteristic placental
diffuse suppurative placentitis (Fig. 4-77) and extensive lesions and the appearance of the organism in impression
necrosis of cotyledonary villi and intercotyledonary tropho- smears stained by a modified acid-fast technique. More defini-
blasts (Fig. 4-78). In contrast, the inflammatory cells in the tive methods using direct or indirect fluorescent antibody
interstitium of the chorioallantoic arcade are largely mono- techniques and tests to detect Coxiella DNA are available.
nuclear, with a predominance of plasma cells. The lesion, Co-infection with Chlamydophila and Toxoplasma is common
which on gross section appears to be largely confined to the in sheep and goats. Cutoff points may assist in determining if
intercotyledonary region, is frequently found on histology to the infection is relevant to abortion, but correlation with
be also extensive in the cotyledons, especially at the periphery. lesions is always advised.
The vasculitis that develops with Chlamydophila infections is
not usually a feature of placentitis caused by Coxiella. Smears
of placental exudate contain large numbers of organisms, which Further reading
can be stained by the modified Ziehl-Neelsen or Macchiavello Agerholm JS. Coxiella burnetii associated reproductive disorders
stain. The organism produces microcolonies within tropho- in domestic animals—a critical review. Acta Vet Scand 2013;
blasts, which distend the cytoplasm (see Fig. 4-78). These 55:13.
416.e1
Further reading
Berri M, et al. Shedding of Coxiella burnetii in ewes in two pregnancies
following an episode of Coxiella abortion in a sheep flock. Vet
Microbiol 2002;85:55-60.
Moore JD, et al. Pathology and diagnosis of Coxiella burnetii infection
in a goat herd. Vet Pathol 1991;28:82-84.
Roest HJ, et al. Q fever in pregnant goats: pathogenesis and excretion
of Coxiella burnetii. PLoS ONE 2012;7:e48949.
Roest HI, et al. Q fever diagnosis and control in domestic ruminants.
Dev Biol (Basel) 2013;135:183-189.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 417
Hazlett MJ, et al. A prospective study of sheep and goat abortion Nocardioform placentitis in mares
using real-time polymerase chain reaction and cut point estimation This disease, caused by actinomycete bacteria, is found sporadi-
shows Coxiella burnetii and Chlamydophila abortus infection cally throughout the world. All ages and breeds of mares are
concurrently with other major pathogens. J Vet Diagn Invest affected. The mare shows no outward signs of illness except,
2013;25:359-368. as with other near-term abortions, premature development of
Muskens J, et al. Prevalence of Coxiella burnetii infections in aborted the mammary gland and lactation may occur. Infection is
fetuses and stillborn calves. Vet Rec 2012;170:260. cleared early, and rebreeding has not been accompanied by
problems. The bacteria involved are gram-positive branching
filamentous organisms and include at least 3 different genera
Mare reproductive loss syndrome and of bacteria: Crossiella equi, Streptomyces, and 3 species of
late-term abortions Amycolatopsis. No risk factors have been identified, nor has
A syndrome of abortion reached epidemic proportions in the the condition been reproduced.
spring of 2001 and to a lesser extent in 2002. It is of major The lesion in the placenta is somewhat unique in that
concern to the equine industry in various states but especially infection does not seem to start at, nor communicate with,
in Kentucky. Several hundred late-term fetuses were exam- the cervical star. The chorionic surface of the most cranial
ined. Most were aborted or stillborn at term or several weeks portion of the body and entrance to the uterine horns is
before term, well preserved, and enclosed within the placenta. covered with thick brown exudate containing sloughed cho-
There were few or no premonitory signs of illness in the mares. rionic cells, neutrophils, and bacteria. The bacteria invade the
Lesions observed in the fetus included hyphema and little or chorionic epithelium but have not been identified in fetal
no inflation in the lungs. Hemorrhages were frequently fluids and organs.
observed on the chorion, amnion and amniotic segment of the
umbilical cord, pleura, and heart. The surface of the amniotic
segment of the cord was dull gray to yellow, roughened, and Further reading
thickened by stromal edema. On microscopic examination, Erol E, et al. An investigation of a recent outbreak of nocardioform
the amniotic portion of the umbilical cord had bacteria on the placentitis caused abortions in horses. Vet Microbiol 2012;158:425-
surface, and where there was loss of epithelium, there were 430.
light to heavy infiltrations of neutrophils and macrophages. Giles RC, et al. Causes of abortion, stillbirth, and perinatal death in
Similar light infiltrates were seen in the stroma of the horses: 3,527 cases (1986-1991). J Am Vet Med Assoc 1993;
chorioallantois. 203:1170-1175.
Cultures of the fetus and placenta yielded non–β-hemolytic Labeda DP, et al. Amycolatopsis kentuckyensis sp. nov., Amycolatopsis
Streptococcus spp. and/or Actinobacillus spp. in 50% and 20% lexingtonensis sp. nov., and Amycolatopsis pretoriensis sp. nov.,
of the specimens cultured, respectively. Similar bacteria were isolated from equine placentas. Int J Syst Evol Microbiol 2003;
also cultured from lung, stomach content, and placental mem- 53:1601-1605.
branes. Microscopic lesions included funisitis, amnionitis,
pneumonia, fetal bacteremia, and sometimes chorionitis.
Further investigations supported unusually warm weather and Miscellaneous infections causing abortion
rate of change from cool to warm as major factors, which in mares
correlated with increased bacterial growth and eastern tent The bacterial infections in foals that produce the syndromes
caterpillar (ETC) development. In a controlled study, investi- variously known as joint ill, navel ill, foal septicemia, and
gations involving the feeding of ETC to pigs caused abortion. pyosepticemia neonatorum can also produce abortions and
A similar study in mares revealed that abortion occurred only stillbirths. The implication is that these diseases of the newborn
on feeding of the insect exoskeleton and that hair remnants can be continuations of intrauterine disease. The organisms
resembling ETC setae were embedded in the submucosa of involved, in approximately the order of frequency, are:
the digestive tract of aborting gilts and of an aborting mare. β-hemolytic streptococci, E. coli, Pseudomonas, Staphylococcus
Studies of a similar disease caused by processionary caterpil- aureus, Klebsiella pneumoniae, and Actinobacillus equuli. These
lars show that the setae penetrate the intestine after ingestion and organisms may occasionally reach the chorion by way of the
subsequently migrate to the pregnant uterus by direct penetration. bloodstream of the dam, but most ascend through a patent
With them go bacteria that induce infection of the pregnant cervix (Fig. 4-79). This produces inflammatory thickening of
uterus and fetus and placenta. the cervical star region of placenta adjacent to and radiating
from the internal os of the cervix.
Aspergillus fumigatus is the most commonly isolated fungus,
Further reading but Lichtheimia (Absidia) corymbifera and other Aspergillus
Cawdell-Smith AJ, et al. Equine amnionitis and fetal loss: mare abortion
spp. have been recovered.
following experimental exposure to processionary caterpillars
Actinobacillus equuli is an important cause of neonatal
(Ochrogaster lunifer). Equine Vet J 2012;44:282-288.
death of foals in most countries. Foals may become infected
McDowell KJ, et al. Invited review: the role of caterpillars in mare
in utero and be aborted, as discussed previously; they may die
reproductive loss syndrome: a model for environmental causes of
of septicemia in the early neonatal period; or they may survive
abortion. J Anim Sci 2010;88:1379-1387.
for several days and develop foci of localization in many
Todhunter KH, et al. Processionary caterpillar setae and equine
tissues. It is probable that some of these infections are acquired
fetal loss: 2. Histopathology of the fetal-placental unit from
during or after parturition. Aborted foals and those dying
experimentally exposed mares. Vet Pathol 2014;doi:10.1177
acutely of septicemia do not have distinctive lesions. After a
/0300985813516639.
course of 3 or 4 days or more, localization of the infection
with miliary microabscesses and polyarthritis develops. The
417.e1
Further reading
Cohen ND, et al. Descriptive epidemiology of late-term abortions
associated with the mare reproductive loss syndrome in central
Kentucky. J Vet Diagn Invest 2003;15:295-297.
Sebastian MM, et al. Review paper: mare reproductive loss syndrome.
Vet Pathol 2008;45:710-722.
Volkmann D, et al. Hormone profiles of mares affected by the mare
reproductive loss syndrome. Reprod Domest Anim 2008;43:
578-583.
417.e2
Further reading
Donahue JM, et al. Crossiella equi sp. nov., isolated from equine pla-
centas. Int J Syst Evol Microbiol 2002;52:2169-2173.
Volkmann DH, et al. The first reported case of equine nocardioform
placentitis in South Africa. J S Afr Vet Assoc 2001;72:235-238.
418 CHAPTER 4 • Female Genital System Abortion and Stillbirth
microabscesses, which are embolic in origin, may be found in vacuoles that were filled with elongated gram-positive organ-
many organs, and they are readily visible to the naked eye in isms. These were positively identified by PCR and electron
the renal cortices. The renal abscesses are small, being only microscopy as E. cuniculi. No organisms were identified in the
1-3 mm in diameter, and numerous. Histologically, bacterial joints.
colonies are obvious in the glomeruli and intertubular capil-
laries and are enclosed in foci of intense suppuration. The
arthritis is fibrinopurulent. Further reading
There is little information on the epidemiology and patho- Donahue JM, et al. Classification of Actinobacillus spp isolates from
genesis of actinobacillosis. Mares, which are caused to abort horses involved in mare reproductive loss syndrome. Am J Vet Res
by this infection, are not ill, and the organism does not persist 2006;67:1426-1432.
for long in the uterus after abortion. However, the same mare Patterson-Kane JC, et al. Placentitis, fetal pneumonia, and abortion due
may abort successive pregnancies, a fact which suggests that to Rhodococcus equi infection in a Thoroughbred. J Vet Diagn
the uterus can be reinfected from some endogenous asymp- Invest 2002;14:157-159.
tomatic focus. A. equuli can occasionally be found in the Patterson-Kane JC, et al. Encephalitozoon cuniculi placentitis and
intestine and tissues of healthy animals and also as an oppor- abortion in a quarterhorse mare. J Vet Diagn Invest 2003;15:
tunist in pathologic tissues such as verminous thromboses. It 57-59.
is, however, seldom of significance in adult animals, although Williams N. Mare reproductive loss syndrome. Equine Q 2002;
septicemia has been observed. 10:4-7.
Rhodococcus equi is an important cause of pneumonia and
colitis in foals <6 months of age, and a rare cause of placentitis
and abortion. The fetus may be expelled within the mem- Mycotic abortion in cattle
branes. The cervical star and surrounding region may be red; Sporadic cases of bovine abortion result from infection with
the lungs are pale and fail to float. R. equi may be isolated in a variety of fungal species, with Aspergillus fumigatus the most
pure culture from the placenta, lungs, liver, and stomach frequent isolate in North America. Zygomycetes (Lichtheimia
content. The lesion in the placenta consists of a perivascular [Absidia], Mortierella, Rhizomucor, Rhizopus) are also com-
macrophage infiltrate with a few lymphocytes and neutro- monly responsible. Mixed fungal infections are relatively
phils. The macrophages contain numerous gram-positive coc- common, in which case both septate and nonseptate hyphae
cobacilli. Inflammation is most extensive on the allantoic may be observed in the placenta. A small number of abortions
surface. On microscopic examination, there is multifocal result from Pseudallescheria boydii and yeast (Candida, Toru-
hypertrophy and hyperplasia of allantoic epithelial cells, and lopsis) infections. The portal of entry is not known, but the
small numbers of neutrophils and large macrophages are initial development of lesions in placentomes indicates hema-
loosely scattered within the amnion. Pulmonary alveoli togenous arrival. Extension from either respiratory or rumen
contain a few granulocytes and many macrophages, some of infections is possible. With the exception of Rhizopus, these
which are multinucleated. organisms are well-known secondary pathogens. Abortion
Encephalitozoon cuniculi is a microsporidial organism that occurs late in gestation, between the sixth and eighth month,
is a rare cause of placentitis and abortion in a wide range of and the placenta is often firmly retained.
animals, including horses. A Quarter Horse mare aborted a The fetus may appear normal, but often there are character-
fetus and placenta 6 weeks before term; viscous yellow istic cutaneous lesions in the form of irregular elevated plaques
exudate was scattered over the chorionic surface of the pla- resembling ichthyosis or extensive ringworm. These lesions are
cental body and both horns. In addition, the joints of the foal seen most commonly about the periorbit, occiput, shoulders,
were swollen and contained tan to red gelatinous material. On back, and sides (Fig. 4-80). Affected areas are slightly elevated,
microscopic examination, there was necrotizing placentitis, gray, and irregular in outline and tend to coalesce. Histologi-
and trophoblasts contained large numbers of intracytoplasmic cally, the infection is seen to be superficial, involving the
418.e1
Further reading
Hong CB, et al. Etiology and pathology of equine placentitis. J Vet
Diagn Invest 1999;5:56-63.
Mohan K, et al. Strains of Actinobacillus spp. from diseases of animals
and ostriches in Zimbabwe. Onderstepoort J Vet Res 1997;64:195-
199.
Monga DP, et al. Mycotic abortions in equines. Mykosen 1983;26:612-
614.
Morehead JP, et al. Evaluation of early fetal losses on four equine farms
in central Kentucky: 73 cases. J Am Vet Med Assoc 2003;220:1828-
1830.
Piancastelli C, et al. Isolation and characterization of a strain of Lich-
theimia corymbifera (ex Absidia corymbifera) from a case of bovine
abortion. Reprod Biol Endocrinol 2009;7:138.
Platt H. Infection of the horse fetus. J Reprod Fertil Suppl 1975;23:605-
610.
Prickett ME. Abortion and placental lesions in the mare. J Am Vet Med
Assoc 1979;157:1465-1470.
Swerczek TW. Equine fetal diseases. In: Morrow DA, editor. Current
Therapy in Theriogenology. Philadelphia: WB Saunders; 1986.
p. 699-704
Takai S. Epidemiology of Rhodococcus equi infections: a review. Vet
Microbiol 1997;56:167-176.
Wolfsdorf KE, et al. Theriogenology question of the month. J Am Vet
Med Assoc 2000;216:1915-1916.
Zink MC, et al. Corynebacterium equi infections in horses, 1958-1984:
a review of 131 cases. Can Vet J 1986;27:213-217.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 419
Further reading
Johnson CT, et al. The bovine placentome in bacterial and mycotic
abortions. Vet Rec 1994;134:263-266.
Knudtson WU, Kirkbride CA. Fungi associated with bovine abortion in
the northern plains states (USA). J Vet Diagn Invest 1992;4:181-
185.
Figure 4-81 Mycotic placentitis primarily involving the cervical Piancastelli C, et al. Isolation and characterization of a strain of Lich-
star area of an equine placenta. theimia corymbifera (ex Absidia corymbifera) from a case of bovine
abortion. Reprod Biol Endocrinol 2009;7:138.
Further reading
Cordes DO, et al. Mycotic pneumonia and placentitis caused by Mor-
tierella wolfii. Vet Pathol 1972;9:190-201.
Hill MW, et al. Pathogenesis of experimental bovine mycotic placentitis
produced by Aspergillus fumigatus. Vet Pathol 1971;8:175-192.
Jensen HE, et al. Bovine mycotic abortion—a comparative study of
diagnostic methods. Zentralbl Veterinarmed B 1991;38:33-40.
420 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Further reading
Stott JL, et al. Experimental transmission of epizootic bovine abortion
(foothill abortion). Vet Microbiol 2002;88:161-173.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 421
Further reading
Edwards JF, Dubey JP. Toxoplasma gondii abortion storm in sheep on
a Texas farm and isolation of mouse virulent atypical genotype T.
gondii from an aborted lamb from a chronically infected ewe. Vet
Parasitol 2001;192:129-136.
Hazlett MJ, et al. A prospective study of sheep and goat abortion using
real-time polymerase chain reaction and cut point estimation shows
Coxiella burnetii and Chlamydophila abortus infection concurrently
with other major pathogens. J Vet Diagn Invest 2013;25:359-368.
Kim JH, et al. Porcine abortion outbreak associated with Toxoplasma
gondii in Jeju Island, Korea. J Vet Sci 2009;10:147-151.
Wiengchareon J, et al. Transplacental transmission in cattle: is Toxo-
plasma gondii less potent than Neospora caninum? Parasitol Res
2011;108:1235-1241.
422 CHAPTER 4 • Female Genital System Abortion and Stillbirth
zoites may be seen in myocytes and Purkinje fibers in myo- trophoblasts, and more often no significant lesions are seen in
cardium. Less consistent lesions include multifocal hepatic the placenta. Mononuclear cells are found in areas of focal
necrosis, focal nonsuppurative interstitial nephritis, interstitial necrosis in the cotyledons. Neospora, although rarely identified
pneumonia, and adrenalitis. Large numbers of N. caninum–like in placenta by immunohistochemistry, may be positive on
zoites are rarely observed in poorly defined cysts within PCR.
On light microscopy, N. caninum can be distinguished from
cysts of Toxoplasma and Sarcocystis, as the cyst wall is slightly
thicker. All stages can be differentiated from other protozoans
using immunohistochemistry, which is used successfully to
demonstrate protozoa in brain (Fig. 4-87), spinal cord, lung,
kidney, heart, and skeletal muscle of fresh or autolysed fetuses
and also, but with more difficulty, in mummified fetuses. Isola-
tion of N. caninum from autolysed tissues in cell cultures is
rarely successful because of the effects of autolysis. Tissue
cysts may be rare in in utero–infected fetuses; however, serol-
ogy on fetuses aborted at >5 months of gestation has proved
useful in detecting antibodies to N. caninum. Maternal anti-
bodies to Neospora may also be detected but decline within
2-5 months of abortion.
N. caninum has also been identified as a cause of abortion
in sheep and possibly in goats. Lesions appear to be similar in
bovine and ovine aborted fetuses, and clinically affected
bovine, ovine, canine, and feline neonates. The role of Neos-
Figure 4-85 Neospora-like organism in bovine abortion. Focal pora spp. (N. caninum or N. hughesi) in equine abortions is
necrosis is surrounded by a narrow zone of glial cells in brain. under investigation.
B
A
C
Figure 4-86 Neospora-like organisms in brain. A. Clusters of zoites in vessel. B. Clusters of zoites
in endothelial cell. C. Clusters of zoites lying free in parenchyma. D. Cluster of zoites in paren-
chyma surrounded by cyst-like wall.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 423
Further reading
Almería S, López-Gatius F. Bovine neosporosis: clinical and practical
aspects. Res Vet Sci 2013;95:303-309.
Dubey JP, Schares G. Neosporosis in animals—the last five years. Vet Figure 4-88 Sarcocyst in endothelium of small vessel of the
Parasitol 2011;180:90-108. Peyer’s patch in an aborted bovine fetus.
Leon A, et al. Molecular detection of Coxiella burnetii and Neospora
caninum in equine aborted foetuses and neonates. Prev Vet Med
2012;104:179-183.
Wouda W. Diagnosis and epidemiology of bovine neosporosis: zoites, although often difficult to find, are most easily distin-
a review. Vet Q 2000;22:71-74. guished in nervous tissue, maternal caruncle, and endome-
trium away from the site of inflammation.
Diagnosis is based on finding typical lesions of nonsuppura-
Sarcocystis species causing abortion in cattle, goats, tive meningoencephalitis, multifocal necrosis in soft tissues,
sheep, and pigs and the presence of cysts containing zoites with a tropism for
Sarcocystis spp. cause abortion, stillbirth, and neonatal deaths endothelium. If the organism cannot be found on routine
in cattle, goats, sheep, and pigs. In contrast to some of the other sectioning, it can readily be located using specific fluorescent
protozoa, they are usually specific for their intermediate host. antibody or immunohistochemistry.
Transmission, pathogenesis, lesions, and diagnosis are similar
in all intermediates, and only lesions observed in cattle will be
described. Ingesting food or water contaminated by feces con- Further reading
taining oocysts, which are immediately infective to the inter- Dubey JP, Lindsay DS. Neosporosis, toxoplasmosis, and sarcocystosis
mediate host, infects the animal. Definitive hosts include the in ruminants. Vet Clin North Am Food Anim Pract 2006;22:
dog, coyote, wolf, red fox, and raccoon for the pathogenic 645-671.
organism S. cruzi.
The pathogenesis of Sarcocystis-induced abortion is uncer-
tain, but may involve anemia in the dam, leading to fetal Genital tritrichomoniasis
hypoxia and death, premature induction of parturition This is a specific contagious venereal disease of cattle caused
through release of PGF2α from damaged endothelial cells, by the flagellated protozoan Tritrichomonas foetus and trans-
fever, or direct infection of the fetus. Infection in the dam may mitted at coitus or artificially via contaminated semen.
result in acute necrotizing endometritis, followed by multiple Infection in the bull remains in the preputial cavity and
foci of necrosis in the soft tissues of the fetus. Why the organ- must be considered, in the absence of effective treatment, as
ism is sometimes visible only in the dam but at other times permanent. In early infections, there is balanoposthitis of
also in the fetus is not known. In the dam, the zoite-containing moderate severity, with preputial swelling and a slight puru-
cysts may be observed in the endometrium or caruncle fol- lent discharge. As the infection becomes chronic, the inflam-
lowing abortion, but if it passes to the fetus, in spite of autoly- matory reaction disappears and the organisms become fewer
sis and near absence of gross lesions, extensive lesions are in number. There is a tendency for them to concentrate on
evident microscopically. In the brain and meninges, there are the head of the penis and adjacent areas of the prepuce, and
multifocal areas of necrosis surrounded by undifferentiated they may be detected by culture or PCR testing of preputial
mononuclear cells and lymphocytes. Cardiac muscle, kidney, washings.
liver, lung, and chorioallantoic membranes may have similar Females are not readily infected, if at all, except by service
lesions, some of which are mineralized and undergoing fibro- or experimentally by placing a culture of the organism in the
sis. Endothelial cells in several soft tissues may contain thin- vagina. A few days after infection, acute vaginitis with swelling
walled cysts that bulge into the lumen (Fig. 4-88) of the of the vulva develops, and there is a moderate amount of
frequently thrombosed vessel. The cysts, packed with elongate mucoid floccular discharge in the vagina. The protozoa may
423.e1
Further reading
Anderson M, et al. Neosporosis in dairy cattle. Jpn J Vet Res
2012;60(Suppl.):S51-S54.
Goodswen SJ, et al. A review of the infection, genetics, and evolution
of Neospora caninum: from the past to the present. Infect Genet
Evol 2013;13:133-150.
Williams DJ, et al. Endogenous and exogenous transplacental transmis-
sion of Neospora caninum—how the route of transmission impacts
on epidemiology and control of disease. Parasitol 2009;136:
1895-1900.
423.e2
Further reading
Anderson ML, et al. Protozoal causes of reproductive failure in domes-
tic ruminants. Vet Clin North Am Food Anim Pract 1994;10:439-
461.
Buxton D. Protozoan infections (Toxoplasma gondii, Neospora caninum
and Sarcocystis spp.) in sheep and goats: recent advances. Vet Res
1998;29:289-310.
424 CHAPTER 4 • Female Genital System Abortion and Stillbirth
be easy or impossible to find in this exudate. The vaginitis disease. Effects also vary greatly depending on the stage of
resolves quickly, and the infection localizes in the uterus and gestation and may result in early farrowing of stillbirths and
cervix. Immediately prior to the estrus, which follows the mummified fetuses.
infective service, large numbers of organisms can usually be Initial clinical findings in infected pregnant gilts are
found in exudate aspirated from the cervix, but as estrus anorexia, lethargy, depression, and mild fever; cyanosis of the
advances, the number of protozoa is greatly reduced. snout, ears, tails, vulva, and abdomen occurred commonly in
The manifestations of established trichomoniasis in females European outbreaks but are rarely observed in North America.
are cervicitis and endometritis that result in repeat breeding, This is commonly followed by a sudden increase in early far-
abortion, or pyometra. The inflammatory changes in the endo- rowing, late-term abortions, stillbirths, mummified fetuses, infertil-
metrium and cervix are relatively mild and nonspecific, ity, and sometimes death. Live piglets with respiratory signs,
although the mucopurulent exudate may be rather copious. muscle tremors, and splayleg also occur. Transplacental passage
Discharge of exudate into the vagina may be more or less may result in fetal antibody production. After an outbreak of
continuous or intermittent, and the numbers and activity of reproductive failure, previous levels of reproductive perfor-
the trichomonads in the discharge vary considerably over mance may not be achieved. Variable degrees of endometritis
short periods. The discharge may not be apparent at the vulva. and myometritis may be present.
The pattern of repeat breeding in tritrichomoniasis is the Gross and microscopic lesions in piglets are variable to absent
same as that in venereal Campylobacter infections. Return to and often obscured by autolysis. “Paintbrush” hemorrhages have
service occurs at irregular intervals, a fact that indicates that been observed on the placenta, and petechial hemorrhages
fertilization and implantation are followed by embryonic and necrosis occur on umbilical vessels, skin, and renal cortex.
death. When the embryo or fetus dies, it may be resorbed, Microscopic lesions include lymphoplasmacytic and histio-
aborted, or retained with the development of pyometra. cytic infiltrates within and around small capillaries at the
Trichomonad abortions may occur at any time, but mainly in periphery of the tunica adventitia of umbilical arteries. Mild
the first half of pregnancy. There are no specific fetal lesions, but to moderate, multifocal to diffuse, histiocytic and proliferative
large numbers of protozoa may be found in the fetal fluids and interstitial pneumonia characterized by mononuclear cell
stomach. The placenta is not severely altered as in brucellosis; septal infiltration is commonly observed. Hypertrophy and
it may be covered by white or yellow flocculent exudate in hyperplasia of type 2 pneumocytes is occasionally present.
small amounts, thickened, and slightly tough; hemorrhage Mild segmental necrotizing and lymphohistiocytic arteritis has
without much necrosis may be evident on the cotyledons. been seen in lungs. Mild segmental necrotizing and lympho-
Pyometra is one of the remarkable changes of trichomoniasis, histiocytic, suppurative and, less often, eosinophilic hepatitis
but it is a relatively uncommon complication. Its pathogenesis may be present. Mild multifocal perivascular lymphohistio-
follows the scheme outlined earlier, and its character is cytic myocarditis and, rarely, multifocal myocardial hemor-
remarkable only for the copiousness of the exudate; any rhages are present.
volume up to 4 L or more may be present. The exudate may The diagnosis is established by isolating the PRRSV, PCR
be watery with floccules, colostrum-like, or brown and sticky. assay, or by in situ hybridization or immunohistochemical
It is without odor and swarms with trichomonads. (IHC) detection of the virus in formalin-fixed tissues. The
virus is rapidly inactivated in aborted, stillborn, or mummified
fetuses, and isolation is therefore inconsistent. PCR becomes
Further reading valuable in diagnosis as there are no consistent gross or micro-
Rae DO, Crews JE. Tritrichomonas foetus. Vet Clin North Am Food scopic lesions of this syndrome in fetuses, and PCR testing
Anim Pract 2006;22:595-611. modalities are impacted the least by the adverse effects of
autolysis.
Further reading
Guerra AG, et al. Use of pooled protozoal cultures of preputial scrap-
ing samples obtained from bulls for the detection of Tritrichomonas
foetus by means of a real-time polymerase chain reaction assay.
J Am Vet Med Assoc 2014;244:352-356.
Mukhufhi N, et al. Evaluation of a PCR test for the diagnosis of Trit-
richomonas foetus infection in bulls: effects of sample collection
method, storage and transport medium on the test. Theriogenol
2003;60:1269-1278.
Rhyan JC, et al. Fetal and placental lesions in bovine abortion due to
Tritrichomonas foetus. Vet Pathol 1988;25:350-355.
424.e2
Further reading
Cheon DS, Chae C. Comparison of virus isolation, reverse transcription-
polymerase chain reaction, immunohistochemistry, and in situ
hybridization for the detection of porcine reproductive and respira-
tory syndrome virus from naturally aborted fetuses and stillborn
piglets. J Vet Diagn Invest 2000;12:582-587.
Rossow KD. Porcine reproductive and respiratory syndrome. Vet Pathol
1998;35:1-20.
Scruggs DW, Sorden SD. Proliferative vasculopathy and cutaneous
hemorrhages in porcine neonates infected with the porcine repro-
ductive and respiratory syndrome virus. Vet Pathol 2001;38:
339-342.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 425
The virulence of CSFV varies from avirulent to highly viru- accordance with this, fetuses collected from sows infected
lent. Pigs infected with highly virulent CSFV may have a high during this period may show general lymphoid hyperplasia
fever, depression, incoordination, reddening of the skin, diar- and development of primary follicles. Kidney and brain
rhea, respiratory distress, and death with widespread hemor- may have mild lesions with scattered focal mononuclear
rhage resulting from severe necrotizing vasculitis. Moderately cells, and spleen and kidney may have foci of necrosis and
virulent and virulent strains of CSFV cause subacute and hemorrhage.
chronic disease with similar but milder signs. During an inap- For diagnosis, CSFV can be isolated from a variety of fetal
parent viremic phase in a pregnant sow, the virus may be tissues, including the placenta and from the serum of PI swine,
carried to the fetus and result in embryonic death, malforma- or detected by various PCR tests. Fetal antibody may be
tions, mummification, stillbirth, or birth of live clinically normal present in late-gestation fetuses, but carrier sows may or may
pigs or pigs with tremors. Persistently infected (PI) piglets may not have antibody. In addition, the virus may be identified by
be born at term and appear clinically normal or weak but, in the fluorescent antibody technique in tissue sections. In some
either circumstance, eventually succumb to the effects of the laboratories, CSFV is routinely differentiated from BVDV and
virus. BDV infections and, in some instances, CSFV vaccine strains
The virus can be transmitted from carrier or clinically from field strains. This may be very important in large eradica-
affected pigs through their secretions and excretions or tion and control programs.
through the ingestion of contaminated wastes. Birds, parasites,
and fomites have also been identified as the source of virus in
outbreaks. At one time, the use of vaccines containing CSFV Further reading
of low virulence was the cause of severe losses caused by in Dewulf J, et al. An experimental infection with classical swine fever
utero infections in pigs. virus in pregnant sows: transmission of the virus, course of the
After exposure of a pregnant sow, the virus multiplies in disease, antibody response and effect on gestation. J Vet Med B
the tonsils and spreads to other lymphoid organs, eventually Infect Dis Vet Public Health 2001;48:583-591.
reaching the fetus between 13 and 18 days. During the viremic Haines FJ, et al. Development and validation of a multiplex, real-time
stage, the virus crosses the uteroplacental interface, infecting RT PCR assay for the simultaneous detection of classical and African
all or only some fetuses. In the latter situation, the virus may swine fever viruses. PLoS ONE 2013;8:e71019.
continue to pass from fetus to fetus in utero, eventually infect-
ing many.
Lesions produced in a fetus following in utero infection are
variable and depend on the virulence of the infecting virus, Bovine viral diarrhea virus infection of
the stage of gestation when the infection occurs, and an appar- the pregnant uterus
ent variation in the development time of immune competence Species Bovine viral diarrhea virus (BVDV), genus Pestivirus,
to CSFV in fetal piglets. In general, and with many exceptions, family Flaviviridae, is closely related to Border disease virus of
early infections result in embryonic or fetal death or persistent sheep and less closely to Classical swine fever virus. For further
infections. Early to mid-gestation infections result in malfor- discussion, see the section on border disease virus infection in
mations, including pulmonary hypoplasia, pulmonary artery sheep and goats, later. These 3 viruses have been shown to cross
malformation, micrognathia, arthrogryposis, and CNS malfor- infect naturally between species. The various strains of BVDV,
mations (including cerebellar hypoplasia, microcephaly, and although similar, differ in virulence and can be distinguished
defective myelination in brain and spinal cord). Infections antigenically. Two biotypes exist, one that is cytopathic for cell
during the last trimester may produce no abnormalities, or cultures (cp-BVDV = CB, cytopathic biotype) and one that is
may result in mummification or stillbirths. not cytopathic (ncp-BVDV = NCB, noncytopathic biotype).
Persistent infections in piglets most commonly follow expo- Both cause disease in cattle. In addition, there is type 2 BVDV,
sure to the virus from 22-70 days of gestation and, rarely, up which can infect fetuses and exists in cytopathic and noncy-
to 100 days. These fetuses may or may not die in utero and topathic forms as well.
often show retarded development and runting. Many show no BVDV and Akabane virus are probably the most important
signs until sometime after birth, and PI pigs living to 11 viral pathogens of the bovine fetus. BVDV is distributed
months have been reported. The latter commonly have worldwide, and persistently infected (PI) cattle are reported
marked depletion of lymphocytes (especially in the thymic to make up about 1% of the general population. They do not
cortex), and B-cell–dependent regions of lymph nodes and develop antibody to the homologous strain to which they are
spleen. Lesions are also observed in heart (degeneration of infected, but may respond to heterologous strains used in vac-
endothelium and valvular fibrosis), liver (portal fibrosis), intes- cines. Cattle persistently infected with ncp-BVDV or tempo-
tine (villus atrophy and ulceration), lungs (interstitial pneu- rarily infected with cp-BVDV may excrete virus in feces,
monia), skin (necrosis and degeneration of epithelial cells), semen, urine, milk, nasal, ocular, and uterine secretions. Sus-
and CNS (neuronal degeneration and hydranencephaly). ceptible animals can acquire the virus by inhalation, ingestion
Many PI piglets are born alive with a congenital tremor and or when bred with contaminated semen. Cows may also
CNS dysgenesis, cerebellar hypoplasia, and hypomyelination. become infected from contaminated embryo transfer fluids
Piglets with tremor, which survive for long periods, have where serum from carrier animals is used. Cytopathic BVDV
reduced clinical signs but continue to excrete CSFV. The is derived from mutations of ncp-BVDV. The ncp biotype may
similarity of this to the syndrome in border disease virus– persistently infect the immunologically incapable fetus. There is
infected “shaker lambs” suggests a similar pathogenesis. no report of a cytopathic biotype being isolated from an
Many fetal piglets show some ability to respond immuno- infected animal without the noncytopathic biotype also being
logically to CSFV between 70 and 90 days of gestation with present; the cp form has no means of maintaining itself in the
an immunoglobulin of low specificity and avidity. In population of animals without the ncp form.
425.e1
Further reading
Choi C, Chae C. Localization of classical swine fever virus from chron-
ically infected pigs by in situ hybridization and immunohistochem-
istry. Vet Pathol 2003;40:107-113.
Elbers AR, et al. Assessment of the use of gross lesions at post-mortem
to detect outbreaks of classical swine fever. Vet Microbiol
2003;96:345-356.
Gomez-Villamandos JC, et al. African swine fever and classical swine
fever: a review of the pathogenesis. Dtsch Tierarztl Wochenschr
2003;110:165-169.
Penrith ML, et al. Classical swine fever (hog cholera): review of aspects
relevant to control. Transbound Emerg Dis 2011;58:187-196.
426 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Reproductive disease in cattle induced by BVDV includes necrotizing, nonsuppurative retinitis and usually accompanies
oophoritis, fertilization failure, embryonic death, absorption or the cerebellar lesions. Microphthalmia and optic neuritis with
abortion, mummification, stillbirth, birth of calves small for ges- subsequent atrophy also occur.
tational age or with congenital defects, and weak calves or near– Other lesions associated with BVDV infections in the fetus
normal-looking calves born PI with ncp-BVDV. Abortion storms include thymic cortical atrophy (with only epithelial stroma
can occur, and occasionally severe losses resulting from BVDV and macrophages persisting in the cortex), multifocal myocar-
may follow superovulation and embryo transfer. This may be ditis, peribronchiolar lymphoid hyperplasia, pulmonary hypo-
related to the creation of a population of fetuses of the same plasia, multifocal perivascular dermatitis, and hypotrichosis.
gestational age (and therefore equally susceptible to the infec- Cellular accumulations are usually mononuclear, lymphocytic,
tion) or contamination of transfer fluids by BVDV. Present and plasma cell rich. Plasmablasts, plasma cells, and lympho-
evidence suggests that ncp-BVDV infects the bovine fetus blasts may be prominent in lymphoid tissues.
following oronasal exposure of the dam and only causes Antibody in fetal fluids, culture of virus from fluid and
embryo injury when it mutates to the cp form of fetal tissues, and PCR-based tests are sensitive methods to deter-
infection. mine if fetal infection has occurred. The presence of specific
Fertilization failure may occur when the virus is introduced antibody in an aborted fetus only indicates the fetus was
in utero to seronegative cows. Conception and pregnancy rates infected in utero. Fluorescent antibody and immunohisto-
in animals viremic at or shortly after insemination were chemical detection of virus are frequently used to indicate the
approximately half of noninfected controls at gestation day association of the virus with a lesion.
77. Surviving embryos were not infected. These data strongly Naturally occurring BVDV infections in pregnant sows and
support BVDV infection as being detrimental to early embryo goats have been reported to pass to the fetus, causing stillbirth
development. Acutely infected bulls shed the virus in their and neonatal death similar to chronic swine fever and border
semen for at least 14 days and may have abnormal semen for disease. Piglets infected in utero can either carry the virus
several months. Spread of the virus is more likely to occur (without antibody), develop antibody later, or become clini-
with natural service than with artificial insemination. Carrier cally affected and develop intestinal lesions, depending on the
and newly infected cows infect the fetus through the stage of gestation when infection occurs. On postmortem,
placenta. infected piglets may also have nonsuppurative meningitis and
In the period from 45 to 125 days gestation, the ncp choroiditis. Swine fetuses dying early in gestation from in
biotype will probably not cause fetal loss, but if it changes to utero infections with BVDV may also be absorbed.
the cp form, it may result in intrauterine growth retardation.
Only the ncp biotype can cause persistent infection. If born
alive, these PI animals constitute the main source of virus for Further reading
other animals. CNS malformations follow infections with Byers SR, et al. The effects of exposure of susceptible alpacas to alpacas
BVDV between 80 and 150 days of gestation. This is probably persistently infected with bovine viral diarrhea virus. Can Vet J
associated with the stepwise development of immune capabil- 2011;52:263-271.
ity in the fetus, along with the corresponding gradual develop- Lanyon SR, et al. Bovine viral diarrhoea: pathogenesis and diagnosis.
ment of its nervous system. Abnormalities attributed to BVDV Vet J 2014;199:201-209.
include microencephaly, cerebellar hypoplasia, hydranenceph- Webb BT, et al. Effects of in utero pestivirus infection on bovine fetal
aly, secondary hydrocephalus, hypomyelinogenesis, myelina- bone geometry, biomechanical properties and composition. Vet J
tion defects, microphthalmia, cataracts, retinal degeneration, 2013;198:376-381.
optic neuritis, brachygnathism, thymic aplasia, hypotrichosis,
alopecia, pulmonary hypoplasia, and growth retardation with
growth-arrest lines in long bones. Porencephaly, hydranen- Border disease virus infection in sheep and goats
cephaly, and secondary hydrocephalus have been described, Species Border disease virus (BDV), Classical swine fever virus
but the association with BVDV is less clearly documented. It (CSFV), and Bovine viral diarrhea virus (BVDV) are in the
is believed by some that only the cp biotype causes abnormali- family Flaviviridae, genus Pestivirus. All are related antigeni-
ties. Cerebellar hypoplasia may be inapparent or severe. cally and cause significant disease in animals. BDV and BVDV
Normal and severely affected folia may be adjacent. Early are closely related, whereas CSFV is distinct. Some strains of
lesions consist mainly of edema, hemorrhage, and necrosis of BDV appear to be more closely related to certain strains of
external germinal cells. Remnants of severely affected folia BVDV than to other strains of BDV, whereas others cannot
consist of fluid-filled cavities lined by flattened astrocytes sur- be differentiated from each other. BDV, BVDV, and CSFV
rounded by a thin layer of neuropil containing many have been shown to cross infect between species, and this may
hemosiderin-laden macrophages. Some folia have only reduced occur naturally. Border disease is the result of in utero infec-
myelin content. Purkinje cells may be reduced in number and tion of pregnant sheep or goats by BDV; prevalence of BDV
with a disorderly or absent external germinal cell layer. Peri- is variable in sheep and rare in goats. Infection can result in
vascular mononuclear cells and a few neutrophils may be embryonic or fetal death, abortion, mummification, dysmorpho-
present in neural parenchyma and meninges in cerebrum and genesis, early postnatal death, and birth of weak or clinically
cerebellum. Spongiform alterations of brainstem white matter normal young. Clinically normal kids or lambs can be persis-
have been recorded, along with spongiform alteration and tently infected (PI). Infection in the nonpregnant adult animal
liquefactive necrosis of ventral funicular white matter in the may result in fever and leukopenia, but clinical signs are
spinal cord. Focal malacia of the ventral horns occurs follow- usually absent.
ing degeneration of ventral horn neurons along with glial satel- Transmission of BDV is believed to occur mainly between
litosis. Cataracts and retinal atrophy may be present in the sheep; however, natural and experimental infections of
eye, and the latter is presumed to follow focal-to-diffuse BVDV from cattle to sheep have been reported and can
426.e1
Further reading
Harding MJ, et al. Role of bovine viral diarrhea virus biotype in the
establishment of fetal infections. Am J Vet Res 2002;63:1455-1463.
Kelling CL, Topliff CL. Bovine maternal, fetal and neonatal responses
to bovine viral diarrhea virus infections. Biologicals 2013;41:20-25.
Porter BF, et al. Hypomyelination associated with bovine viral diarrhea
virus type 2 infection in a longhorn calf. Vet Pathol 2010;47:658-
663.
Terpstra C, Wensvoort G. A congenital persistent infection of bovine
virus diarrhoea virus in pigs: clinical, virological and immunological
observations. Vet Q 1997;19:97-101.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 427
cause BDV-like outbreaks. BDV can be transmitted by oral, immunofluorescence, BDV antigen has been demonstrated in
conjunctival, intranasal, and genital routes. As congenitally skin follicles of fetuses infected at 45 days of gestation, starting
infected sheep can have lifelong viremia, they are probably the at 40 days postinoculation and continuing in lambs up to 5
main reservoir for the virus. PI ewes can transmit the virus to months of age.
their fetus through the placenta (over several pregnancies), Intrauterine growth retardation commonly occurs with BDV
and in rams, the virus has been observed in the seminiferous infection in goats and sheep and was reported to be of similar
tubules of the testes and can be transmitted in the semen. degree to that seen in fetal starvation, cardiac anomalies, and
BDV has been demonstrated in the germinal cells of the placentitis, except for lung and brain, which were more
ovaries of sheep; the significance of this site in the transmission severely affected. Growth-arrest lines (unmodelled metaphy-
of the virus is not known. seal trabeculae) are commonly observed in the long bones of
A wide variety of fetal tissues are affected by BDV infec- BDV-infected fetuses and lambs. Arthrogryposis and kypho-
tion, and the name hairy shaker was coined because of the scoliosis occur infrequently in conjunction with hydranen-
frequently observed hairy appearance of the wool and the cephaly, cerebellar dysmorphogenesis, and hypoplasia in
tremor associated with hypomyelinogenesis. Abnormalities BDV-infected fetuses.
induced in the fetus, as in cattle, depend mainly on the stage BDV infection in sheep and goats causes placentitis and
of gestation and reflect the stepwise development of fetal endometritis that are particularly evident when infection
immunocompetence to the virus. Strains of the virus also vary occurs during the first trimester of gestation. Early in the
in virulence, as does the susceptibility of breeds of sheep to infection, multiple white 1-2 mm foci of necrosis appear in
the effects of the agent. As the ovine and caprine fetus the caruncles at the base of the crypts. These may fuse into a
becomes immunocompetent to BDV by about 90 days, most continuous band of necrosis, which may become mineralized
injury follows infections occurring before this time. and infiltrated with connective tissue and a few macrophages,
CNS lesions include hypoplasia and dysplasia of the cere- or the entire base of the caruncle may be infarcted, necrotic,
bellum, microcephaly, porencephaly, hydranencephaly, leuko- and infiltrated with neutrophils. The lesion is believed to be
encephalomalacia, and reduced weight and length of the associated with endothelial swelling and thrombosis of capil-
spinal cord. The most consistent lesion is dysmyelination or laries in the endometrium and adjacent caruncle. The tropho-
hypomyelination, which usually occurs without signs of blast does not usually undergo necrosis but may atrophy.
inflammation. Definitive diagnostic tests can be selected with confidence
The mechanisms responsible for hypomyelination have not when several kids or lambs show typical signs of BDV infec-
been completely defined. It has been suggested that BDV has tion. However, diagnosis may be difficult when BDV occurs
a specific affinity for oligodendrocytes; however, evidence sup- only as reproductive failure with embryo or fetal death, fol-
porting this is lacking. There is strong evidence that the hypo- lowed by absorption, abortion, or mummification. Frequently
myelination seen in the brain and spinal cord in BD may be in goats, abortion may be the principal sign. In aborted fetuses
due to lowered activity of oligodendrocytes with subnormal with congenital abnormalities, diagnosis requires the detection
thyroxine production. In the tested lambs with BDV, there of the virus, virus-specific antigens, fetal antibodies against the
were significantly decreased concentrations of serum triiodo- virus, or PCR-based tests in or of cavity fluids. The cotyledons,
thyronine and thyroxine, and many of the thyroid follicle cells or preferably the caruncles, are the best source of virus. It is
contained BDV. As in many other tissues occupied by BDV variably recovered from aborted fetuses and almost never
in PI animals, little cell death or associated inflammation was from those that are mummified. Although isolates are usually
present. Further support for the hormonal theory of hypomy- noncytopathic, viral antigen can be demonstrated by direct or
elinogenesis came on finding significantly lower concentra- indirect immunofluorescence, and immunohistochemistry of
tions of the thyroid hormone–dependent enzyme 2′,3′-cyclic selected tissues from affected lambs or the caruncle following
nucleotide-3′-phosphodiesterase (CNP) in oligodendrocytes abortion.
from affected animals. CNP is normally found in oligodendro- Sheep have been reported to retain BVDV in the uterus
cytes, and its activity, which is dependent on the presence of from one estrus to the next and to produce PI offspring when
both thyroxine and growth hormone, increases with myelina- naturally bred or artificially inseminated by semen collected
tion. Work in congenitally hypothyroid mice and thyroidecto- from PI rams.
mized rats has shown that growth hormone and thyroxine are
necessary for normal myelination of nerve fibers.
Abnormalities in the fleece are commonly seen in fetuses Further reading
following in utero infections with BDV. In smooth-coated Nettleton PF, et al. Border disease of sheep and goats. Vet Res
ewes and nannies infected between 50 and 85 days of gesta- 1998;29:327-340.
tion, the fleece of the fetus may become hairlike and curly. Toplu N, et al. Neuropathologic study of border disease virus in natu-
The hairiness is associated with enlargement of primary fol- rally infected fetal and neonatal small ruminants and its association
licles, increased size of fiber, increased proportion of fibers with apoptosis. Vet Pathol 2011;48:576-583.
with a central medulla, and increased diameter of the medulla.
Around 90 days of gestation, animals become immunocom-
petent to the virus, and infection at that time may result in Equine arteritis virus infection of the pregnant
only a diminished number of secondary follicles. The reduc- uterus in mares
tion has been suggested to be the result of reduced fetal Equine viral arteritis (EVA) is a disease of horses caused by
nutrition because of placentitis. In pigmented breeds, there species Equine arteritis virus (EAV), a positive-stranded RNA
may be large patches of abnormally pigmented black or brown virus, family Arteriviridae, genus Arterivirus. Genetic diversity
fleece, especially along the neck. Exactly why these changes of the virus is generated in the course of persistent infection
are induced has not been determined. However, using of the carrier stallion, and the genetic changes that maintain
427.e1
Further reading
Pratelli A, et al. Genomic characterization of pestiviruses isolated from
lambs and kids in southern Italy. J Virol Methods 2001;94:81-85.
Thur B, et al. Immunohistochemical diagnosis of pestivirus infection
associated with bovine and ovine abortion and perinatal death. Am
J Vet Res 1997;58:1371-1375.
428 CHAPTER 4 • Female Genital System Abortion and Stillbirth
EVA in the stallion’s reproductive tract likely affect pheno- Wesselsbron virus infection of the pregnant uterus
typic properties of the virus, such as virulence. Strains of the in sheep and cattle
virus vary greatly in virulence. Consequences of infection Species Wesselsbron virus (WESSV) is in the family Flaviviri-
range from subclinical to mild fever; ocular and nasal dis- dae, genus Flavivirus, in the yellow fever virus group. It is
charges; edema around the eyes, legs, and scrotum; skin rash; spread primarily by mosquitoes. Infection is often fatal in the
and, in severe forms, diarrhea, respiratory distress, and rarely ovine and bovine fetus, in newborn lambs, and pregnant sheep.
death. Embryonic death and resorption rates are permanently It may also produce congenital anomalies in bovine and ovine
increased, and 40-80% of pregnant animals abort or deliver a fetuses. Human illness is not fatal and is characterized by fever,
stillborn foal. Abortion usually occurs 1-4 weeks after the chills, muscle pain, hyperesthesia, and a skin rash. Information
onset of fever and is probably the most grievous manifestation is largely incomplete with regard to the pathogenesis and
of the disease, although in some outbreaks, severe interstitial pathology of this infection in pregnant animals.
pneumonia and necrotizing enteritis may occur in foals. The disease is widespread in the southern and western parts
The virus is spread by aerosolization of respiratory secre- of Africa in sheep and cattle; however, in spite of a high preva-
tions among closely associated animals. Stallions are probably lence and high annual infection rate, mortality is low. In a
the most important means of spread, as they shed the organism naïve flock of sheep, however, mortality in newborn lambs and
in semen for a short or very long period, even for life, and pregnant ewes may be high. Pregnant ewes may die before or
transmit the disease sexually. There are minimal consequences after abortion, whereas nonpregnant ewes, wethers, and year-
of sexually acquired infection, with little effects on conception lings usually show no signs of illness. Changes in the liver
rate, unless a mare is infected in the late stages of gestation, caused by WESSV infection may precipitate acute copper toxicity,
in which case she may abort. Stallions that are shedding the thereby inflating the perceived mortality directly caused by
organism should not be used for breeding unless they are bred this virus.
to seropositive mares that have received the organism from Pregnant sheep infected with WESSV develop a fever asso-
either vaccination or natural infection. In contrast, although ciated with initial viremia and often abort at this stage because
mares may spread the virus during their illness or shortly after, of the systemic effects of the virus on the dam. Under these
they generally do not remain carriers, and after recovery, circumstances, neither virus nor antibody is detected in the
neither mares nor stallions shed the virus in nasal passage fetus. If the ewe does not abort during the primary viremia,
secretions, urine, or blood. Most horses develop long-term the virus can invade the placenta and fetus in association with
immunity to EAV after natural infection of the virus. a second growth phase and result in death of the fetus. The
Aborted fetuses are usually well preserved, but gross and fetus may be absorbed, mummified, aborted, or carried to
microscopic lesions are rarely observed as the virus seldom pro- term and be delivered dead. The death rate for lambs infected
duces active infection in the fetus. In foals surviving for more in utero approaches 100%, and even those born alive die soon
than 24 hours, fever, leukopenia, and/or thrombocytopenia are after. Both wild and attenuated strains of WESSV have been
sometimes observed. Widespread inflammatory lesions in sec- shown to cause nonsuppurative meningoencephalitis, hydran-
tions of the brain, liver, and spleen have been recorded. On encephaly, arthrogryposis, and hydrops amnii in fetal sheep;
microscopic examination, findings include interstitial pneu- however, this is probably infrequent under field conditions.
monia, lymphocytic periarteritis with fibrinoid necrosis of the In pregnant cattle, WESSV probably only crosses the pla-
tunica media, and renal tubular necrosis. Moderate arteritis centa and infects the fetus in a low percentage of animals,
with necrosis and mononuclear cell myocarditis has been even in the face of prolonged maternal viremia. When the
reported of a few fetuses. In the uterus of the mare, however, virus does infect the fetus, abortion may occur or the calf may
there may be acute multifocal necrotizing myometritis and be born weak and die shortly after. These calves have typical
replication of the virus in smooth muscle cells. Uterine infec- liver lesions and precolostral antibody to WESSV. However,
tion might be the critical process contributing to abortion. virus may not be recovered. Many pregnant cows, even after
In the live mare and stallion during the early stages of prolonged viremia, give birth to normal live calves that show
disease, the presence of EAV may be determined by culture no serologic or virologic evidence of infection. In cattle, as
or PCR assay of swabs taken from nasopharynx and conjunc- described in sheep, certain strains of the virus occasionally
tiva, from white blood cells, or from semen. The virus may be produce nonsuppurative meningoencephalomyelitis, poren-
recovered from semen or revealed by breeding unexposed cephaly, and cerebellar hypoplasia in the fetus.
mares, which may then develop a fever or become clinically Gross and microscopic descriptions of findings in aborted
ill. Serologic tests are available to detect previously infected fetuses, or stillborn lambs and calves, are limited. Experimen-
animals. Samples for culture from the conceptus should tally infected newborn lambs have a slight to moderately
include placenta, lung, and spleen. Diagnosis can also be enlarged, yellow to orange, variably congested liver. On micro-
obtained by immunohistochemistry, virus isolation, and PCR- scopic examination, hepatocyte necrosis is slight to extensive,
based tests. but is usually single cell and generalized. Eosinophilic, intra-
nuclear inclusion bodies of various shapes are frequently present.
Separated, individual hepatocytes may be round, shrunken,
Further reading and have intensely pink-staining cytoplasm and nuclear lysis
Balasuriya UB, et al. Equine arteritis virus. Vet Microbiol 2013;167:93-
(Councilman-like bodies). Kupffer cell hyperplasia is promi-
122.
nent, particularly in the central vein region, and Kupffer cells
Holyoak GR, et al. Equine viral arteritis: current status and prevention.
filled with yellow or pink granular material often bulge into
Theriogenol 2008;70:403-414.
sinusoids. The sinusoids also contain large numbers of mono-
Snijder EJ, et al. Arterivirus molecular biology and pathogenesis. J Gen
nuclear cells and degenerating neutrophils. Bile ducts and
Virol 2013;94:2141-2163.
canaliculi are frequently distended with bile. In portal areas,
there is bile duct hyperplasia, moderate numbers of
428.e1
Further reading
Del Piero F. Equine viral arteritis. Vet Pathol 2000;37:287-296.
Eichhorn W, et al. Equine viral arteritis with abortions: serological and
virological evidence in Germany. J Vet Med Ser B 1995;42:
573-576.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 429
macrophages, and some neutrophils and plasma cells. There For diagnosis, viral antigen is demonstrable by the fluores-
are petechial and ecchymotic hemorrhages on the mucosal cent antibody test in affected tissues of embryos and mum-
surface of the abomasum, and the content is dark brown. mified and stillborn fetuses, and a highly sensitive DNA probe,
Other nonspecific lesions, consistent with a viremia, are also specific for PPV-infected cells, is available. Identification of
described. specific antibody, particularly IgM, in fetal fluids indicates fetal
The diagnosis of WESSV infection in pregnant animals is infection, and with other appropriate findings, it is supportive
based on clinical findings, histology, and culture from liver and evidence for the cause of reproductive failure. When the only
brain. The lesions produced by Rift Valley fever virus infection manifestations are small litters or pigs that recycle, the causal
may easily be confused with Wesselsbron disease, and, although relationship of these signs with PPV is difficult to establish,
the liver lesions tend to be different, complications resulting and knowledge of titers of antibody against PPV in the gilt or
from precipitation of copper toxicity may make the differen- sow before and after the event may be the only incriminating
tiation difficult. evidence. Various tests, including an ELISA, have been devel-
oped for this purpose.
Further reading
Ali H, et al. Common, emerging, vector-borne and infrequent aborto- Further reading
genic virus infections of cattle. Transbound Emerg Dis 2012; Krakowka S, et al. Viral wasting syndrome of swine: experimental
59:11-25. reproduction of postweaning multisystemic wasting syndrome in
gnotobiotic swine by coinfection with porcine circovirus 2 and
porcine parvovirus. Vet Pathol 2000;37:254-263.
Porcine parvovirus infection of Wolf VH, et al. Molecular basis for porcine parvovirus detection in dead
the pregnant uterus fetuses. Genet Mol Res 2008;7:509-517.
Species Porcine parvovirus (PPV), family Parvoviridae, subfam-
ily Parvovirinae, genus Parvovirus, is an important and common
cause of reproductive failure in pigs, and manifests as embry- Bovine parvovirus infection of the pregnant
onic death with reabsorption, mummification, stillbirths, and uterus in cattle
reduced litter size. Farrow-to-finish farms are affected nearly Species bovine parvovirus (BPV), family Parvoviridae, subfam-
twice as often as feeder pig farms, probably because of the ily Parvovirinae, genus Bocavirus. It is widely distributed in
maintenance of a continual reservoir of PPV in the finishing cattle populations throughout the world. It is reported to cause
pigs. The virus is most commonly spread by the ingestion of enteritis and diarrhea in young calves and abortion and birth of
contaminated feces and will adhere to the zona pellucida of weak calves when infections occur in naïve pregnant cows.
embryos. Viremia develops in susceptible pigs, and in pregnant The organism is not considered a major cause of abortion, but
pigs the virus enters the placenta and passes to the embryo or this may be because it is not looked for consistently in submis-
fetus 23-32 days following oral inoculation. Up to a fetal age sions. Anywhere from 10-100% of the cattle in a population
of 70 days, the virus may cause death of the embryo (with will have antibody to parvovirus, and work in the United
absorption) or fetus (with mummification); however, the States suggests that when reproductive problems, including
porcine fetus becomes increasingly resistant to the effects of repeat breeding, embryonic mortality, and abortion, are con-
the virus after 36 days and is immunocompetent by about 70 sidered, animals with antibody to BPV had about 3 times as
days. Death of the fetus may be due to the total effect of the many of these problems as compared to control seronegative
virus on rapidly dividing cells, including neurons and capillary animals.
endothelium of the cortical laminae in cerebellum and cere- BPV is excreted in the feces of affected and normal animals,
brum, and in cells in the lung, liver, pancreas, and chorioal- and the oral route is important in transmission. Inoculation of
lantois. Movement of virus from one fetus to another may be parvovirus into pregnant cows can cause in utero fetal death
affected by development of maternal antibody, increasing and abortion in the early stages of gestation. Some calves
resistance of fetuses with advancing age, and the variability of may be born with cerebellar hypoplasia because of lysis associ-
the circulation and contact between the placental membranes ated with the multiplication of BPV in cells of the external
of adjacent fetuses. granular layer. Cerebellar hypoplasia is believed to follow
When PPV is introduced by the uterine route, it causes infection occurring in the period of rapid cell multiplication
inflammation in the ovaries and degeneration of uterine epi- (107-150 days of gestation) in the cerebellum. Intranuclear
thelium, both of which may contribute to reproductive failure inclusions are seen in external granular cells, hepatocytes,
but do not otherwise cause clinical signs. Uterine changes may adrenal cortical cells, and intestinal crypt cells associated with
include marked variation in surface epithelial cell height, epi- areas of necrosis. Bovine fetuses are capable of forming IgM
thelial cell basophilia, degeneration, and ulceration. Light infil- antibody to the virus by 93 days of gestation; infections in the
tration of neutrophils, eosinophils, and lymphocytes may be third trimester usually only result in antibody formation with
present throughout the endometrium. Corpora lutea contain no abortion.
foci of mononuclear cells, many of which are lymphoplasma- For diagnosis, BPV may be recovered in a variety of
cytic. In the fetus, lesions are most commonly observed in older tissues, including placenta, amniotic fluid, adrenal glands, and
fetuses and may be present in kidney, liver, brain, and placenta. liver. When infection occurs in midgestation, detection of spe-
In the cerebrum, which is the most dependable site, perive- cific antibody in fetal serum may be used as putative evidence
nous accumulations of plasma cells and other mononuclear of the cause of abortion. The presence of antibody may inter-
cells occur in white and gray matter and in meninges. Similar fere with recovery of the virus but probably will not com-
accumulations are observed in the renal interstitium, hepatic pletely prevent isolation, as the virus is frequently cell
portal regions, and in the chorioallantois. associated.
429.e1
Further reading
Hubalek Z, et al. Arboviruses pathogenic for domestic and wild animals.
Adv Virus Res 2014;89:201-275.
Mushi EZ, et al. Wesselsbron disease virus associated with abortions in
goats in Botswana. J Vet Diagn Invest 1998;10:191.
429.e2
Further reading
Mengeling WL, et al. The effect of porcine parvovirus and porcine
reproductive and respiratory syndrome virus on porcine reproduc-
tive performance. Anim Reprod Sci 2000;60-61:199-210.
430 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Further reading
Liggitt HD, et al. Immunologic responses of the bovine fetus to parvo-
virus infection. Am J Vet Res 1982;43:1355-1359.
Storz J, et al. Parvovirus infection of the bovine fetus: distribution of
infection, antibody response, and age-related susceptibility. Am J
Vet Res 1978;39:1099-1102.
430.e2
Further reading
Decaro N, et al. Molecular characterization of canine minute virus
associated with neonatal mortality in a litter of Jack Russell terrier
dogs. J Vet Diagn Invest 2012;24:755-758.
Schwartz D, et al. The canine minute virus (minute virus of canines) is
a distinct parvovirus that is most similar to bovine parvovirus. Virol
2002;302:219-223.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 431
processes may be involved in the development of CNS lesions serogroup, and is most closely related to African horsesickness
caused by BTV infections in bovine fetuses: Infarction, from virus within the orbiviruses. CHUV has been incriminated as
viral-induced vascular injury, is probably responsible for the the cause of an epizootic in the Kyushu district of Japan,
large areas of necrosis and cavitation occurring in the rostral wherein 2,463 calves, mostly beef breeds, were affected. A
regions of the cerebrum, whereas viral destruction of clusters high percentage of newborn calves were born with hydranen-
of individual cells, including glial cell precursors, results in foci cephaly and cerebellar hypoplasia. A subsequent seroepidemio-
of necrosis and accounts for microcavitation. Collapse of these logic investigation revealed evidence to suggest the virus had
cavities may facilitate dilation of the lateral ventricles and been spread from the most southerly island of Japan to the
secondary hydrocephalus. Death of calves with hydranen- mainland in the north. Cattle in the region did not have anti-
cephaly pre-empts them spreading the virus by an arthropod body to the virus previous to this epizootic.
vector, even if they are viremic. The earliest evidence of anti- Calves involved in the epizootic were born alive and were
body activity against BTV group antigen in bovine fetuses normal in size and weight. Clinical signs and congenital abnor-
occurs at around 145 days of gestation; by 200 days, there is malities included corneal opacity, blindness, nystagmus, cere-
significant neutralizing antibody activity; therefore no virus is bellar ataxia, tremor, and opisthotonos. Postmortem lesions
detectable at birth. included hydranencephaly, secondary hydrocephalus, micro-
Diagnosis of in utero infections in cattle and sheep is based cephaly, and cerebellar hypoplasia. No lesions were seen in
on finding the typical lesions and specific fetal antibody to other organs, and no virus was isolated from any of the calves;
BTV in cavity fluid or blood. Virus isolation after fetal immu- however, 44 of 49 precolostral serum samples checked for
nocompetence to BTV is unlikely but not invariable. Maternal neutralizing antibody to CHUV were positive. Experimental
precipitating antibody (agar gel immunodiffusion test) may infection of 15 cows at 89-150 days of gestation resulted in
be absent at term, whereas neutralizing antibody may be more 14 normal calves and one calf with severe hydranencephaly
persistent. The c-ELISA for specific neutralizing antibody is and cerebellar hypoplasia.
more specific and sensitive. To culture the virus from blood, For diagnosis, CHUV can be recovered from blood for up
animal inoculation or washed erythrocytes may need to be to 56 days after inoculation. It is closely associated with red
used because the organism is closely associated with red cells. blood cells, even in the presence of antibody. Demonstration
BTV and epizootic hemorrhagic disease virus (EHDV) can be of specific antibody in the serum of precolostral calves will be
detected and differentiated by multiplex RT-PCR. incriminating.
Further reading
Falconi C, et al. BTV infection in wild ruminants, with emphasis on red
deer: a review. Vet Microbiol 2011;151:209-219.
Ohashi S, et al. Identification and PCR-restriction fragment length
polymorphism analysis of a variant of the Ibaraki virus from natu-
rally infected cattle and aborted fetuses in Japan. J Clin Microbiol
1999;37:3800-3803.
Rasmussen LD, et al. Transplacental transmission of field and rescued
strains of BTV-2 and BTV-8 in experimentally infected sheep. Vet
Res 2013;44:75.
van der Sluijs MT, et al. Transplacental transmission of bluetongue virus
serotype 1 and serotype 8 in sheep: virological and pathological
findings. PLoS ONE 2013;8.
Wouda W, et al. Epizootic congenital hydranencephaly and abortion
in cattle due to bluetongue virus serotype 8 in the Netherlands.
Tijdschr Diergeneeskd 2009;134:422-427.
431.e2
Further reading
Yamaguchi R, et al. Encephalopathy in suckling mice infected with
Kasba (Chuzan) virus. J Comp Pathol 1999;120:247-256.
Yamakawa M, Furuuchi S. Expression and antigenic characterization of
the major core protein VP7 of Chuzan virus, a member of the
Palyam serogroup orbiviruses. Vet Microbiol 2001;83:333-341.
432 CHAPTER 4 • Female Genital System Abortion and Stillbirth
Figure 4-89 Renal hemorrhages in a newborn pup. This lesion is Further reading
very characteristic for canine herpesvirus infection. Ström Holst B, et al. Canine herpesvirus during pregnancy and non-
pregnant luteal phase. Reprod Domest Anim 2012;47(Suppl.
6):362-365.
Further reading
Decaro N, et al. Canine adenoviruses and herpesvirus. Vet Clin North
Am Small Anim Pract 2008;38:799-814.
Evermann JF, et al. Canine reproductive, respiratory, and ocular diseases
due to canine herpesvirus. Vet Clin North Am Small Anim Pract
2011;41:1097-1120.
Schulze C, Baumgartner W. Nested polymerase chain reaction and in
situ hybridization for diagnosis of canine herpesvirus infection in
puppies. Vet Pathol 1998;35:209-217.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 433
Further reading
Gortazar C, et al. Natural Aujeszky’s disease in a Spanish wild boar
population. Ann N Y Acad Sci 2002;969:210-212.
Hsu FS, et al. Placental lesions caused by pseudorabies virus in pregnant
sows. J Am Vet Med Assoc 1980;177:636-641.
433.e2
Further reading
Edington N, et al. Porcine cytomegalovirus (PCMV) in early gestation.
Vet Microbiol 1988;17:117-128.
Narita M, et al. Morphologic study of inclusions in tissues from pigs
inoculated with cytomegalovirus. Am J Vet Res 1987;48:
1398-1402.
434 CHAPTER 4 • Female Genital System Abortion and Stillbirth
tissue cultures. Results are also available quickly. Fluorescent inclusions were observed in large alveolar cells. Similar inclu-
antibody techniques on frozen tissue sections of kidney, liver, sions were also seen in cells of bile duct epithelium, myocar-
or placenta and tissue cultures of these samples can be used dium, spleen, and epithelium of renal tubules. The virus was
for detection of virus. Viral DNA may also be detected by not isolated from this animal, but the inclusions seen on light
PCR. To identify antibodies to BoHV-1, the ELISA has a and electron microscopy were typical of cytomegaloviruses.
higher validity in differentiating a negative from a positive To confirm the diagnosis, fetal lung, liver, and kidney should
sample than the serum neutralization test. With BoHV-1, be cultured for the virus, and fluorescent antibody techniques
cows abort such a long time after initial infection that most may also be used to demonstrate its presence. A nested duplex
animals have very low titers to the virus at that time. On an PCR assay has been used to detect BoHV-1 and BoHV-4 in
individual basis, therefore, antibody titers are of little value in lymph nodes and peripheral blood leukocytes. The virus has
diagnosis. Also, as the fetus dies quickly, there is usually no been demonstrated in aborted fetuses by in situ hybridization.
evidence of fetal antibody production. Neutralization tests are usually unsatisfactory for the detec-
tion of antibody as the virus elicits a low antibody response.
The ELISA and an IIF test have been found to be more sensi-
Further reading tive and may have value on a herd basis. Antibodies may also
Gould S, et al. An evaluation of the prevalence of bovine herpesvirus be detected in cavity fluid of aborted fetuses and are evidence
1 abortions based on diagnostic submissions to five U.S.-based at least of fetal infection.
veterinary diagnostic laboratories. J Vet Diagn Invest 2013;25:243-
247.
Nandi S, et al. Bovine herpes virus infections in cattle. Anim Health Res Further reading
Rev 2009;10:85-98. Chastant-Maillard S. Impact of bovine herpesvirus 4 (BoHV-4) on repro-
duction. Transbound Emerg Dis 2013;doi:10.1111/tbed.12155;
[Epub ahead of print].
Bovine herpesvirus 4 (cytomegalovirus) infection of Deim Z1, et al. Detection of bovine herpesvirus 4 DNA in aborted
the pregnant uterus in cattle bovine fetuses. Can J Vet Res 2007;71:226-229.
Species Bovine herpesvirus 4 (BoHV-4, bovine cytomegalovi-
rus, Movar virus) is in the family Herpesviridae, subfamily
Gammaherpesvirinae (cell-associated herpesviruses), genus Equid herpesvirus 1 abortion in horses
Rhadinovirus. It has worldwide distribution in cattle and has Species Equid herpesvirus 1 (EHV-1, equine abortion virus) is
been associated with a wide variety of clinical conditions, in the family Herpesviridae, subfamily Alphaherpesvirinae,
including pneumonia, enteritis, metritis, mammillitis, and the genus Varicellovirus. It is widespread throughout the world
disease syndrome “epivag.” Epivag is characterized by vaginitis, and causes respiratory, neurologic, and generalized neonatal
salpingitis, and oophoritis, or epididymitis. disease, as well as abortion. The virus can be separated into 2
BoHV-4 is considered an important cause of abortion in distinct subtypes (1 and 2) on the basis of restriction endo-
cattle; however, experimental evidence confirming a causal nuclease cleavage of the viral DNA. Both subtypes cause
relationship is incomplete. The virus is less virulent than respiratory disease, abortion, and neonatal disease. Subtype 1,
BoHV-1, and concurrent infections of BoHV-4 with other however, causes a more severe (but less frequently encoun-
pathogens are frequent (up to 75%). It has been suggested tered) respiratory disease than subtype 2 and is the more
that the virus is immunosuppressive and thereby intensifies frequent isolate from aborted foals and neonatal disease. Also,
the effects of other agents. BoHV-4 has been isolated along it is probably the only type causing neurologic disease. Subtype
with bovine viral diarrhea virus and border disease virus from 2 is commonly isolated from mild upper respiratory disease
abortions, and with Mycobacterium paratuberculosis from in horses and less so from abortion. Respiratory disease caused
animals with Johne’s disease. by EHV-1 is common in some areas, whereas abortion is rare;
As the virus is carried within mononuclear cells in blood, this may be explained to some extent by the presence of a
grows on mucosal surfaces, and is also considered a poor subtype less likely to produce abortion but capable of produc-
immunogen, it elicits a low level of neutralizing antibody that ing respiratory disease.
is also of low avidity. It is transmitted from cow to cow in oral EHV-1 is very widespread, and first exposure usually
and nasal secretions and, during viremia, is carried to the occurs before the foal is 1 year of age. Mild to severe upper
placenta, where it multiplies and invades the fetus. The virus respiratory disease is produced, and secondary bacterial infec-
may remain latent in mononuclear blood cells and in the tion, frequently with Streptococcus zooepidemicus or other
trigeminal nerve ganglion. Recrudescence can be induced with streptococci, is common. Because the virus is so widespread
dexamethasone. Herds tested for BoHV-4 antibodies vary and contact so likely at an early age, abortion usually occurs
greatly in the proportion of cattle with antibody to the virus. in an animal that has had previous experience with the virus.
Mummification and birth of weak pigs have also been As with herpesviruses generally, the level of immunity is low,
reported in association with BoHV-4 infections in sows. Fetal and the virus is transported in leukocytes through the blood-
pigs are capable of developing antibody to the virus by 74 stream to the placenta and hence the fetus. Death of the fetus
days of gestation. Recrudescence induced by dexamethasone does not occur until the onset of the usually prompt and
has been reported in sheep and pigs, with spread of virus to uncomplicated abortion. The dam shows no premonitory
other animals. signs, and the fetus is aborted in a fresh state. The time from
Descriptions of the lesions seen in the aborted bovine fetus exposure, whether by recrudescence of latent virus or reinfec-
are limited. In one report, no gross lesions were observed in tion, until abortion varies from 9 days to several months.
the fetus, but on histologic examination, there was thickening Respiratory disease in the mare is usually not observed follow-
of alveolar septa in the lungs, where many large intranuclear ing the infection that results in abortion. It is reported that
435.e1
Further reading
Kirkbride CA. Viral agents and associated lesions detected in a 10-year
study of bovine abortions and stillbirths. J Vet Diagn Invest
1992;4:374-379.
Muylkens B, et al. Bovine herpesvirus 1 infection and infectious bovine
rhinotracheitis. Vet Res 2007;38:181-209.
435.e2
Further reading
Sheldon IM, et al. Uterine diseases in cattle after parturition. Vet J
2008;176:115-121.
436 CHAPTER 4 • Female Genital System Abortion and Stillbirth
lung, liver, spleen, or thymus or by immunohistochemistry on of gestation is less severe; however, there are inflammatory
placenta is definitive. Determination of the specific subtype lesions without malformation in the brainstem.
may be accomplished using monoclonal antibodies and PCR- AKAV is carried by a midge or mosquito from a viremic
based tests. Serologic examination for antibody is of little use to a susceptible animal, and at no time does the dam show
in the diagnosis of abortion because most animals are exposed clinical signs of infection. Viremia lasts for about 4 days,
to the virus at several intervals in their life, and abortion may during which time the virus invades the placenta, replicates
occur too long after the last exposure, making interpretation in trophoblastic cells, and finally crosses the placenta and
impossible, even on the basis of paired samples. infects the fetus. If AKAV is inoculated immediately after the
Equid herpesvirus 4 causes a similar disease, but is less integration of the placental cotyledon with the maternal car-
common and is sporadic. uncle, viral invasion of the chorioallantoic membrane occurs
rapidly. Lesions in the brain and possibly in muscle are prob-
ably due to the direct cytopathic effect of the virus on devel-
Further reading oping neurons. A regular sequence of events follows the
Gardiner DW, et al. Strain impact on equine herpesvirus type 1 (EHV-1) primary insult of polioencephalitis; focal necrosis in the brain
abortion models: Viral loads in fetal and placental tissues and foals. may progress to malacia and, depending on the extent of
Vaccine 2012;30:6564-6572. the injury and time, to porencephaly and hydranencephaly.
Szeredi L, et al. Detection of equine herpesvirus-1 in the fetal mem- Neuronal death in brain and ventral spinal cord motor
branes of aborted equine fetuses by immunohistochemical neurons is followed by denervation atrophy of muscle and
and in-situ hybridization techniques. J Comp Pathol 2003;129: arthrogryposis.
147-153. Autopsy findings in affected species are similar. In the brain,
gross lesions have a broad range, including microcephaly, poren-
cephaly, and hydranencephaly. Cystic cavities vary from being
Akabane virus infection of the pregnant uterus visible only microscopically to having almost complete loss of
Species Akabane virus (AKAV) is in the family Bunyaviridae, parenchyma. The cerebellum may be normal to markedly
genus Orthobunyavirus, Simbu serogroup. In Australia, the atrophic. Microscopically, there is encephalitis with macro-
Simbu serogroup includes Akabane, Tinaroo, Peaton, Aino, phages, plasma cells, and lymphocytes within areas of necrosis
Douglas, Thimiri, and Facey’s Paddock viruses; Akabane and and around vessels. Lesions are sometimes most prominent in
Tinaroo viruses are naturally occurring reassortants. Akabane the brainstem and spinal cord. The cerebral cortex may have
disease, commonly known as enzootic bovine arthrogryposis and multifocal areas of necrosis with gliosis and perivascular
hydranencephaly (ag/he), occurs in Australia, Japan, Korea, mononuclear cells. In the cerebellum, there may be loss and
Israel, and Kenya. Evidence of disease in postnatal cattle, malpositioning of Purkinje cells and reduced size of molecular
sheep, and goats is minimal; only slight leukopenia in goats and granular layers.
and mild keratoconjunctivitis in cattle have been reported, Lesions induced in the brain early in gestation, because of
plus one report of encephalomyelitis in cows. In contrast, extensive destruction of cells, may proceed to hydranenceph-
infection of nonimmune pregnant sheep, goats, and cows has aly with subsequent arthrogryposis. Lesions produced late in
resulted in extensive losses in Japan, Israel, and Australia. the first trimester usually consist of multifocal encephalitis
AKAV is transmitted by various insects, including the and proceed only to porencephaly. Infections late in the
hematophagous midge Culicoides brevitarsis in Australia and second trimester may produce lesions consisting of multifocal
various species of mosquitoes, including Aedes vexans, Culex necrosis and gliosis with less development of cavities.
tritaeniorhynchus, and C. pipiens. Losses are seasonal and con- Lesions in the spinal cord can be bilateral or unilateral and
fined geographically by the range of the insect. Animals consist of mineralization of meninges, atrophy of the cord, and
beyond this range constitute a naïve population, and if for hydromyelia. Necrosis and depletion of ventral horn motor
some reason infected insects invade this area, extensive losses neurons may proceed to cavitation. Light or heavy accumula-
may occur. tions of perivascular lymphocytes may be present throughout
Infections by AKAV before 30 days of gestation can produce the cord with decreased numbers of axons and hypomyelin-
multiple congenital abnormalities and can result in normal or ation in the lateral and ventral tracts.
malformed fetuses that may be aborted; mummified; or delivered Joints of the front legs are more commonly affected than
alive or stillborn, early, on due date, or late. Many are delivered those of the hind, and both may be fixed in either flexion or
with difficulty because of the congenital malformations. extension. There is slight to marked atrophy of skeletal muscle
Anomalies observed include microcephaly, porencephaly, groups in affected limbs. The muscles are edematous, pale, and
hydranencephaly, hydromyelia, arthrogryposis, kyphosis, lor- flabby to firm. On microscopic examination of muscle, sarco-
dosis, scoliosis, brachygnathia, and muscle atrophy. Additional plasmic nuclei are either swollen or pyknotic. Loss of stria-
abnormalities reported in lambs include spina bifida, cyclops, tions, hypereosinophilia, and empty sarcolemmic cylinders
Arnold-Chiari syndrome, and anal atresia. When the fetus is may be present. Replacement of muscle by connective tissue
infected between 41 and 50 days of gestation, thick perivas- and fat occurs finally. Well-preserved fibers may be present
cular cuffing of macrophages, lymphocytes, and plasma cells adjacent to areas of complete loss of muscle mass. Polymyo-
is observed, coupled with very prominent glial nodules. The sitis, from which the virus can be isolated, has been reported
large variety of CNS malformations caused by AKAV is attrib- in some infected fetuses.
uted to differences in the fetal age at infection, the vulnerabil- The diagnosis of AKAV infection may be made by demon-
ity of neurons to direct injury, and the nature of tissue response strating virus or antibody in affected animals. Virus may be
to such injury. Affected lambs are reported to weigh signifi- recovered from various fetal tissues and fluids, including
cantly less than normal lambs, even though gestation length brain, spinal cord, cerebral fluid, skeletal muscle, chorioallan-
overall is slightly extended. Infection of the fetus after 90 days tois, and amnion. It may be grown on hamster lung cells
437.e1
Further reading
Gerst S, et al. Detection of EHV-1 and EHV-4 in placental sections of
naturally occurring EHV-1- and EHV-4-related abortions in the UK:
use of the placenta in diagnosis. Equine Vet J 2003;35:430-433.
Léon A, et al. Detection of equine herpesviruses in aborted foetuses
by consensus PCR. Vet Microbiol 2008;126:20-29.
Schlafer DH. Examination of the equine placenta. In: McKinnon A,
et al., editors. Equine Reproduction. 2nd ed. Ames, Iowa: Wiley-
Blackwell; 2010. p. 99-110.
van Maanen C. Equine herpesvirus 1 and 4 infections: an update. Vet
Q 2002;24:58-78.
438 CHAPTER 4 • Female Genital System Abortion and Stillbirth
and can cause reduced litter size, transplacental infection van den Brom R, et al. Epizootic of ovine congenital malformations
of the fetus, and birth of live, weak young. AKAV can also associated with Schmallenberg virus infection. Tijdschr Dierge-
grow in the brain of intracranially inoculated suckling mice. neeskd 2012;137:106-111.
As the fetus is capable of producing antibody from an early Veldhuis AM, et al. Schmallenberg virus in Dutch dairy herds: potential
stage of gestation, inferred evidence of the cause of malforma- risk factors for high within-herd seroprevalence and malformations
tion and abortion may be determined by finding specific anti- in calves, and its impact on productivity. Vet Microbiol 2014;
body to AKAV in fetal cavity fluids, including fluids from 168:281-293.
stored tissues or precolostral blood samples from affected
newborn animals.
Aino virus infection in cattle
Aino virus (AINOV, syn. Shuni virus) is closely related to
Further reading Akabane virus, and is similarly in the family Bunyaviridae,
Jun Q1, et al. A serological survey of Akabane virus infection in cattle genus Orthobunyavirus, Simbu serogroup. As with AKAV,
and sheep in northwest China. Trop Anim Health Prod 2012;44:1817- AINOV is mainly transmitted by the midge Culicoides brevi-
1820. tarsis but has also been isolated from mosquitoes, including
Kirkland PD. Akabane and bovine ephemeral fever virus infections. Vet Culex tritaeniorhynchus and a mixture of C. pipiens and C.
Clin North Am Food Anim Pract 2002;18:501-514. pseudovishnui. The range of the organism, as determined by
Noda Y, et al. Demonstration of Akabane virus antigen using immuno- serum antibody titers, extends along the northern and eastern
histochemistry in naturally infected newborn calves. Vet Pathol coasts of Australia (from just within Western Australia to
2001;38:216-218. central New South Wales) and is well within the range of C.
brevitarsis. The virus is also present in Japan. Using antibody
titers as evidence of previous infection, fewer species overall
Schmallenberg virus infection of cattle, sheep, and fewer animals within affected species appear to be
and goats infected with AINOV compared to AKAV.
During the summer and fall of 2011, cattle in northwestern Cattle that are infected do not have clinical signs; however,
Germany and in the Netherlands became ill with a febrile insofar as precolostral antibodies to the organism are found in
condition that was associated with drop in milk production, deformed newborns, the organism is capable of crossing the
hypothermia, and watery diarrhea. Later in the fall, some bovine placenta and causing abortion. Lesions consist of placen-
cattle in these and other European countries aborted or gave tal edema and necrosis, renal tubular necrosis with interstitial
birth to calves with neurologic disease and skeletal anomalies. lymphoplasmacytic infiltrates, nonsuppurative meningitis, and
Aborted fetuses had abnormally developed heads, spines, and interstitial pneumonia with mononuclear cells and some neu-
limbs. Laboratorians were able to identify a novel orthobun- trophils. Experiments conducted with sheep indicate that,
yavirus that had the molecular structure of the Shamonda although the virus can infect the fetus after direct inoculation,
viruses. This virus was named the “Schmallenberg virus” (SBV) it does not cross the placenta after inoculation into the preg-
after a town in Germany near which a farm had a sick cow nant ewe.
from which this virus was isolated. SBV is in the family Lesions induced in young calves following intracerebral
Bunyaviridae, genus Orthobunyavirus, Simbu serogroup, and inoculation of AINOV and AKAV are reported to be different.
is a reassortant of Sathuperi and Shamonda viruses. An With AINOV, nonsuppurative encephalomyelitis developed
RT-qPCR test was developed which was subsequently used to first in the cerebrum adjacent to the ventricles and spread to
identify the agent, conduct epidemiologic studies, and to the medulla and the brainstem, but remained mild in the
examine the pathogenesis of the disease. Transmission of spinal cord. Using animals inoculated with AKAV as controls,
SBV is associated with exposure to biting midges, mosquitoes, nonsuppurative encephalomyelitis was produced in the brain-
and sandflies. SBV can be transmitted via the semen of stem and spinal cord only. Intravenous inoculation of virus
infected bulls. into susceptible pregnant cows at various stages of gestation
Schmallenberg virus infection of pregnant sheep also may give a more valuable comparison.
results in similar teratogenic lesions, and significant losses have Diagnosis is based on immunohistochemistry or fluorescent
been reported in Europe. Experimental inoculation of preg- antibody testing on frozen sections or smears of homogenates
nant sheep causes subclinical infections in most animals. Infec- of fetal kidney, lung, and liver. Prospective serology on
tion was established in only about half the ewes inoculated. cows at pregnancy diagnosis and at abortion may be useful.
Affected fetuses and offspring of infected ewes or cows, have Aino and Akabane bunyaviruses can be differentiated by
hydranencephaly, scoliosis, and/or arthrogryposis—a spectrum nested PCR.
of lesions similar to those of other Simbu group bunyaviruses,
such as Akabane virus.
Amniotic fluid collected from fetal stomachs, and samples Further reading
of fetal cerebrum and fetal spinal cords have proven to be Ali H, et al. Common, emerging, vector-borne and infrequent aborto-
good samples from which SBV nucleic acids can be identified genic virus infections of cattle. Transbound Emerg Dis 2012;
by RT-qPCR. ELISAs have been developed for antibody detec- 59:11-25.
tion, and serologic surveys have been conducted.
Further reading
Buxton D, Henderson D. Infectious abortion in sheep. In Pract
1999;21:360-368.
Charles JA. Akabane virus. Vet Clin North Am Food Anim Pract
1994;10:525-546.
Jagoe S, et al. An outbreak of Akabane virus-induced abnormalities in
calves after agistment in an endemic region. Aust Vet J 1993;70:56.
Parsonson IM, et al. Transmission of Akabane virus from the ewe to
the early fetus (32 to 53 days). J Comp Pathol 1988;98:215.
Szabo KT. Hydranencephaly. Cerebellar hypoplasia. Arthrogryposis. In:
Szabo KT, editor. Congenital Malformation in Laboratory and Farm
Animals. London: Academic Press; 1989. p. 112, 124, 184.
438.e2
Further reading
Conraths FJ, et al. Schmallenberg virus, a novel orthobunyavirus infec-
tion in ruminants in Europe: potential global impact and preventive
measures. N Z Vet J 2013;61:63-67.
Garigliany MM, et al. Schmallenberg virus: a new Shamonda/Sathuperi-
like virus on the rise in Europe. Antiviral Res 2012;95:82-87.
438.e3
Further reading
Akashi H, et al. Detection and differentiation of Aino and Akabane
Simbu serogroup bunyaviruses by nested polymerase chain reac-
tion. Arch Virol 1999;144:2101-2109.
Yanase T, et al. Genetic characterization of Aino and Peaton virus field
isolates reveals a genetic reassortment between these viruses in
nature. Virus Res 2010;153:1-7.
Pathology of the Genital System of the Nongravid Female Abortion and Stillbirth 439
America. Serologic data indicate it infects pigs, horses, rac- The diagnosis of CVV infections resulting in fetal loss and
coons, foxes, and domesticated and wild ruminants, including congenital anomalies in lambs is most easily accomplished by
cattle, sheep, caribou, and deer, as well as humans. It is believed examining precolostral serum or cavity fluids of lambs with
to be spread by insects and has been isolated from a variety arthrogryposis and hydranencephaly for antibodies to CVV.
of mosquitoes and midges, including Culiseta inornata, Pso- CVV antigen may be detected in aborted fetuses by immu-
rophora columbiae, Aedes sollicitans, Ae. taeniorhynchus, Anoph- nohistochemistry, in situ hybridization, or PCR. Differential
eles grabhamii, An. crucians, An. uadrimaculatus, and Culicoides diagnoses should include infection by Akabane virus, as the
spp. lesions are remarkably similar.
There is considerable evidence supporting CVV as the
cause of a severe epizootic in a flock of sheep in Texas, where,
of 360 lambs delivered, 92 were mummified, stillborn, or born Further reading
with congenital anomalies. Sixty-nine lambs had arthrogryposis Rodrigues Hoffmann A, et al. Identification of the target cells and
and hydranencephaly. All of the ewes bearing affected lambs sequence of infection during experimental infection of ovine
had neutralizing antibody to CVV, and affected lambs had fetuses with Cache Valley virus. J Virol 2012;86:4793-4800.
precolostral antibody to the virus. In the months before preg-
nancy, 5% of ewes had antibody to the virus and after preg-
nancy, 63.4% were positive. Following the outbreak, a sentinel Rift Valley fever virus infection of cattle and sheep
sheep was placed in the area, and CVV was eventually recov- Species Rift Valley fever virus (RVFV) is in the family Bunya-
ered from a blood sample. viridae and is the type species of genus Phlebovirus (Zinga
Examination of 15 lambs stillborn at term during the epi- virus is a strain of RVFV). RVFV infects many domestic, wild,
zootic revealed that CNS and muscle and joint lesions were and laboratory animals and humans. It occurs in at least 18
frequently present in the same animal, and lesions between countries over a 6,700-km north-south range in Africa, plus
lambs mainly differed in severity. Gross lesions in limb joints Saudi Arabia. Infection by RVFV causes a disease characterized
consisted of articular rigidity with articulations held in the by rapid onset and high mortality in lambs, low mortality in adult
flexed position. The limbs appeared long for the size of the sheep and calves, and even lower or no mortality in cattle. There
body. In addition, kyphosis, scoliosis, and torticollis were fre- is frequently a high rate of abortion, approaching 100% in sheep
quently observed. Muscles associated with the affected limbs and cattle. People may also become infected, often from
and spine were described as shrunken, pale, and firm. Lesions contact with body fluids or organs of infected animals, and
in the brain consisted of hydrocephalus, porencephaly, and develop influenza-like illness; mortality is generally low, but
hydranencephaly. The cerebrum, cerebellum, and spinal cord morbidity is high and the degree of debility often extreme.
were often markedly reduced in size, and the cerebellum was Hepatic necrosis is the prominent lesion and occurs in all affected
occasionally mildly lissencephalic. species and age groups, including the fetus. Host resistance to
Microscopic lesions were observed in skeletal muscles, fatal hepatic disease has been shown in laboratory animals to
brain, and 2 placentas. In affected muscle, fibers were small, be inherited as a simple Mendelian dominant gene. Suscepti-
lacked striations, and nuclei were sparse. Fibers were separated bility is age and sex related; the young are more susceptible,
by loose connective tissue and adipocytes; rarely, a few neu- and males less resistant than castrates and females. Although
trophils and mononuclear cells were present. Histologic exam- 2/3 of sheep are genetically resistant to fulminant hepatic
ination of the brain confirmed gross findings, and cavities not disease, sheep are regarded as the most susceptible domestic
visible grossly were occasionally observed. In regions of animal.
marked hydranencephaly, the cerebral cortex was reduced to RVFV is transmitted primarily by mosquitoes, and Culex
a few layers of neurons within the meninges. Entire lobes of pipiens is a major vector in parts of Africa. Generalized infec-
the cerebellum were often absent, but adjacent lobes were tion in the mosquito is necessary before transmission occurs
often near normal, with only minor loss of cells in the molecu- effectively, and movement of virus from the insect gut is
lar layer. The density of axons in the spinal cord was markedly facilitated by the presence of microfilariae in ingested blood.
reduced, especially in dorsal tracts, and whereas ventral horn Aedes spp. are capable of transovarial transmission. Aedes
neurons were only slightly reduced in the cranial cord, hardly albopictus, a strain of mosquito in the United States, can trans-
any remained in caudal portions. Inflammatory cells were mit the virus, and movement of animals either incubating
scant in lesions except in 2 of the 5 placentas examined, infection or in viremia raises the possibility of international
wherein a mild perivascular neutrophil infiltrate was evident. spread of the virus. Biting midges and ticks are also implicated
Inoculation of 36 ovine fetuses in utero with CVV has added in transmission. The virus probably does not spread from
further credibility to the role of CVV as the cause of the animal to animal in the absence of insects; however, experi-
epizootic. Following in utero inoculation of the virus, several mentally the virus can be transmitted by just about every
of the fetuses developed arthrogryposis and hydranencephaly; route, including aerosols or application into nasal passages,
some were mummified, others died and were absorbed, and a to scarified skin, or on the conjunctiva. Aborted fetuses and
few had oligohydramnios. Lambs infected at 27-35 days of membranes have a very high titer of virus. Epizootics often
gestation had the greatest mortality rate, whereas lambs follow a period of heavy rain, particularly after drought,
infected between days 36 and 45 of gestation had more and outbreaks may be separated by periods of 10-15 years
congenital anomalies. Virus was recovered from fetuses before without a case.
69 days but not after 76, regardless of when they were In mature sheep, cattle, or camels, the disease is manifest
infected, and this was coincident with the development of in peracute, acute, subacute, chronic, and convalescent forms. In
neutralizing antibody in the fetus. The virus was recovered sheep, the subacute form, in which the animal is febrile for
from allantoic fluid in 11 of 17 fetuses euthanized at <76 days 24-96 hours, is common, and up to 100% of pregnant ewes
of gestation. can abort during this phase or when convalescing. In cattle,
439.e1
Further reading
Chung SI, et al. Congenital malformations in sheep resulting from in
utero inoculation of Cache Valley virus. Am J Vet Res 1990;51:1645.
Edwards JF. Cache Valley virus. Vet Clin North Am Food Anim Pract
1994;10:515-524.
Rodrigues Hoffmann A, et al. Ovine fetal immune response to Cache
Valley virus infection. J Virol 2013;87:5586-5592.
Wang H, et al. A duplex real-time reverse transcriptase polymerase
chain reaction assay for the detection of California serogroup and
Cache Valley viruses. Diagn Microbiol Infect Dis 2009;65:
150-157.
440 CHAPTER 4 • Female Genital System Miscellaneous Lesions
the peracute form is rare, and abortions occur during the acute
or convalescent period in 10-85% of pregnancies. Camels sero-
convert and may amplify the virus locally; some may die.
Deaths in cows are uncommon. Infertility occurs in both
sheep and cattle and may follow retention of fetal membranes
and endometritis. Signs are unpredictable in goats. They tend
to be less susceptible than sheep, but if infected can abort.
During viremia, the organism is carried to the placenta and
fetus, where the liver appears to be the primary site of multiplica-
tion. Hepatocyte destruction is probably related to the
repeated cycles of virus growth and release of virus from
infected cells.
Lesions are much the same in cattle or sheep fetuses and,
except for one report where experimental inoculation of preg-
nant ewes with an attenuated RVFV resulted in hydranen-
cephaly and arthrogryposis, infection by RVFV usually results
in death of the fetus in utero. This occurs at any gestational age
and, as it occurs rapidly, the fetus is aborted in an autolysed Figure 4-96 Fetal myocarditis in an aborted piglet, caused by
state. On gross examination, the liver is swollen and discolored porcine circovirus 2.
orange to brown and occasionally to dark red. Microscopically,
the most consistent lesion seen in almost 100% of fetuses
examined is multifocal to massive hepatic necrosis. A few degen- 1991 and has since been found in the United States and in
erating neutrophils may be present in these lesions. Acidophilic many European and Asian countries. The disease primarily
intranuclear inclusions of various shapes (fusiform, round, affects pigs 5-18 weeks of age and is characterized by failure to
oval) are frequently present in hepatic cells of ovine fetuses grow and eventual emaciation. Affected pigs may have gastric
and are helpful in the diagnosis. These are seen less often in ulcers in addition to a wide variety of lesions, including pneu-
bovine fetuses and may be difficult to find when autolysis is monia and diarrhea.
advanced. Mineralization of individual or clusters of hepato- A reproductive failure syndrome has been observed in several
cytes is also common. Cholestasis may be evident in canaliculi. herds and is characterized by late-term abortions of mummi-
Other lesions reported include degeneration of lymphocytes fied, macerated, or autolysed piglets, and piglets born weak or
in spleen and lymph nodes and degenerative lesions in heart stillborn. Lesions in these piglets included enlargement of the
muscle and renal tubules. liver; congestive heart failure, with excess fluid in the thorax;
The hepatic lesion is considered diagnostic; however, in and abdominal cavities. The heart may be enlarged and irregu-
areas where the condition is not endemic, definitive diagnosis lar in shape, and on histologic examination, extensive areas of
depends on identification of the virus. It can be detected early myocardial degeneration, edema, and necrosis with mild fibro-
in infection in blood or serum by RT-PCR. It is abundant in sis and diffuse infiltrates of lymphocytes and macrophages
fetal tissues and placenta and may be cultured or detected may be observed (Fig. 4-96). The virus can be demonstrated
using the indirect fluorescent antibody technique on frozen by immunohistochemistry in heart muscle cells. No other
sections of liver or by immunohistochemistry. Differential viruses were detected in this investigation. Stress factors and
diagnoses in sheep include infections by bluetongue virus and co-infections with other porcine viruses were not detected;
Wesselsbron virus. however, environmental, husbandry, and genetic factors may
be important in the progression of clinical PMWS.
Further reading
Ikegami T, Makino S. The pathogenesis of Rift Valley fever. Viruses Further reading
2011;3:493-519. Cushing TL, et al. Pathology in practice: myocarditis attributable to
Odendaal L, et al. Sensitivity and specificity of real-time reverse tran- PCV-2 infection in a pig fetus. J Am Vet Med Assoc 2013;242:317-
scription polymerase chain reaction, histopathology, and immuno- 319.
histochemical labeling for the detection of Rift Valley fever virus in Hansen MS, et al. Detection of porcine circovirus type 2 and viral
naturally infected cattle and sheep. J Vet Diagn Invest 2014; replication by in situ hybridization in primary lymphoid organs from
26:49-60. naturally and experimentally infected pigs. Vet Pathol 2013;50:
980-988.
Further reading
Gerdes GH. Rift valley fever. Vet Clin North Am Food Anim Pract
2002;18:549-555.
Van der Lugt JJ, et al. Distribution of viral antigen in tissues of new-born
lambs infected with Rift Valley fever virus. Onderstepoort J Vet Res
1996;63:341-347.
440.e2
Further reading
Segalés J, et al. The natural history of porcine circovirus type 2: from
an inoffensive virus to a devastating swine disease? Vet Microbiol
2001;165:13-20.
Segalés J, et al. Porcine circovirus diseases. Anim Health Res Rev
2005;6:119-142.
Silva FM, et al. Porcine circovirus-2 viral load versus lesions in pigs:
perspectives for post-weaning multisystemic wasting syndrome.
J Comp Pathol 2011;144:296-302.
West KH, et al. Myocarditis and abortion associated with intrauterine
infection of sows with porcine circovirus 2. J Vet Diagn Invest
1999;11:530-532.
Pathology of the Cervix, Vagina, and Vulva Pathology of the Cervix 441
Figure 4-97 Subinvolution of placental sites (SIPS) in a bitch. The uterine mass adjacent to the uterine lumen is composed
Fusiform enlargement of uterine horns at sites of failure of of an admixture of amorphous eosinophilic debris, fibrin,
involution. degenerating placental site tissue, and regenerating endome-
trium (Fig. 4-98). The deeper tissue contains numerous
irregular-shaped cells with large nuclei and abundant vacuo-
lated cytoplasm (Fig. 4-99). They are interpreted as syncytial
trophoblasts or alternatively as decidual cells, and are far more
numerous than in the normal gravid uterus. Some degree of
invasion of the myometrium by these cells is not unusual, and
in some cases there is perforation of the serosa, allowing
uterine contents to escape into the peritoneal cavity. The
condition appears to be more prevalent in young bitches, but
the cause has not been established.
Further reading
LeBlanc SJ. Postpartum uterine disease and dairy herd reproductive
performance: a review. Vet J 2008;176:102-114.
Sontas HB, et al. Full recovery of subinvolution of placental sites in an
American Staffordshire terrier bitch. J Small Anim Pract 2011;
52:42-45.
Further reading
Fernández PE, et al. Characterisation of cytotrophoblastic-like cells
present in subinvolutioned placental sites of the bitch. Histol Histo-
pathol 1998;13:995-1000.
442 CHAPTER 4 • Female Genital System Pathology of the Vagina and Vulva
propria and mononuclear cells; especially, lymphocytes are observed in ewes and cows as a consequence of dystocia. A
present. The uterine tubes are involved, but to a less severe number of influences, mainly prolonged pressure necrosis, lac-
degree. eration, and abrasion, usually acting in combination, are
The virus can produce similar lesions on the mucous mem- responsible for the lesion. Severe necrotic cervicovaginitis is
brane of the penis of infected bulls. Because recrudescence frequently fatal, either with direct extension of the inflamma-
with viral shedding is a feature of this as well as other herpetic tion to the peritoneum or with the uterine complications of
diseases, animals with inapparent infections can also transmit prolonged dystocia and fetal emphysema.
the disease. Lacerations associated with dystocia commonly occur in
A herpesvirus identified as equid herpesvirus 3 produces a mares, sometimes extending to involve the rectum and
comparable genital disease in horses—equine coital exanthema. perineum. Scarring of the vulva from previous trauma from
It is discussed with diseases of the penis, in Vol. 3, Male genital delivery is a common finding in large domestic animals (Fig.
system. Caprine herpesvirus infection in goats causes a com- 4-106). Disfigurement may result from neoplasms that invade
parable disease of the vulva also. the perineal area (Fig. 4-107).
invading the tissues. From the initial lesions, the organisms are
disseminated in the blood to other parts of the body, and
edematous swellings occur where they localize. Infection of
the blood may be intermittent or continuous, and there may
be few organisms or many, depending on the virulence of the
strain and the susceptibility of the host. Strains of low viru-
lence may not be demonstrated in the blood by direct smears,
but may be demonstrated by centrifuging plasma or directly
by transfusing blood in large volumes. In these mild infections,
it may also be possible to demonstrate the organisms in genital
washes or discharges, but diagnostic problems are simplified
by an efficient complement-fixation test.
The signs and course of the infections vary considerably,
depending on the virulence of the organism and on the sus-
ceptibility of the host. The resistance of the host can be greatly
modified by climatic conditions, physical condition, intercur-
rent disease, and nutritional status, and the South African
varieties of the disease can be asymptomatic in animals that
are well husbanded. Animals affected with this insidious type
of the disease do act as carriers and reservoirs of infection.
When the infection is attended by clinical signs, the course is
variable; it may be severe and fatal in a few weeks, fatal after
Figure 4-106 Disfigured vulva of a sow, resulting from trauma a chronic or intermittent course of from several months to 2
during delivery. years, or clinical recovery may occur.
The signs of dourine can be divided into genital, cutaneous,
nervous, and general manifestations, which occur separately or
concurrently. The initial signs are usually genital, but may be
nervous or cutaneous. The incubation period of the genital
signs varies from several days to several months, during which
the organisms are present in genital discharges or washings.
The external genitalia are swollen and doughy, but character-
istically the swellings are neither hot nor painful. The degree
of swelling varies considerably from case to case and periodi-
cally in an established case, with a tendency to be permanent
because of induration in chronic infections. The swelling,
when severe, extends to the perineum and ventral abdominal
wall. The lymphocytic follicles of the mucosa of the female
genitalia become hyperplastic and ulcerate, and at this stage,
there may be copious fluid discharge. In males, the swelling
involves the head of the penis as well as the prepuce, and may
cause prolapse of the urethra and penis. In virulent infections,
flat circular ulcers develop in the head of the penis. Healed
ulcers in both males and females often remain as depigmented
scars, and pigmentary atrophy of the skin and genital mucosa
may also occur in the absence of ulceration, the loss of pigment
being, when present, a very characteristic sign of this disease.
Cutaneous lesions may never occur in the mild disease. In
virulent infections, edematous urticaria-like plaques, usually
Figure 4-107 Multinodular pigmented masses involving the circular but sometimes linear or in rings, occur in the skin,
vulva and perineum of a mare. This malignant melanoma had also especially on the sides of the body and croup. The swelling
metastasized to regional lymph nodes. These are common neo- may be up to 15 cm in diameter and painless and free of itch.
plasms that involve the vulva and perineum of the mare. Squa- They disappear in a few days and new ones form. There is
mous cell carcinomas also occur in this area. usually no residuum, but sometimes there are local distur-
bances of sweating and pigmentation.
Nervous manifestations develop late in the course and usually
months, in which the organisms are not present in these sites, lead to death. There is acute hyperesthesia initially, which may
so infected animals are not always infective for others at be generalized or localized to the distribution of particular
breeding. The organisms penetrate intact mucosa at the site nerves. Later there is diminished sensitivity or even anesthesia,
of implantation and proliferate in the submucosal lymph and this is accompanied by paresis or paralysis of individual
spaces. The incubation period may be several weeks or months, motor nerves. The pareses are either unilateral in distribution
during which time trypanosomes are present in the genital or asymmetric in severity and most commonly involve the
discharges, so there is a possibility that they may proliferate facial nerves and the motor nerves of the hindlimbs. Decubi-
in the lumen of the genital tract for long periods before tus follows.
Pathology of the Cervix, Vagina, and Vulva Neoplastic Conditions of the Tubular Genitalia 447
The general manifestations are chiefly of continued or neoplasms, there is as yet no precise knowledge of the role of
remittent fever, emaciation, and severe anemia. Noninflamma- estrogen.
tory synovial effusions, superficial lymphadenopathy, uveitis, Genital smooth muscle tumors may grow to be as large as
and optic atrophy are described. 10-12 cm in diameter but most are not invasive. The smaller
Apart from changes in the peripheral nerves that are tumors are cellular but, as they enlarge, become firm or hard
responsible for the paralytic phenomena, pathologic changes (hence the clinical term fibroid) because of the connective
additional to those that are clinically observable are not tissue stroma. On cut surface, they have a watered-silk appear-
reported. Degenerative changes occur chiefly in the lumbar ance, and the color, whether more cellular or white, depends
and fifth and seventh cranial nerves, being most severe in on relative amounts of muscle and connective tissue. Figure
the roots and also involving the ganglia. The neuropathy is 4-108 shows characteristic gross features of a smooth muscle
probably preceded by edema and inflammation, and these tumor in the uterus of a cow. These tumors are not encapsu-
may still be present at death. The large nerve trunks are trans- lated but are well demarcated, firm, light tan to white, and
formed into fibrous cords that are fused with the surrounding easily shelled out. In almost all cases, the tumors project as
muscular fascia. Microscopically, there is edema, mononuclear
cells, and fibrosis of the perineurium. There is slight endoneu-
ral reactivity in fascicles, in which there is extensive fiber
degeneration. Sclerosing changes are also present in the
ganglia.
Further reading
Bryans JT, Allen GP. In vitro and in vivo studies of equine “coital”
exanthema. Proc 3rd Int Conf Equine Infect Dis 1973;322-336.
Kirkland PD, et al. Infertility and venereal disease in cattle inseminated
with semen containing bovine herpesvirus type 5. Vet Rec
2009;165:111-113.
Nandi S, et al. Bovine herpes virus infections in cattle. Anim Health Res
Rev 2009;10:85-98.
NEOPLASTIC CONDITIONS OF
THE TUBULAR GENITALIA
Isolated reports have described both benign and malignant
tumors of all histologic components of the tubular genitalia.
Some are common in some locales and warrant brief
A
discussion.
Tumors of the vulva are similar to the tumors of the skin.
Squamous cell carcinoma is well known in the mare, cow, and
ewe, and indeed, a high incidence in cows is reported in tropi-
cal countries. These bovine cases are analogous to the orbital
tumors of cattle, thought to be initiated in a solar dermatosis,
their incidence negatively correlated with the degree of local
epithelial pigmentation.
Further reading
Afshar A, et al. Granular vulvovaginitis (nodular venereal disease) of
cattle associated with Mycoplasma bovigenitalium. Vet Rec
1966;78:512-519.
Katz JB, et al. Clinical, bacteriologic, serologic, and pathologic features
of infections with atypical Taylorella equigenitalis in mares. J Am
Vet Med Assoc 2000;216:1945-1948.
Roth C, et al. Antigenic variation in Trypanosoma equiperdum. Res
Microbiol 1991;142:725-730.
Zablotskij VT, et al. The current challenges of dourine: difficulties in
differentiating Trypanosoma equiperdum within the subgenus Try-
panozoon. Rev Sci Tech 2003;22:1087-1096.
448 CHAPTER 4 • Female Genital System Neoplastic Conditions of the Tubular Genitalia
Further reading
Belov K. Contagious cancer: lessons from the devil and the dog. Bioes-
says 2012;34:285-292.
Cave TA, et al. Uterine carcinoma in a 10-month-old golden retriever.
J Small Anim Pract 2002;43:133-135.
Garcia-Iglesias MJ, et al. Incidence and pathomorphology of uterine
tumours in the cow. Zentralbl Vet A 1995;42:421-429.
McEntee K. Reproductive Pathology of Domestic Mammals. San Diego:
Academic Press; 1990
Mizuno S, et al. Role of lymphocytes in dogs experimentally
re-challenged with canine transmissible sarcoma. Jpn J Vet Sci
1989;51:86-95.
Pérez-Martínez C, et al. Expression of cytokeratins and vimentin in
normal and neoplastic tissue from the bovine female reproductive
tract. J Comp Pathol 2001;124:70-78.
Tanaka H, et al. Nodal, uterine and meningeal gamma(delta) T-cell
lymphomas in cattle. J Vet Med A Physiol Pathol Clin Med
2003;50:447-451.
Whitney KM, et al. Caprine genital leiomyosarcoma. Vet Pathol
2000;37:89-94.
Yang TJ. Immunobiology of a spontaneously regressive tumor, the
canine transmissible venereal sarcoma. Anticancer Res 1988;
8:93-96.
Pathology of the Cervix, Vagina, and Vulva Pathology of the Mammae 451
Mechanical injury
Machine milking of dairy cattle is prone to induce significant
Table • 4-1 damage to the ends of the papilla when milking procedures
and the milking equipment are not optimal. This damage,
Normal mammary tissue arrangement in associated with high vacuum, poor liners, ineffective pulsa-
tions, and overmilking, leads to partial eversion of the duct,
domestic species
ulceration, fibrosis, and bacterial growth. Papillary injury from
Species Mammae* Glands per mamma† overmilking reduces the keratin plug that helps protect from
ascending infections.
Bovine 4 1
Porcine 12 2 Innate and acquired resistance of mammae
Equine 2 2 The major factors in whether an animal develops mastitis are
Ovine 2 1 the innate immune response, the pathogen, and the environ-
ment. The major focus is the innate immune response, reduc-
Caprine 2 1
ing exposure to pathogens, and minimizing the effects of the
Canine 10 Up to 14 puerperium.
Feline 8 3-7 Reducing contamination of the mammary papilla is the
Camelids 4 2 cornerstone of prevention of mastitis as it reduces potential
exposure to pathogens. Reducing trauma at milking and
*Previously and commonly called mammary gland, or quarter in
cattle. chemical injury to the papilla is also well recognized in reduc-
†
Functional unit is the mammary gland. Many species have more than ing intramammary infections through reducing “teat end
one gland in each mamma. lesions,” which are circular or horseshoe-shaped rings around
452 CHAPTER 4 • Female Genital System Pathology of the Mammae
the opening of the papilla. Mastitis only occurs when bacteria Mastitis is an inflammatory disease rather than an infec-
enter the gland; this requires entry through the physical tious disease; it is the host response to bacteria that determines
barrier of the papillary duct (streak canal). This opens at par- if there is local or systemic disease and how severe it is. The
turition when the offspring suckle and during milking. It process ranges from transient to persistent and from mild or
remains open for 1-2 hours after milking; this is when most subclinical to severe, peracute, and fatal. Notwithstanding the
mammary infections occur. When closed, the canal seals with large number of microbial species that may be isolated from
keratin and a waxy plug. Mastitis often occurs in the peripar- the diseased mammary gland, bovine mastitis is dominated by
turient period when neutrophil migration is inhibited and staphylococci and coliforms; the streptococci are now much
fewer reactive oxygen species are produced. less common because of dry cow therapy. Some infections,
Once inside the lactiferous sinus or ducts, bacteria encoun- such as caused by Cryptococcus and the atypical mycobacteria,
ter macrophages and neutrophils (called somatic cells) in milk are usually iatrogenic. Some other infections, such as caused
and the lining epithelial cells. These have specific pattern by Pseudomonas and Prototheca, indicate heavy environmental
recognition receptors (PRR), especially toll like receptors contamination.
(TLR), which recognize bacterial pathogen-associated molec-
ular patterns (PAMP) and induce the innate or nonspecific Staphylococcal mastitis
immune response. Activation of intracellular pathways results Staphylococcal mastitis is predominantly an infection of
in release of immune modulating substances, such as TNF-α, heifers (“heifer mastitis”) at the time of parturition and their
interleukin-8 (IL-8),and RANTES (regulated on activation, first mechanical milking. Coagulase-negative staphylococci
normal T-cell expressed and secreted) that attract neutrophils are the most common cause of heifer mastitis, mastitis around
and induce inflammation. the time of the first parturition, and before the application of
Complement (C5a), lactoferrin, and lysozyme facilitate mechanical milking. S. aureus, a coagulase-positive bacterium,
this response. Complement 5 is present in mammary secretions is a more common cause of mastitis in the older age groups.
and is cleaved to C5a, probably by mammary macrophages, Pathogenic strains of staphylococci are always of human or
the dominant cell in healthy mammary glands. C5a induces animal origin and persist as permanent inhabitants of the skin
the release of proinflammatory cytokines, attracts neutrophils, and mucous membranes; thus infection of the udder is conta-
and enhances phagocytosis. Lactoferrin is an iron-binding gious. Little is still known of the pathogenicity of the staphy-
protein present in secretions and in neutrophils that inhibits lococci as some strains may produce gangrenous mastitis on
multiplication of bacteria with high iron requirements. The some occasions and only a mild disease on others, with little
high concentration of citrate in normal milk prevents the correlation of toxin production to toxigenicity.
action of lactoferrin, but it is effective in the secretion of Staphylococcal mastitis can be subclinical or clinical; mild
the nonlactating gland. Lysozyme is locally synthesized in the or severe and fulminating; and peracute, acute, or chronic. The
gland, and although the concentration in milk is low, there is severe forms of the disease typically occur shortly after par-
some correlation between milk titer and susceptibility to turition, and there is necrosis (gangrene) of affected mammae
infection. The titer may be increased during inflammation. and high mortality. The affected mammae are swollen and
The most common pathogens in cows are E. coli and Staphy- tense, hot and firm, and very painful. There is almost complete
lococcus aureus. E. coli mediates inflammation through endo- stagnation of secretion, and only a few milliliters of brown,
toxin and PRR such as TLR-4. S aureus mediates inflammation blood-stained, or straw-colored watery fluid can be expressed
by exotoxins and lipoproteins, peptidoglycans, and lipotei- from the papilla. Uninfected mammae are also swollen and
choic acid. TLR-2 is important. Adaptive immune mecha- tense, and the secretion is reduced but otherwise normal.
nisms occur but are not as important as the innate system. Gangrene (Fig. 4-115) usually first affects the papilla and
There are differences between species in the nature of immu- adjacent portions of or the whole mamma. The tissues become
noglobulins in colostrum and milk. In the cow, the immuno-
globulins are predominantly of the IgG class and are selectively
transferred from serum to milk. The levels are low in normal
glands, but permeability changes in inflammation allow the
titer to increase. The same class of antibody is identified with
the concentration of plasma cells in the distal papillary part
of the lactiferous sinus and papillary duct, and may affect
organisms resident in the papillary duct. The major role of these
antibodies is to promote opsonization of microorganisms. IgA is
also present in milk and may have a defensive effect on bacte-
rial adherence to epithelial surfaces.
Bovine mastitis
Bovine mastitis is typically a response to ascending infection
of the gland, and bacteria are the most common pathogens.
Potential mammary pathogens are ubiquitous. Modern tech-
niques of microbial classification have identified more than
100 species, subspecies, and serovars isolated from the
mammary gland. Streptococcus agalactiae and some types of
Staphylococcus aureus are obligate parasites of the gland and
inevitable pathogens, but the great majority of infections are
opportunistic. Figure 4-115 Gangrenous mastitis in a cow.
Pathology of the Cervix, Vagina, and Vulva Pathology of the Mammae 453
blue and eventually black and are softer, insensitive, and cold.
There is pitting edema of the inguinal area, flank, and ventrum,
and the necrotic skin begins to exude serum and to slough,
and gas bubbles develop beneath it. The amount of tissue
involved in the gangrenous process is quite variable, and
groups of necrotic lobules adjoin others that are near normal.
Separation of the gangrenous areas begins a week after onset,
proceeds slowly, and the surface is suppurative and fistulae
develop.
The changes in glands shedding nonhemolytic, coagulase-
negative staphylococci of low pathogenicity without
clinical signs of infection are mild progressive fibrosis and
lobular atrophy. Hemolytic coagulase-positive staphylococci
Figure 4-118 Prominent mammary lobules in clinical mastitis in
produced lobular lesions of greater extent and rate of
a cow. It is difficult to differentiate involuting gland from inflamed
progression.
mammary tissue.
The nongangrenous and mild forms of the disease are the
same for the majority of bacterial mastitides. The gross appear-
ance varies according to severity. The lesions are mostly in the and ductal lumens of some lobules (Fig. 4-119). There is
distal portion of the gland about the lactiferous sinus and large minimal interstitial vascular change. Neutrophils migrate from
ducts. The lactiferous sinus and ducts fill with secretion in the venules through the interstitium (Fig. 4-120), and epithelium
early stage of the disease, the secretion being serous and floc- to contribute to somatic cells in milk. Epithelia of the ducts
cular or distinctly purulent (Fig. 4-116). The epithelial lining become hyperplastic and with increasing severity, develop
of the sinus and papilla may be normal, or it may be red and squamous metaplasia. Lymphocytes and plasma cells accumu-
granular (Fig. 4-117). The adjacent glandular tissue is swollen late in the interstitium, and lymphoid follicles can form, espe-
and turgid (Fig. 4-118). Surface lobulations are distinct cially around the lactiferous sinus and ducts. With increasing
because the swollen lobules protrude. There is no recognizable severity, there is death of the epithelium, sloughing of cells
interstitial edema. The affected lobular tissue is gray and often into the lumen, and erosion. Granulation tissue will form, and
cannot be differentiated from involuting glands, whereas the periductal fibrosis develops. In experimental infection, the
normal lactating tissue is milky white. With time, the lactifer- bacteria enter the tissues and induce a severe reaction with
ous sinus and larger ducts have a thickened lining and small interstitial edema and emigration of neutrophils throughout
rounded polypoid projections into the lumen. The periductal all the tissues. Stromal lymphatics are widely dilated and
tissues become white and tough with fibrosis and a lack of contain numerous neutrophils. The acinar epithelium becomes
glandular tissue. The tissues away from the ducts are not as vacuolated and dies. Granulation and fibrosis progress and
affected. Histologically, the range of changes is very wide, eventually obliterate many of the acini. The inflammation and
depending on the severity, which depends on invasiveness of retention of milk and exudate causes involution in affected
the bacteria, toxin production, and the degree of the host and unaffected acini nearby. The processes of fibrosis and
response. In subclinical mastitis, neutrophils enter the acinar involution continue until the end stages, when some lobules
454 CHAPTER 4 • Female Genital System Pathology of the Mammae
Coliform mastitis
Coliform bacteria, especially E. coli, produce mastitis that is
usually severe and in some herds are the major causative
agents. Little is known of the pathogenesis, but coliform mas-
titis is a serious problem in herds where the more common
mammary infections are suppressed or eliminated. The other
Enterobacteriaceae that cause mastitis include bacteria of the
genera Enterobacter, Klebsiella, Citrobacter, Serratia, and
Proteus. These organisms are part of the environmental flora,
and they do not have a predilection for the mammary gland;
Figure 4-120 Early lesion in streptococcal mastitis in a cow. mammary infection may be correlated with the level of envi-
Neutrophils within the interstitium of the gland migrate from ronmental exposure. Each usually produces a clinically severe
venules to the lumen of glandular acini, where the bacteria are form of the disease with systemic reaction and, especially in
present. the case of E. coli, endotoxemia. A milder progressive type of
disease can also occur.
show normally involuted tissue, some are obliterated by fibro- It is generally accepted that coliform mastitis is an ascend-
sis, and others have combinations of the two. Because infection ing infection. This infection is often limited to one mamma,
and inflammation progress to involve adjacent tissue, many and typically there is a distinct region of dead gland sharply
lobules are out of phase with each other; and there is a suc- demarcated from surrounding normal gland (Figs. 4-121,
cession of events from mild to severe as more gland is involved. 4-122). Extensive edema and, if very severe, hemorrhage, is
Progressive involvement of ducts results in granulation tissue characteristic. The content of the lactiferous sinus and major
and fibrosis, and obstruction to milk flow. Upstream tissues ducts is often scant and watery or cloudy and blood stained;
are dilated and contain stagnant milk, exudate, and numerous it contains floccules of fibrin and coagulated casein. Coagu-
organisms. There is concomitant proliferation of periductal lated protein forms plugs in the lactiferous ducts. There is
fibrous tissue spreading centrifugally to involve and obliterate usually severe edema of the subcutis of the gland and ventral
large amounts of lobular tissue. Such granulation tissue in time abdomen (see Fig. 4-121).
cicatrizes, and the duct epithelium can be restored. Similar Microscopically, the inflammatory reaction is centered on
changes occur in the larger lactiferous ducts and sinus, but the ducts. The lining of the larger ducts is missing and replaced
they are less exuberant, and the epithelium can become squa- by fibrinosuppurative exudate. The lining of the smaller, intra-
mous and sometimes keratinized. lobular ducts is also destroyed and contain plugs of necrotic
Persistent foci of infection transition into a granulomatous detritus. The acini are filled with serous fluid in which there
reaction previously known as botryomycosis. Initially, necrotic are vacuolated desquamated epithelial cells, but leukocytes
foci form and are surrounded by an intense neutrophilic and are few or absent, either in the alveoli or in the septa (Fig.
histiocytic response, and fibrosis develops rapidly. Each granu- 4-123). The septal tissues, especially the interlobular septa, are
lomatous focus is up to 2 cm in diameter and may be numer- widened by edema, and the lymphatics are widely dilated
ous and involve a large proportion of the mamma. The and contain fibrin. This can transition to interstitial fibrosis
Pathology of the Cervix, Vagina, and Vulva Pathology of the Mammae 455
Summer mastitis
(Fig. 4-124). In areas of hemorrhage, red blood cells are “Summer mastitis” or “Holstein udder plague” is mastitis of
throughout the septal connective tissue and within acini. dairy cows that occurs during the summer months, tradition-
If the course of the severe inflammation is prolonged ally the dry cow period. This is usually a mixed bacterial
beyond 1-2 days, extensive death of tissue may occur. If the infection affecting immature and nonlactating glands of
animal survives, the necrotic tissue, usually most of one animals at pasture. Trueperella (Arcanobacterium) pyogenes is a
quarter, forms a sequestrum. common isolate along with S. dysgalactiae, Peptostreptococcus
indolicus, Bacteroides melaninogenicus, Fusobacterium necropho-
Streptococcal mastitis rum, and microaerophilic and unidentified obligate anaerobes.
Bacteria of the family Streptococcaceae are important potential Infection is acquired via the papillary ostium and duct and
causes of bovine mastitis, but modern preventive techniques contamination by flies attracted to pre-existing lesions of the
largely control disease. Streptococcus agalactiae, S. dysgalac- mammary papilla.
tiae, and S. uberis are the most frequently implicated. The The lesion is suppurative, necrotic, and centered on the
common streptococci have the mammary gland of the cow, lactiferous sinus and ducts, thus it is a necrosuppurative
456 CHAPTER 4 • Female Genital System Pathology of the Mammae
Mycoplasma mastitis
Mycoplasmas are prominent causes of bovine mastitis in some Figure 4-125 Mycoplasma bovis mastitis in cattle differs from
herds. There is rapid spread from an infected mamma to other causes of mastitis in having prominent lymphocytes and
adjoining mammae and to others in the herd. Response to plasma cells within the glandular interstitium. Neutrophils are
therapy is poor. Shedding of the organisms from infected within glandular acini.
quarters is inconsistent, adding to the challenge of clinical
diagnosis and control.
The diseases produced by Mycoplasma spp. and Achole-
plasma spp. are similar. Mycoplasma bovis is the most fre-
quent of these infections, although infections by M. canadense,
M. bovigenitalium, and M. californicum are also common.
The disease begins with a sudden onset of agalactia. The
mamma is initially swollen, firm, and painless. Ordinarily there
are no systemic signs, but other manifestations of systemic
Mycoplasma infection, such as arthritis, may occur. Coexisting
mammary infection with bacteria occur, and the clinical signs
are worse than with a sole infection. The disease spreads
rapidly in a herd; animals in full lactation tend to be affected
simultaneously in all glands. The milk from an infected
mamma appears as normal, but separates into floccular and
clear components. The presence of pus or blood probably
indicates coexistent bacterial infection.
Affected mammae are, in the active stages, swollen and
firm but later become flaccid as rapid involution occurs.
Altered secretion and mammary enlargement may persist for
Figure 4-126 Marked dilation of lactiferous ducts with necrotic
several weeks. Clinical recovery may occur without return to
debris in Mycoplasma mastitis. The gross appearance is caseous
full normal function, and such animals may continue to
exudate.
excrete the organism intermittently for more than a year. It is
not clear whether clinical relapses occur or whether over this
long period there is cumulative mammary injury.
The route of infection of the mammary gland is not clear. septa and subsequent alveolar atrophy. The ductal epithelium
The experimental disease is induced by intramammary or becomes hyperplastic too, and squamous metaplasia develops.
intravenous inoculation and is severe. The usual clinical disease There is also surrounding progressive fibroplasia. The numbers
suggests spread from mamma to mamma, but the occurrence of interstitial lymphocytes continue to increase. Concurrent
of arthritis indicates systemic dissemination. epithelial erosion occurs, and exuberant granulation tissue
The histologic lesions in the gland are different from other forms. When severe, there are polypoid protrusions into the
types of mastitis. Neutrophil migration begins within a few lactiferous ducts and sinuses. Retention of exudate occurs in
hours of experimental infection as perivascular accumulations small ducts, with subsequent mineralization and granuloma
in walls of the lactiferous sinus and lobular interstitium, which formation (Fig. 4-126).
is edematous. The reaction is patchy at first but quickly
involves most of the parenchyma. After several days, lympho- Miscellaneous infections
cytes, plasma cells, and macrophages appear and become There are hundreds of potential mammary pathogens. From a
dense focal lymphocytic aggregates in the intralobular and historical perspective, tuberculous mastitis is an important
periductal connective tissue (Fig. 4-125). These persist for classic disease. It is rare in a majority of countries, but is still
many months. The epithelial cells of alveoli and ducts develop important in those without a modern dairy industry. Its impor-
large lipid vacuoles that are discharged into the lumen. The tance is in its zoonotic potential. Mammary tuberculosis
alveolar epithelium becomes hyperplastic and multilayered. usually develops insidiously without clinical signs of inflam-
This transitions over several weeks to fibrosis of intralobular mation. The gland progressively increases in size and firmness,
Pathology of the Cervix, Vagina, and Vulva Pathology of the Mammae 457
Figure 4-127 Multiple variably sized abscesses and pyogranulo- Figure 4-128 Chronic galactophoritis results in nodules of lym-
mas in Nocardia mastitis in a cow. phoid hyperplasia and epithelial hyperplasia of the lactiferous
ducts in bovine mastitis.
and the majority do not have the classic miliary lesions seen more than one mamma and is recognized when there is an
in other organs. The caseous inflammation of the lactiferous accompanying severe systemic reaction.
sinus and ducts (galactophoritis) form also occurs. Lactiferous An important syndrome in sows is known as the mastitis-
ducts are especially involved, and bacilli are in the milk before metritis-agalactia syndrome or postpartum dysgalactia syn-
gross lesions of tuberculosis are evident. The milk may be drome. Sows become lethargic; anorexic; and develop fever, a
physically normal for a long period after infection, even vulvovaginal discharge and mammary redness, edema, swell-
though it contains the bacilli. In the later stages, there is ing, firmness, and agalactia. Failure of lactation and systemic
reduced watery secretion with floccules of caseous exudate signs dominate the syndrome. The syndrome involves a
and large numbers of bacilli. Mycobacterium bovis is the main complex interaction between environment, host, and
pathogen. The inflammatory reaction is similar to other loca- pathogens.
tions with granulomatous caseous inflammation, pyogranulo- Chronic granulomatous mastitis (previously known as bot-
matous inflammation with distinct granulomas, and/or a ryomycosis) affecting one or more glands is occasionally
diffuse histiocytic reaction. observed in old sows, and most cases are caused by S. aureus.
Nocardia spp., other Mycobacterium spp., fungi and yeasts
(Cryptococcus neoformans, Candida spp.), and algae (Proto- Mastitis in horses
theca zopfii) produce granulomatous mastitis. These usually Mastitis in mares is rare. They are seldom used as dairy
develop from environmental contamination or after infusion animals and therefore do not have the usual environmental
of contaminated intramammary preparations. Herd outbreaks exposure and mechanical injury that accompanies milk har-
or sporadic individual cases occur. vesting. Bacteria cultured from lactating mares are similar in
These agents may be present in mammary secretions for spectrum to other species and include streptococci and staph-
months without causing clinical signs of mastitis. In other ylococci. Mastitis is recognized as excessive swelling of a
cases, the response to infection is a mild chronic involvement mamma in a lactating mare. Lesions are similar to those in
of the mammary gland, whereas in yet other cases, the reac- other species.
tion is of sudden onset and severe clinical course. Severe
reactions occur near the time of parturition especially. There Mastitis in sheep and goats
may be spread of infection to mammary lymph nodes and Mastitis in the ewe and goat is usually caused by S. aureus or
lungs in some cases. Affected quarters enlarge rapidly and Mannheimia haemolytica. Corynebacterium pseudotuberculosis
become firm from fibrosis. In some cases, there is a palpable and T. pyogenes also occur. Mastitis in the ewe and doe is
nodularity, the nodules being 2-5 cm in diameter. These may especially important in dairy animals and because the case
be sinus tracts discharging on to the skin. In nocardial mastitis, fatality rate can be as high as 50%. Except for infection by M.
some infections are purulent in small foci (Fig. 4-127), but agalactiae, clinical mastitis usually affects only one mamma.
larger abscesses occur when there is a mixed infection with The range of organisms causing bacterial disease includes the
Pseudomonas aeruginosa, T. pyogenes, or other organisms. The species pathogenic in the cow.
lesion in the majority of infections is galactophoritis, similar S. aureus mastitis has a similar course and consequences to
to summer mastitis (Fig. 4-128). The range of inflammatory the disease in the cow. The morbidity, however, is higher and
reactions is identical to infections elsewhere. may approach 25% of a flock. M. haemolytica causes mastitis
in sheep on summer range at or near the end of lactation and
Mastitis in swine affects ~5% of a flock. This is a severe disease with systemic
E. coli, S. aureus, and, to a lesser extent, Streptococcus spp. are reaction; if the ewe survives, the systemic reaction subsides
important mammary pathogens of sows. Little is known of the within 48 hours. The affected gland, usually one side, is greatly
pathogenesis, but the range of lesions is identical to bovine mas- enlarged, tense, blue-black, and the secretion becomes watery
titis. In particular, clinical mastitis caused by coliform bacteria and contains flakes. Widespread necrosis of tissue occurs.
occurs as a severe infection shortly after parturition. It affects Animals that do not die develop abscesses in the course of a
458 CHAPTER 4 • Female Genital System Pathology of the Mammae
Further reading
Aalbaek B, et al. Mycoticc and algal bovine mastitis in Denmark. APMIS
1994;102:451-456.
Baer C, Bilkei G. Ultrasonographic and gross pathological findings in
the mammary glands of weaned sows having suffered recidiving
mastitis metritis agalactia. Reprod Domest Anim 2005;40:544-547.
Benites NR, et al. Aetiology and histopathology of bovine mastitis of
spontaneous occurrence. J Vet Med 2002;49:336-370.
Bhutto AL, et al. Udder shape and teat-end lesions as potential risk
factors for high somatic cell counts and intra-mammary infections
in dairy cows. Vet J 2010;183:63-67.
Bradley A. Bovine mastitis: an evolving disease. Vet J 2002;164:116-
128.
Burton JL, Erskine RJ. Immunity and mastitis: some new ideas for an
old disease. Vet Clin North Am Food Anim Pract 2003;19:1-45.
LeMaréchal C, et al. Molecular basis of virulence in Staphylococcus
aureus mastitis. PLoS ONE 2012;6:e27354.
Oelrichs PB, et al. Isolation and identification of a compound from
avocado (Persea americana) leaves which causes necrosis of the
acinar epithelium of the lactating mammary gland and the myocar-
dium. Nat Toxins 1995;3:344-349.
Pedersen LH, et al. Early pathogenesis and inflammatory response in
experimental bovine mastitis due to Streptococcus uberis. J Comp
Pathol 2003;128:156-164.
Regassa A, et al. Prevalence, risk factors, and major bacterial causes of
camel mastitis in Borana Zone, Oromia Regional State, Ethiopia.
Trop Anim Health Prod 2013;45:1589-1595.
Sanchis R, et al. Inoculation of lactating ewes by the intramammary
route with Mycoplasma agalactiae: comparative pathogenicity of
six field strains. Vet Res 2000;31:329-337.
Stevens MG, et al. Compromised neutrophil function and bovine E. coli
mastitis: is C5a the missing link? Vet Immunol Immunopathol
2012;149:151-156.
Tibary A, et al. Infectious causes of reproductive loss in camelids.
Theriogenol 2006;66:633-647.
Whelehan CJ, et al. Experimental Staphylococcus aureus infection of
the mammary gland induces region-specific changes in innate
immune gene expression. Vet Immunol Immunopathol 2011;140:
181-189.
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 459
Preziuso S, et al. Experimental maedi visna virus infection in sheep: a Mammary hypertrophy is when a whole mamma or
morphological, immunohistochemical and PCR study after three mammae become larger than normal for the physiologic state.
years of infection. Eur J Histochem 2003;47:373-378. It is common in dogs because of their propensity to lactate
Wellnitz O, Bruckmaier RM. The innate immune response of the bovine during pseudopregnancy, as an adaptation to enhance survival
mammary gland to bacterial infection. Vet J 2012;192:148-152. of pups in a pack situation. Precocious mammary develop-
ment and lactation occurs with exposure to exogenous hor-
mones, such as transcutaneous human hormonal replacement
MAMMARY MASSES INCLUDING therapy. Some high-producing lines of dairy cattle and goats
NEOPLASIA have mammary hypertrophy and lactation, including males.
Some dogs spayed while in diestrus will develop hypertrophy
Neoplasia of mammae is extremely important from an indi- and lactation because of a prolactin surge in response to a
vidual or comparative perspective. Not every mass in a sudden reduction in progesterone concentration. The histo-
mamma is neoplastic, but neoplasia is usually the top of the logic change is generalized hyperplasia of all mammary tissue.
list of diagnostic hypotheses. Neoplasia is very common in the Localized mammary hyperplasia is recognized when the
dog, less so in the cat, and rare in other species. The prognosis gland should be involuted (Fig. 4-131). Hyperplasia within a
for neoplasia in the mammary glands is most important. It is gland is either of the epithelium of a duct or of the lobule of
usually poor for all species except the dog. Diagnosis of a gland. Papillary hyperplasia within a duct is often an inci-
mammary neoplasia is best achieved by excisional biopsy; dental finding or causes cystic ductal dilation. Lobular hyper-
cytology can be of use in identifying inflammation and malig- plasia (Fig. 4-132) or subsequent dysplasia occurs at any stage
nant stromal neoplasms in dogs, and is very accurate in all of mammary physiologic events and results in enlargement of
other species, especially in cats. one or more lobules, a whole mammary gland, and or mamma
This section will cover non-neoplastic diseases first; neo- and mammae. Lobular hyperplasia has 3 main manifestations.
plastic disease will follow. The first is hyperplasia of the epithelium of the glandular
acini, often with luminal dilation from secretion. Second is
Non-neoplastic mammary enlargement
and masses
Mammary tissue undergoes physiologic change at the time of
puberty when ducts proliferate under hormonal influences of
estrogen, progesterone, growth hormone, and prolactin, to
name a few. With pregnancy, the gland undergoes further
development and enlargement, especially with lactation. Invo-
lution of the gland follows, and acinar tissue disappears in
most species. The common non-neoplastic lesions of the
mammary gland are cystic dilation of mammary ducts and
mammary hypertrophy and hyperplasia.
Cystic dilation of mammary ducts (Fig. 4-130) is very
common, especially in dogs and cats. It is usually secondary
to obstruction of a duct or the papillary canal by periductal
fibrosis, localized hyperplasia, or neoplasia. Continued secre-
tion and buildup of content dilates the duct, and the epithe-
lium accommodates the larger diameter by a lining that is
attenuated or normal in appearance.
Figure 4-131 Focal hyperplasia of the mammary gland in a cow.
Figure 4-130 Cystic dilation of mammary ducts secondary to Figure 4-132 Mammary lobular hyperplasia with lactation in
obstruction of secretion outflow in a cat. a dog.
460 CHAPTER 4 • Female Genital System Mammary Masses Including Neoplasia
Figure 4-133 Proliferation of lactiferous ducts and surrounding Prognosis and grading of mammary neoplasia
stroma in fibroepithelial mammary hyperplasia in a young cat. The basis of prognosis of neoplasia is determining phenotype
and relating this to patient outcome, often with determining
a grade. More than 35 phenotypes are described for mammary
adenosis (also called epitheliosis), when the epithelium under- neoplasia; 7 are benign and the rest are considered histologi-
goes hyperplasia and the lumen is filled with basiloid epithe- cally malignant (Table 4-2). The large number of types and
lial cells. The third is fibroadenomatous hyperplasia. subtypes is because of wide heterogeneity of mammary
Fibroadenomatous hyperplasia is common in cats, espe- tumors in dogs. Surprisingly, studies of prognosis based on
cially intact female cats <2 years of age. This spontaneous patient outcome are few and often have considerable meth-
condition occurs in the luteal phase of estrus, early in preg- odologic bias. Results vary greatly, so it is difficult to provide
nancy or after progestin therapy, and accompanies a high accurate survival data.
serum concentration of progesterone. The majority of publications concern canine mammary
Progesterone mediates hyperplasia through growth carcinoma. Little is written about mammary sarcomas or
hormone and insulin-like growth factor 1 in the ductal buds. those with malignant epithelial and stromal elements (carci-
In young queens, there may be an exaggerated tissue response nosarcomas) (see later). Some specific types of mammary
to prolactin. Resolution is spontaneous; antiprogestin therapy neoplasia have a poor prognosis. Mammary osteosarcoma, ana-
or ovariohysterectomy are effective. Megestrol acetate or plastic carcinoma, lipid-rich carcinoma, micropapillary inva-
other progestins will induce this in old neutered males and sive carcinoma, inflammatory carcinoma, comedocarcinoma,
females, and drug withdrawal and mastectomy is curative. and squamous cell carcinoma are aggressive and usually have
Whole lobules, glands, or mammae are affected. Clinical short survival times after diagnosis. These are the minority of
enlargement is dramatic, and the affected mamma or mammae cases.
are hot and painful, mimicking mastitis. The histologic change
is dramatic proliferation of lactiferous ducts that are widely Benign mammary neoplasms
separated by loosely arranged and often concentrically arranged Mammary neoplasms with an epithelial and mixed epithelial
fibrous stroma (Fig. 4-133). Hemorrhage and/or coagulative and myoepithelial component are the most common type in
necrosis of affected glands may occur. dogs. Benign neoplasms represent more than half of mammary
Galactostasis is when a lactating mammary gland is filled masses. Affected dogs may have one clinically detectable
with milk, but there is no let-down of milk because of inhibi- tumor, but they usually have multiple microscopic neoplasms.
tion of release of oxytocin, often from stress. It also occurs It is common to see different types within the same mamma.
after weaning or in pseudopregnancy. It is common in dairy The masses are usually well circumscribed and solid (Fig.
animals of all species. The mammae become engorged, hot, 4-134). They have a histologically benign appearance, includ-
and painful from milk retention; there is no systemic illness ing lack of invasion, minimal anisokaryosis/pleomorphism,
or other indicators of mastitis. Agalactia is the other extreme, and a low mitotic index (usually <10 per 10 high-power
where no mammary enlargement or lactation occurs after fields). These are divided into adenomas (simple, complex,
parturition. This is rare and the cause is unknown. The udders and basaloid) (Fig. 4-135), fibroadenomas (low and high cel-
are hard (hence the colloquial name of “hard udder”), but no lularity), benign mixed tumors (those complex tumors con-
milk is produced. In caprine arthritis encephalitis virus taining bone), and ductal papillomas (Fig. 4-136).
(CAEV) in goats and maedi-visna virus (MVV) infection in
sheep, there is usually microscopic lymphocytic interstitial Mammary carcinomas
inflammation. Although less common than their benign counterparts,
mammary carcinomas are usually the main focus of studies of
Mammary neoplasia in dogs pathogenesis and prognosis. They are very heterogeneous, and
There is much research in canine mammary neoplasia because classification schemes are becoming increasingly complex.
it is common and may be a model for breast cancer in women. There are special types of carcinoma with a poor prognosis
Little is known of its cause or pathogenesis. Risk factors are and short survival times; for the others there are prognostic
well known, and age at neutering has a major effect on its factors. Few studies have an end point of death from neoplas-
development. Overall prevalence of mammary neoplasia is tic disease. Many studies use the end point of carcinoma
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 461
Table • 4-2
Histologic classification of canine
mammary tumors
Benign mammary Adenoma, simple
tumor Intraductal papillary adenoma
Ductal adenoma (subtypes include
basaloid adenoma and adenoma with
squamous differentiation)
Fibroadenoma
Myoepithelioma
Complex adenoma
Benign mixed tumor
Mammary Carcinoma, in situ
carcinomas Carcinoma, simple (subtypes are tubular,
tubulopapillary, cystic-papillary,
cribriform) Figure 4-134 Multiple mammary adenomas in a dog.
Carcinoma, solid
Carcinoma, anaplastic
Carcinoma, micropapillary invasive
Comedocarcinoma
Carcinoma arising in a complex adenoma/
mixed tumor
Carcinoma, complex type
Carcinoma and malignant myoepithelioma
Carcinoma, mixed type
Ductal carcinoma
Intraductal papillary carcinoma
Mammary Squamous cell carcinoma
carcinomas, Adenosquamous carcinoma
special types Mucinous carcinoma
Lipid-rich (secretory) carcinoma
Spindle cell carcinomas
Malignant myoepithelioma
Squamous cell carcinoma, spindle cell
variant
Carcinoma, spindle cell variant Figure 4-135 Complex mammary adenoma with epithelial and
Inflammatory carcinoma myoepithelial components. Myoepithelial proliferation predomi-
Mammary Osteosarcoma nates in this example in this dog.
sarcomas Chondrosarcoma
Fibrosarcoma
Hemangiosarcoma
Other sarcomas
Malignant mixed Carcinosarcoma, malignant mixed
mammary tumor mammary tumor
Figure 4-137 A well-circumscribed mammary carcinoma in a dog Figure 4-139 Lymphatic invasion of a canine mammary carci-
showing compressed fibrous tissue at the periphery. The prognosis noma indicates a very poor prognosis.
is much better than a similar carcinoma that has peripheral
invasion.
Figure 4-138 A poorly circumscribed canine mammary carci- Figure 4-140 Anaplastic canine mammary carcinoma has poor
noma with peripheral invasion has a poor prognosis. differentiation and invasion; both are poor prognostic indicators.
variation in the survival times reported, but only low numbers a 12-month survival versus 73% for well-circumscribed
of these metastasize. Cytology and metastatic potential do not examples.
correlate well. In general, the prognosis of mammary carcino- Lymphatic invasion (Fig. 4-139) or lymph node metastasis
mas is based on: (clinical stage) in mammary neoplasms carries a poor progno-
• Age of dog at diagnosis sis with short survival intervals after diagnosis. This is particu-
• Size of neoplasm larly the case in the subtype of mammary carcinoma known
• Peripheral infiltrative growth pattern (poorly circum- as inflammatory carcinoma. Inflammatory carcinoma is named
scribed tumors) for its clinical signs of swelling and heat. Histologically, there
• Lymphatic invasion are neoplastic emboli in dermal lymphatics and no histologic
• Lymph node metastasis inflammatory reaction.
• Poor differentiation and special types Carcinomas with decreasing degrees of differentiation are
• Grade more likely to metastasize; thus simple, solid, and anaplastic
A mammary carcinoma >3 cm in diameter has a poorer carcinomas have, in turn, a greater chance of metastasis and a
prognosis, with a significantly shorter disease-free interval and shorter survival time. Thus classification of the tumor is prog-
time until death. nostic (Fig. 4-140). Anaplastic carcinoma, lipid-rich carci-
Infiltration of a carcinoma into surrounding tissue, vari- noma, micropapillary invasive carcinoma, comedocarcinoma,
ously called peripheral invasion, poorly circumscribed, or infil- and squamous cell carcinoma are aggressive and usually have
trative pattern (Figs. 4-137, 4-138), indicates a poor prognosis, short survival times after diagnosis.
with markedly reduced survival after diagnosis. Despite this, Grading schemes for carcinomas, using modification of the
not all carcinomas with this behavior metastasize. Poorly Elston and Ellis/Nottingham method for human breast carci-
circumscribed or invasive types have a much shorter survival noma, are available. There is variability in how the criteria are
time; for example, 26% of invasive solid carcinomas have applied, and the number of cases with good follow-up is
Pathology of the Cervix, Vagina, and Vulva Mammary Masses Including Neoplasia 463
Table • 4-3
Grading scheme for mammary carcinomas
Characteristic Feature Points
Mammary sarcomas
Mammary sarcomas represent about 5% of mammary tumors.
These are located within mammary tissue and are separate
from those that arise in the skin and subcutis. They are identi-
cal to their soft tissue counterparts in their appearance and
histologic criteria (see Neoplasms of skin and soft tissue). The
most well-known is the mammary osteosarcoma (Fig. 4-141),
a unique type of soft tissue osteosarcoma that has an especially
poor prognosis and a very short survival time. The overall
prognosis for mammary sarcoma is very poor, and the 6-, 12-, Figure 4-141 Mammary osteosarcomas in dogs are highly meta-
and 24-month survival is 50, 30 and 10%, respectively. static and have a very short survival time after diagnosis.
Further reading
Dalton LW, et al. Histologic grading of breast cancer: linkage of patient
outcome with level of pathologist agreement. Mod Pathol
2000;13:730-735.
Goldschmidt M, et al. Classification and grading of canine mammary
tumors. Vet Pathol 2011;48:117-131.
Hughes K, Dobson JM. Prognostic histopathological and molecular
markers in feline mammary neoplasia. Vet J 2012;194:19-26.
Im KS, et al. Analysis of a new histological and molecular-based clas-
sification of canine mammary neoplasia. Vet Pathol 2013;51:549-
559.
Morris J. Mammary tumours in the cat: size matters, so early interven-
tion saves lives. J Feline Med Surg 2013;15:391-400.
Peña L, et al. Prognostic value of histological grading in noninflamma-
tory canine mammary carcinomas in a prospective study with two-
year follow-up; relationship with clinical and histological
Figure 4-143 Photomicrograph of tubule formation in a feline
characteristics. Vet Pathol 2013;50:94-105.
mammary carcinoma.
Rasotto R, et al. A retrospective study of those histopathologic param-
eters predictive of invasion of the lymphatic system by canine
prognosis, and a survival time of 6 months is anticipated. mammary carcinomas. Vet Pathol 2012;49:330-340.
Those with a tumor diameter of <2 cm have a median survival
of >3 years, and those between 2 and 3 cm, 2 years. Mammary
carcinomas treated with complete mastectomy appear to have For more information, please visit the companion site:
a longer survival compared to lumpectomy. Clinical stage as PathologyofDomesticAnimals.com
464.e1
Further reading
Bostock DE. The prognosis following the surgical excision of canine
mammary neoplasms. Eur J Cancer 1975;11:389-396.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. The
value of histologic grade in breast cancer: experience from a large
study with long term follow-up. Histopathology 1991;19:403-410.
Giménez F, et al. Early detection, aggressive therapy: optimizing the
management of feline mammary masses. J Feline Med Surg
2010;12:214-224.
Hellmén E, et al. Prognostic factors in canine mammary tumors: a
multivariate study of 202 consecutive cases. Vet Pathol 1993;30:
20-27.
Kristiansen VM, et al. Effect of ovariohysterectomy at the time of tumor
removal in dogs with benign mammary tumors and hyperplastic
lesions: a randomized controlled clinical trial. J Vet Intern Med
2013;27:935-942.
Loretti AP, et al. Clinical, pathological and immunohistochemical study
of feline mammary fibroepithelial hyperplasia following a single
injection of depot medroxyprogesterone acetate. J Feline Med Surg
2005;7:43-52.
Matos AJ, et al. Prognostic studies of canine and feline mammary
tumours: the need for standardized procedures. Vet J 2012;193:
24-31.
Ordás J, et al. Immunohistochemical expression of progesterone recep-
tors, growth hormone and insulin growth factor-I in feline fibroad-
enomatous change. Res Vet Sci 2004;76:227-233.
Overley B, et al. Association between ovarihysterectomy and feline
mammary carcinoma. J Vet Intern Med 2005;19:560-563.
Sleeckx N, et al. Canine mammary tumours, an overview. Reprod
Domest Anim 2011;46:1112-1131.
Valarmathi MT, Biechler SV. Feline mammary neoplasms: the cancer
stem cell hypothesis. Vet J 2013;196:277-278.
CHAP TER 5
Male Genital System
Robert A. Foster
GENERAL CONSIDERATIONS 465 Mixed germ cell−sex cord stromal tumor 496
Sampling of the male genital tract 465 Other primary tumors 496
Spermatogenesis 466 Miscellaneous diseases of the testis and epididymis 497
Oxidative stress and testicular function 467 SPERMATIC CORD 497
Testicular immune function 467 Varicocele 497
Immunity in the reproductive tract 468 Other vascular lesions 498
DISORDERS OF SEXUAL DEVELOPMENT 468 Scrotal hernia 498
SCROTUM 471 Miscellaneous diseases of the spermatic cord 498
VAGINAL TUNICS 473 ACCESSORY GENITAL GLANDS 499
TESTIS AND EPIDIDYMIS 474 Vesicular glands and ampullae 499
Disorders of sexual development 476 Disorders of sexual development 499
Cryptorchidism 476 Inflammation of the vesicular glands 499
Testicular hypoplasia 478 Prostate and bulbourethral glands 500
Other testicular disorders of development 479 Disorders of sexual development 500
Disorders of mesonephric and paramesonephric structures 480 Inflammation of the prostate and bulbourethral gland 501
Variation in testicular and epididymal size 481 Hyperplasia and metaplasia of the prostate and
Testicular atrophy and degeneration 481 bulbourethral gland 502
Testicular hypertrophy 485 Neoplasms of the prostate and bulbourethral gland 503
Inflammation of the testis and epididymis 485 Miscellaneous conditions of accessory genital glands 504
Orchitis 485 PENIS AND PREPUCE 505
Epididymitis 487 Inflammation of the penis and prepuce
Circulatory disturbances 491 (phaloposthitis) 506
Neoplasms of the testis and epididymis 492 Neoplasms of the penis and prepuce 508
Sex cord−gonadal stromal tumors 492
Germ cell tumors 495
465
466 CHAPTER 5 • Male Genital System General Considerations
of the testis of each species to autolysis and handling pressure. and the germinal cells—spermatogonia, spermatocytes, sper-
It is also important to know the orientation of the testicular matids, and spermatozoa.
mediastinum, efferent ductules, and the seminiferous tubules. Sertoli cells are very complex in their structure and func-
The type and number of samples collected will also depend tion. The majority of Sertoli cells are present at birth or soon
on the suspected diseases. after. They extend from the basement membrane to the
One of the simplest evaluations is for testicular neo lumen, and have a large surface area. Attachment between
plasia. Standard formalin-fixed paraffin-embedded samples adjacent Sertoli cells and to germinal cells is by a variety of
of testicular tumors are sufficient for diagnosis. Evaluation junctional complexes, and this forms a major part of the
of the stages of spermatogenesis requires much more blood-testis barrier. Sertoli cells function to maintain the
sophistication. integrity of the germinal cells, compartmentalize the germinal
The first step in evaluating spermatogenesis is to determine cells into basal and luminal compartments, secrete fluid,
how sensitive the testis is to handling pressure and autolysis. form the tubular lumen, phagocytose degenerating and dead
It is best to fix testicular tissues within minutes of anesthesia cells, deliver nutrients to germinal cells, metabolize steroids,
or euthanasia and removal. The testes of rams, for example, translocate germinal cells, secrete proteins, regulate the sper-
require immediate fixation, whereas bovine testes can remain matogenic cycle, and mediate hormonal effects on the germi-
refrigerated for several hours. The testes of some species are nal cells. These many functions are potential targets for
susceptible to the effects of handling and the pressure applied abnormalities.
while tissue slices are made. It is best to always use sharp Spermatogenesis begins with stem cells that proliferate by
instruments and to minimize pressure on the testicular paren- mitosis, undergo a meiotic phase, and finally differentiate.
chyma during sampling. These stages correspond to spermatogonia, spermatocytes, and
Fixation of the testis will depend on the end use. Formalin spermatids, respectively. The spermatogonia are divided into
fixation is adequate for cursory evaluation of spermatogenesis proliferative and differentiating types of stem cells. They
for all species. Detailed evaluation requires the tissue to be divide by mitosis to produce the cells that go on to form
fixed more rapidly and or rendered harder to withstand spermatozoa. Meiotic division has a prolonged prophase, but
histologic section production. Bouin’s solution is a mainstay subsequent phases proceed rapidly. The spermatids are formed
for many laboratories. It is readily available. Davidson’s as a final, differentiating step. Spermiation is the active release
fluid is now being used by many laboratories. Embedding of spermatozoa by Sertoli cells to the lumen, for subsequent
in plastics or acrylics is superior to paraffin but is much transport through the duct system.
more expensive and requires specialized equipment and Spermatogonia are exposed to testicular interstitial tissue
training. fluids. Occluding junctions of Sertoli cells mostly form the
Testicular diseases affect different parts of the testis and blood-testis barrier. Spermatocytes and spermatids within the
different parts of each seminiferous tubule. The number and tubule are “external” to the blood-testis barrier. Apoptosis of
location of sections depends on the unique characteristics of germ cells at each stage of development occurs as a natural
the species at hand and the types of suspected diseases. Mac- phenomenon (see later), and Sertoli cells take up degenerative
roscopic evaluation of the testis usually directs location and and dead cells.
size of appropriate histologic samples. For example, rams often Control of spermatogenesis involves a complex interaction
develop degeneration dorsally and bulls ventrally. Small rumi- of central endocrine and local paracrine-autocrine factors.
nants often develop initial degenerative lesions of the seminif- Central factors involve the hypothalamic-pituitary-gonadal
erous tubules near the testicular mediastinum. axis. Gonadotropin-releasing hormone (GnRH) from the
The evaluation of testicular histology will also vary with hypothalamus stimulates release of luteinizing hormone (LH)
the orientation of the seminiferous tubules. In general, the and follicle-stimulating hormone (FSH) from the pituitary.
seminiferous tubules are oriented perpendicular to the tes- Interstitial endocrine cells have LH receptors that, when
ticular mediastinum. A sample taken from the mediastinum coupled with LH, produce testosterone. Testosterone is essen-
to the testicular capsule will provide multiple cross sections tial for spermatogenesis and several other testicular functions;
of a small number of seminiferous tubules. A sample taken Sertoli cells, germinal cells, and myoid cells have androgen
parallel to the mediastinum will sample a limited portion of receptors, but the contribution of testosterone for the function
many more seminiferous tubules. Routine sampling requires of germinal cells and myoid cells is not known. Testosterone
sagittal sectioning of the testis, multiple transverse sections is known to inhibit apoptosis of germ cells. FSH directly
(bread-loafing), and fixation of testicular tissue so that histol- stimulates the Sertoli cells and perhaps the germinal cells. FSH
ogy can be examined from an appropriate region of normal and testosterone probably act synergistically. FSH action on
and abnormal testis both along and across the path of the Sertoli cells results in release of the hormones estrogen,
seminiferous tubules. inhibin, and activin. Estrogen is important in the function of
other cells and spermatogenesis. Inhibin and activin are
Spermatogenesis members of the transforming growth factor (TGF) superfam-
Spermatogenesis is a complex process involving stem cells, ily. Inhibin enters the blood stream and inhibits FSH produc-
gene expression, cellular interactions, apoptosis, and cytokine tion, whereas activin stimulates FSH production. Both also
and other hormonal interactions. It is clear that testicular have local effects and are part of the paracrine-autocrine
function in general, and spermatogenesis in particular, system. Sertoli cells also produce anti-Müllerian hormone
requires a complex interaction of all cells within the testis and (AMH, previously known as Müllerian inhibitory substance
not just germ cells, Sertoli cells, and interstitial endocrine [MIS]) during development but usually not in adults.
(Leydig) cells. Local control of spermatogenesis is also highly dependent on
The testis is divided into the tubular and extratubular com- local paracrine and autocrine factors; the number of factors
partments. The cells within the tubules are the Sertoli cells recognized is increasing exponentially. The extensive crosstalk
General Considerations 467
between all cell types is essential for spermatogenesis and for Hochereau-de Reiers MT, et al. Spermatogenesis and Sertoli cell
controlling inflammation and the altered immunocompetent numbers and function in rams and bulls. J Reprod Fertil Suppl
state of the testis. Germinal cells, Sertoli cells, peritubular 1987;34:101-114.
myoid cells, and interstitial endocrine cells secrete many cyto- Jan SZ, et al. Molecular control of rodent spermatogenesis. Biochim
kines and growth factors. These cells are influenced, in turn, Biophys Acta 2012;1822:1838-1850.
by a large number of similar signaling molecules. Also impor- Lowseth LA, et al. Age-related changes in the prostate and testes of
tant in spermatogenesis is the presence of death receptors on the beagle dog. Vet Pathol 1990;27:347-353.
germ cells, in particular, Fas (APO-1, CD95), a transmem- Mayerhofer A. Human testicular peritubular cells: more than meets the
brane receptor molecule that transmits an apoptotic signal in eye. Reproduction 2013;145:R107-R116.
the cell when it is bound by a Fas ligand. Sertoli cells express Roser JF. Regulation of testicular function in the stallion: an intricate
Fas ligand, and regulators of apoptosis are found in the testis, network of endocrine, paracrine and autocrine systems. Anim
including the Bcl-2 family of proteins and the p53 protein. Reprod Sci 2008;107:179-196.
Apoptosis is a normal phenomenon regulating cell popula- Russell LD, et al. In: Histological and Histopathological Evaluation of
tions, but induction of apoptosis or increased apoptosis also the Testis. Clearwater FL: Cache River Press; 1990. p. 286.
occurs with exposure to toxic compounds, depletion of growth Turner RM, et al. The emerging pathophysiology of age-related testicu-
factors, alteration of hormonal support, exposure to heat lar degeneration with a focus on the stallion and an update on
or radiation, transient ischemia, free radical status, or treat- potential therapies. Reprod Dom Anim 2012;47:178-186.
ment with drugs. Testes with impaired spermatogenesis, such
as hypospermatogenesis or maturation arrest, may have
increased apoptosis. There are also antiapoptotic proteins and Oxidative stress and testicular function
substances produced in the testis that counterbalance apop- Antioxidative systems are important factors in normal testicu-
totic pathways. lar and epididymal function and, by extension, diseases of the
There are well-recognized changes in spermatogenesis testis. The high rates of cell division cause high rates of oxygen
with age. There is a dramatic increase in testicular size at consumption in a low oxygen tension environment. This is
the time of puberty. The seminiferous tubules increase in combined with large amounts of unsaturated fatty acids and
length and diameter, and the testicular volume increases. The the presence of systems to generate reactive oxygen species
size of the testis then decreases progressively from puberty such as xanthine and NADPH-oxidases and cytochrome
into adult life. From early adulthood onward, there is a gradual P450. The intratubular compartment is particularly vulnera-
reduction in tubular diameter. The absolute number of Sertoli ble to oxidative stress and free radical damage.
cells probably declines from puberty on. A decline in the The protective systems include antioxidant enzymes and
number of spermatocytes and an increase in apoptosis both free radical scavengers, such as intracellular superoxide dis-
contribute to reduced testicular mass to various degrees in mutase, glutathione peroxidase, and glutathione-S-transferase.
different species. A concurrent increase in the mass of the The balance between production and removal is of major
testicular interstitial tissue typically occurs with age, and importance in spermatogenesis.
the basal lamina of the seminiferous tubule increases in
thickness.
Domestic mammals usually have continuous spermatogen- Further reading
esis from puberty until death; however, there is species varia- Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the
tion in the percentage of seminiferous tubules with active testes. Adv Exp Med Biol 2008;636:154-171.
spermatogenesis. Spermatogenesis is normally divided into Koziorowska-Gilun M, et al. Antioxidant enzyme activity and mRNA
stages, and a single cross-section of a seminiferous tubule expression in reproductive tract of adult male European bison (Bison
has a single stage. An adjoining length of the same seminifer- bonasus, Linnaeus 1758). Reprod Dom Anim 2013;48:7-18.
ous tubule will have a different stage, but not necessarily the
next stage. A complete series of stages over time becomes
the cycle of the seminiferous epithelium. Not all seminiferous Testicular immune function
tubules have complete stages of spermatogenesis at any Testicular parenchyma is a unique immunologic environment.
one time, and every species has what is termed normal back- Both innate and acquired immune function is actively sup-
ground change that mimics changes seen at puberty or result- pressed. This environment is maintained by testosterone and
ing from a degenerative event. This is particularly the case its influence on peritubular myoid cells, endothelial cells of
in boars. capillaries, veins and lymphatic vessels, and testicular macro-
phages. This environment is maintained partially because sper-
matocytes, spermatids, and spermatozoa are antigenic, and
Further reading outside the blood-testis barrier. Any condition that causes
Alves MG, et al. Hormonal control of Sertoli cell metabolism regulates leakage of spermatozoa or spermatozoal antigens into the extra-
spermatogenesis. Cell Mol Life Sci 2013;70:777-793. tubular compartment is potentially complicated by inflammatory
Elcock LH, Schoning P. Age-related changes in the cat testis and epi- and immunologic responses. The response to spermatozoa is
didymis. Amer J Vet Res 1984;45:2380-2384. variable, but innate or nonspecific immunity and acquired
Fukuda T, et al. Age related changes in the testes of horses. Equine mechanisms including humoral and cellular defences are
Vet J 2011;33:20-25. involved. This also occurs in the tubules and ducts of the
Giampietri C, et al. Germ cell apoptosis control during spermatogen- reproductive tract, including the epididymis.
esis. Contraception 2013;72:298-302. Spermatozoa incite a foreign body/granulomatous response,
Guazzone VA, et al. Cytokines and chemokines in testicular inflamma- and degradation is slow because of their number and composi-
tion: a brief review. Microscopy Res Techn 2009;72:620-628. tion of fatty acids, lipids, phospholipids, and keratin molecules.
467.e1
Further reading
Carreau R, et al. Oestrogens and spermatogenesis. Phil Trans R Soc
2010;365:1517-1535.
Erkkila K, et al. Testosterone regulates apoptosis in adult human
seminiferous tubules in vitro. J Clin Endocrinol Metab 1997;82:
2314-2321.
Head JR, Billingham RE. Immune privilege in the testis: evaluation of
local factors. Transplantation 1985;40:269-275.
Heindel JJ, Treinen KA. Physiology of the male reproductive system:
endocrine, paracrine and autocrine regulation. Toxicol Pathol
1989;17:441-445.
Hermann M, et al. Aging of the male reproductive system. Exp Geron-
tol 2000;35:1267-1279.
Holdcraft RW, Braun RE. Hormonal regulation of spermatogenesis. Int
J Androl 2004;27:335-342.
Lee J, et al. The Fas system is a key regulator of germ cell apoptosis in
the testis. Endocrinol 1997;138:2081-2088.
Lin WW, et al. In situ end-labeling of human testicular tissue demon-
strates increased apoptosis in conditions of abnormal spermatogen-
esis. Fertil Steril 1997;68:1065-1069.
Moura AA, Erickson BH. Age-related changes in peripheral hormone
concentrations and their relationships with testis size and number
of Sertoli and germ cells in yearling beef bulls. J Reprod Fertil
1997;110:183-190.
Nipken C, Wrobel KH. A quantitative morphological study of age
related changes in the donkey testis in the period between puberty
and senium. Andrologia 1997;29:149-161.
Richburg RH. The relevance of spontaneous- and chemically-induced
alterations in testicular germ cell apoptosis to toxicology. Toxicol
Lett 2000;112-113:79-86.
467.e2
Further reading
Koziorowska-Gilun M, et al. Antioxidant defence system of boar cauda
epididymidal spermatozoa and reproductive tract fluids. Reprod
Dom Anim 2011;46:37-47.
Turner TT, et al. Oxidative stress: a common factor in testicular dysfunc-
tion. J Androl 2008;29:488-494.
468 CHAPTER 5 • Male Genital System Disorders of Sexual Development
In addition, immune responses are florid and many plasma result in a breakdown of the blood-testis barrier and subse-
cells and CD4 and CD8 lymphocytes are present. Up-regulation quent immune reactions. The epididymis and deferent duct
of major histocompatibility complex (MHC) II in epithelial form a single small-diameter tube that is easily obstructed and
cells also occurs. The reaction leads to chronic inflammation damaged, and it is free from the usual systemic immune sur-
and fibrosis, and continued obstruction and disruption of veillance. There is always the specter of inflammation and
tubules. Spermiostasis, spermatocele, and/or further sperm acquired immunity to spermatozoal or secretory products.
granulomas are the consequence. Normally, little immunoglobulin enters the seminal fluids,
Antispermatozoal antibodies are found in serum, genital and with a few exceptions, lymphocytes are rare in the inter-
secretions, or both. They occur in infertile individuals in stitium of reproductive structures in normal male animals.
several species, including humans. There is a lack of informa- Those entering the testis are actively destroyed.
tion on their presence in genital fluids, where they have the Epithelium throughout the reproductive ducts and duct-
greatest impact. Spermatozoal antigens gain entry to the inter- ules can express MHC II molecules if inflammation is present.
stitium as a result of trauma, rupture of a duct or tubule, or The various ducts of the male reproductive tract contain
leakage from either failure of the barrier between tissue and intraepithelial leukocytes, especially CD8 lymphocytes. The
spermatozoa following inflammation or obstruction. Specific accessory genital glands are believed to be the main location
conditions include blind-ended efferent ductules (spermatic for plasma cells, which presumably add immunoglobulins to
granuloma of the epididymal head or efferent ductules), seg- the seminal fluid to help prevent access of ascending agents
mental aplasia of the mesonephric ducts, adenomyosis, and to the deferent duct and epididymis. Local humoral immunity
epididymitis. Infection of dogs with Brucella canis can cause develops in the accessory genital glands, and is predominantly
the formation of antispermatozoal antibody, and it occurs in IgA-based in several species.
vasectomy and other causes of obstruction of ducts. One of the unfortunate side effects of having spermatozoa
Serum immunoglobulin may gain access to the spermato- not recognized as “self” is the necessity of maintaining these
zoa through any part of the reproductive tract, but the effer- cells completely separate from immune surveillance. This pro-
ent ductules and epididymis are probably the most accessible vides microbial organisms a location within the lumen of
sites, because the barrier between the internal and external ducts and tubules where they can grow and cause damage.
compartments is less tight. Local immunoglobulin production Once the body recognizes the injury and recruits inflamma-
can occur at any location in the tract, but the accessory genital tory cells, there often is too much damage to permit repair or
glands are the most common site (see later). regeneration. In addition, the very processes of inflammation,
including the release of free radicals by leukocytes, damage
the tract further. As in many other sensitive tissues, the damage
Further reading done by inflammation may be a major cause of dysfunction.
Chiu WW, Chamley LW. Clinical associations and mechanisms of action
of antisperm antibodies. Fertil Steril 2004;82:529-535.
Hedger MP. Immunophysiology and pathology of inflammation in the Further reading
testis and epididymis. J Androl 2013;23:625-640. Filippini A, et al. Control and impairment of immune privilege in the
Jessop TS, Ladds PW. The immunopathology of unilateral vasectomy in testis and in semen. Hum Reprod Update 2001;7:444-449.
the ram. Vet Immunol Immunopathol 1995;47:123-133. Foster RA, et al. Immunoglobulins and immunoglobulin containing
cells in the reproductive tract of normal rams. Aust Vet J
1988;65:16-20.
Immunity in the reproductive tract Hedger MP. Toll like receptors and signalling in spermatogenesis and
Innate and acquired immunity occur in the male genital tract. testicular responses to inflammation—a perspective. J Reprod
Both male and female reproductive tracts have a unique Immunol 2011;88:130-141.
ability to co-opt immune cells for normal physiologic func- Saramanavuthu V, et al. T and B lymphocyte subsets in spermatic
tions. There are different populations of cells of a similar granulomas in five rams. Vet Pathol 1991;28:482-491.
type—some that are involved in regulation of spermatogenesis Winnall WR, et al. Phenotypic and functional heterogeneity of the
and others that are proinflammatory. Testicular macrophages/ testicular macrophage population: a new regulatory model.
antigen-presenting cells are present in the normal interstitial J Reprod Immunol 2013;97:147-158.
tissues of all species and their importance is increasingly rec-
ognized. They are involved in the regulation of spermatogen-
esis, steroidogenesis, and immune regulation. Those that reside
DISORDERS OF SEXUAL DEVELOPMENT
in the testis contribute to reduced immune function to form
a tolerant environment maintained by natural killer (NK) and Disorders of sexual development (DSD) include all congenital
regulatory T (Treg) cells. Lymphocytes entering the testis are anomalies of the reproductive tract including those of a major
proinflammatory but must overcome the local environment. or minor nature.
Systemic inflammatory disease affects testicular function by Production of a normal ejaculate depends on the normal
the stimulation of immune and inflammatory pathways. development of the reproductive tract, including normal sper-
Pattern recognition receptors such as toll-like receptors are matogenesis, spermatozoa maturation and transport, normal
important in this. accessory genital gland function, and nervous, musculoskele-
The male genital tract has little ability to compensate for tal, and psychological factors.
direct injury. The testes are bound by the tough and relatively Sexual differentiation requires appropriate sequential gene
inelastic capsule, and any sudden increase in internal pressure expression; production of proteins and other hormones; recep-
or swelling, be it caused by hemorrhage or edema, results in tor expression; and the complex development and regression
testicular necrosis. Injury to the seminiferous tubules can of the paramesonephric (Müllerian) ducts, mesonephric
468.e1
Further reading
George L, Carmichael L. Antisperm responses in male dogs with
chronic Brucella canis infections. Am J Vet Res 1984;45:274-281.
Zhang J, et al. Antisperm antibodies in the semen of a stallion follow-
ing testicular trauma. Equine Vet J 1990;22:138-141.
468.e2
Further reading
Bedford JM. Adaptations of the male reproductive tract and the fate
of spermatozoa following vasectomy in the rabbit, rhesus monkey,
hamster and rat. Biol Reprod 1976;14:118-142.
Foster RA, et al. Pathology of reproductive tracts of merino rams in
north western Queensland. Aust Vet J 1989;66:262-264.
Pollanen P, Maddocks S. Macrophages, lymphocytes and MHC II
antigen in the ram and rat testis. J Reprod Fertil 1988;82:
437-445.
Disorders of Sexual Development 469
(Wolffian) tubules and ducts, and the tissues of the gonadal testicular pattern. The mesonephric tubules form the rete
ridge/primitive bipotent gonads. When all steps occur nor- testis and the efferent ductules. The epididymis, deferent
mally, sex chromosome genotypic, gonadal, and phenotypic ducts, and vesicular glands are derived from the mesonephric
sex is matched. Male domesticated mammals normally have ducts. The prostate and bulbourethral glands form from the
an XY genotype, although XX males can occur if a sex- urogenital sinus, and the penis, prepuce, and scrotal sac
determining factor is present. develop from the urogenital sinus and tubercle when testos-
SF1 is a gene activated at the beginning of the sex deter- terone is present.
mination period in both males and females, but it reduces in The male phenotype depends on the production by the
amount dramatically at the end of the sex determination Sertoli cells of AMH, which causes the paramesonephric
period in males. It is also involved in the development of (Müllerian) duct to regress. Interstitial endocrine cells produce
adrenal and hypothalamic-pituitary axis. In normal XY males, testosterone and INSL3 that inhibits further female differen-
SRY, the gene that is the sex-determining region of the Y tiation, prevents the mesonephric ducts from regressing, and
chromosome, encodes a transcription factor that contains a induces development of the prostate, bulbourethral glands,
high mobility group (HMG)-box DNA binding domain. This penis, and scrotum.
binds to specific DNA sequences, causes bending of the DNA The testis, epididymis, and associated structures descend
and results in Sertoli cell differentiation. WT1+KTS, GATA4 from the urogenital ridge into the scrotum. Testicular and
and FOG2 are part of the transcriptional or post-transcriptional epididymal descent occurs in 3 main stages: the relative trans-
regulation of SRY. SRY, the product of SRY, regulates tran- abdominal migration phase, the intra-inguinal phase, and extra-
scription by binding to promoter sites of SRY-like HMG-box inguinal migration. Testosterone is not necessary for testicular
protein 9 (SOX9). SOX9 also has 2 transcriptional activation descent but it does assist in the growth of the vaginal process
domains that act on the testis determining pathway. M33 and gubernaculum. The first phase may be partially controlled
(Cbx2) and ATRX are involved in gonadal development. SRY, by AMH, the second phase requires increased intra-abdominal
M33, and ATRX either activate testis-determining genes or pressure, and the third involves interaction of androgen, cal-
inhibit pro-ovarian genes. citonin gene-related protein, the genitofemoral nerve, and
SRY is very important in Sertoli cell development, and perhaps other factors. In early fetal life, a cranial gonadal
testes do not develop unless there are sufficient Sertoli cells. suspensory ligament supports the testis. It may be retained
Formation of Sertoli cells is influenced by many genes and when there is a lack of androgens, in which case subsequent
products, including SF1 and AMH, the gene that produces development of the testicular gubernaculum also is impaired.
anti-Müllerian hormone (AMH). Activation of AMH, which The testicular gubernaculum is a gelatinous cord of tissue that
causes regression of the paramesonephric ducts, marks the end extends from the caudal pole of the testis to the inguinal area
of the sex determination period in males. DAX1 is a gene that and it exerts traction on the testis. A mutation in the GREAT
appears to act downstream of SRY and is important in early gene, which is highly expressed in the gubernaculum and may
Sertoli cell differentiation. DAX1 inhibits the male sex deter- mediate response to hormones, has been associated with intra-
mining pathway, and if DAX1 is activated in males, a female abdominal cryptorchidism in humans and, experimentally, in
develops. mice. The exact mechanisms are yet to be elucidated in
As part of testicular development, endothelial cells migrate domestic mammals, but they no doubt are complex and
from the mesonephros to the testis. The formation of this involve an interrelationship of systemic and local factors.
extra vasculature is important in testis development, espe- The effects of endocrine disruptors on male development
cially sex cord formation. At this time, the formation and are increasingly important, because multiple disorders of
function of the interstitial endocrine (Leydig) cells is acquired. sexual development, such as reduced anal-genital distance,
Thus the formation of the Sertoli cells, interstitial endocrine delayed preputial separation, hypospadias, and ectopic and
cells and vasculature combined is necessary for testis develop- maldescended testes, can all be induced by antiandrogenic and
ment. Interstitial endocrine cells develop from the same cell estrogenic chemicals (the endocrine disruptors).
population as the adrenal cortex, that is, from vascular smooth Disorders of sexual development (DSD) are now divided
muscle cells and pericytes of testicular capillaries—vascular into 3 general categories: sex chromosome DSD, disorders
cell types that act as stem cells. SF1, desert hedgehog gene with an XX genotype (XX DSD), and XY DSD. XX and XY
(DHH), and PDGFA are involved with this. Also ARX (the DSDs are divided into groups based on whether the gonads
homeobox gene aristaless-related) has a function. are normal or not. Many DSD result in a female or feminine
During early embryonic development, primordial germ phenotype and are considered in more detail in Vol. 3, Female
cells (PGC) migrate to the gonads and there are many genital system. Those mentioned here are mostly DSD with
genes and gene products that can be detected. They are not a male genotype, gonads, or genitalia.
necessary for testicular development. Testicular cord develop- • Sex chromosome DSD are those with an altered sex chromo-
ment results in the blocking of PGC proliferation in the some complement such as the classic XXY (Klinefelter
G0/G1 phase of mitosis and they differentiate into syndrome). These are manifested clinically as ambiguity in
prospermatogonia. phenotype and/or infertility. Animals with XXY chromo-
The constituents of the primitive gonad are the germ cells, somes or a mosaicism with XXY chromosomes may have
mesenchymal cells, coelomic epithelial cells, and mesonephric hypoplastic internal genitalia. Well known of these are
epithelial cells. These form the 4 major cell types in the male tortoiseshell or calico cats. They are almost always
gonad—the germ cells, supporting cells, steroid-producing infertile, and have testicular hypoplasia. Hybrids of the
cells, and unspecialized mesenchyme. SRY causes the germ horse and donkey (with 64 and 62 chromosomes, respec-
cells to go into mitotic arrest, the supporting cells become the tively), the mule and hinny, have 63 chromosomes and are
Sertoli cells, the steroid-producing cells become the interstitial sterile. The classic sex chromosome DSD in animals is the
endocrine cells (of Leydig), and the mesenchyme develops the freemartin (Fig. 5-1).
470 CHAPTER 5 • Male Genital System Disorders of Sexual Development
SCROTUM
The scrotum is an outpouching of perineal skin with an inner
lining of peritoneum and direct communication with the peri-
toneal cavity. Many terrestrial mammals have their testes
within a scrotum, but the reason is the subject of theories. In
these species the intrascrotal temperature is less than core
temperature. Most assume the testis must be lower in tem-
perature but the epididymis also may operate better when
cooler. The maturation of spermatozoa is a slow process and
the epididymis is one long and coiled tube. The testicular
artery is long and coiled, and changes the blood flow from
pulsatile and high pressure to a constant low-pressure system.
This makes the oxygen tension in the testis lower than
Figure 5-6 Miniature Schnauzer dog with an XY disorder of expected, and the oxidant-antioxidant balance is less robust.
sexual development commonly called persistent Müllerian duct The blood supply to the epididymis is separate and shorter.
syndrome. This dog was phenotypically male with retained testes The scrotum maintains the testis and epididymis at a tem-
(sectioned) and well-developed uterine horns and body. perature less than core. The scrotal skin is thinner than skin
elsewhere and has little or no subcutaneous fat or connective
tissue. It is lightly haired, except in the cat, and has prominent
apocrine sweat glands. The contractility of the scrotum is a
testicular DSD, with female phenotype). These usually property of the dartos tunic that consists of fibroelastic tissue
lack androgen receptors—they have testes, no tubular geni- and smooth muscle. Thermoregulatory function is shared with
talia, but are phenotypically female. All species develop the cremaster muscle, which regulates the proximity of the
this type of DSD. testis to the abdominal wall, and the pampiniform plexus of
• A well-recognized but less extreme form is found in Min- testicular artery and veins, which ensures maximum contact
iature Schnauzer dogs that are XY, SRY +, testicular DSD of cooled venous blood with the warmer arterial blood. If the
with male phenotype and retention of paramesonephric testes of the common domestic animals are at or above normal
ducts (Fig. 5-6). They lack functional anti-Müllerian body temperature, degeneration of the seminiferous epithe-
hormone (AMH) receptors and have a syndrome called lium occurs. Retained testes do not develop normal spermato-
persistent Müllerian duct syndrome (PMDS). Affected Min- genesis or testicular and epididymal size.
iature Schnauzer dogs may develop hydrometra and pyo- The formation of the scrotum from the paired genital
metra. Many are also cryptorchids. swellings of the embryo, and its full development at puberty,
Gynecomastia is occasionally seen as a solitary lesion in requires testosterone and is dependent on the development of
males. There are reports of bucks from high milk production normal testes. Disorders of scrotal development include absence
lines that develop mammary glands. It also occurs in hyperes- of the scrotum in cryptorchidism. A bifurcated scrotum and
trogenism syndromes. scrotal clefts or notches represent failures of fusion of the
paired primordia. These may be isolated defects, accompanied
by hypospadias (see Fig. 5-2) and other defects such as atresia
Further reading ani, or occur in a variety of disorders of sexual development.
Amann RP, Veeramachaneni DN. Cryptorchidism in common eutherian Enlargement of the scrotum can be the result of lesions of
mammals. Reproduction 2007;133:541-561. the scrotal skin, vaginal tunics and cavity, testis, epididymis,
Breshears MA, et al. Ambiguous genitalia in a fertile, unilaterally pampiniform plexus, inguinal canal, and superficial inguinal
cryptorchid male miniature schnauzer dog. Vet Pathol 2011;48: lymph node. Disease of each of these anatomic regions is
1038-1040. covered later in this chapter.
Buijtels JJCWM, et al. Disorders of sexual development and associated Thickening of the scrotal skin and dartos tunic is mostly
changes in the pituitary-gonadal axis in dogs. Theriogenol due to edema of local or systemic origin, or because of inflam-
2012;78:1618-1626. mation or neoplasia. The skin of the scrotum can be part of
Hughes IA. Disorders of sex development: a new definition and disease of the skin elsewhere. We will concentrate here on
classification. Best Pract Res Clin Endocrinol Metab 2008;22: diseases that primarily affect the scrotum.
119-134. In bulls, scrotal dermatitis is caused by contact with irritant
Hughes IA, et al. Factors controlling testis descent. Eur J Endocrinol substances from the environment, ectoparasites such as biting
2008;159:S75-S82. insects (Simuliidae and Culicoides), lice (Haematopinus eurys-
Meyers-Wallen VN. Gonadal and sex differentiation abnormalities of ternus), and mites (Chorioptes bovis); fungi; protozoa (Besnoi-
dogs and cats. Sex Dev 2012;6:46-60. tia besnoiti, Trypanosoma spp); bacteria (Dermatophilus
471.e1
Further reading
Benirschke K, et al. Somatic chromosomes of the horse, the donkey
and their hybrids, the mule and the hinny. J Reprod Fertil
1962;4:319-326.
Boulanger L, et al. FOXL2 is a female sex-determining gene in the goat.
Curr Biol 2014;24:404-408.
Centerwall WR, Benirschke K. An animal model for the XXY Klinefel-
ter’s syndrome in man: tortoiseshell and calico male cats. Am J Vet
Res 1975;36:1275-1280.
Quilter CR, et al. X/XY/XYY mosaicism as a cause of subfertility in
boars: a single case study. Anim Genet 2003;34:51-54.
Soller M, et al. Cytogenetics of Saanen goats showing abnormal devel-
opment of the reproductive tract associated with the dominant
gene for polledness. Cytogenetics 1969;8:51-67.
472 CHAPTER 5 • Male Genital System Scrotum
congolensis); and viruses (poxviruses) to name a few. These Figure 5-8 Fistulous tract through the scrotum of a ram with
may occur as diffuse or focal lesions. severe epididymitis and periorchitis.
Range bulls and occasionally rams exposed to extreme cold
may develop scrotal frostbite (Fig. 5-7). A higher incidence of
lesions in old bulls is attributed to their more pendulous affects the prepuce and can secondarily affect the scrotum.
scrotums. Lesions are well demarcated regions of necrosis of Parasitic dermatitis occurs in horses—mostly from the second-
skin on the ventral aspect of the scrotum and can involve up ary effects of self-trauma from rubbing. Biting flies, including
to 75% of the scrotum. Scrotal swelling, tunic adhesions, and Culicoides, and Onchocerca microfilariae in the scrotal skin can
decreased semen quality accompany the more severe lesions. lead to dermatitis. Eosinophilic superficial perivascular or
The scrotal skin of bulls is especially susceptible to infection nodular dermatitis will occur; microfilariae will be found in
by Dermatophilus congolensis. Severe, prolonged infection may onchocerciasis. Habronema larvae infect wounds of the
result in thickening of the skin to 1 cm, with advanced tes- scrotum and cause large granulomatous nodules. The most
ticular degeneration and infertility. Infection of scrotal skin by common neoplasm of the skin of the horse is the equine
Besnoitia besnoiti also may lead to severe testicular degenera- sarcoid, and scrotal masses may occur. Melanoma of the
tion. This infection is not limited to skin, and the small nodules perineum involves the scrotum rarely.
containing white gritty material are seen grossly in the subcu- In rams, parasitic dermatitis from Chorioptes bovis is
tis of the scrotum as well as in the tunics, the parenchyma of common and the scrotum appears to be a preferred site for
the testis, and in the epididymis. Vascular damage is important the mite. The lesions can be mild but are frequently suffi-
in the development of lesions, and large numbers of Besnoitia ciently severe to cause testicular atrophy and infertility. In
cysts may be present in the intima of vessels in the pampini- such cases there is marked thickening of skin and matting of
form plexus. Neoplasia is rare in bulls, but papilloma, mela- overlying hair and wool by secretions and exudate. Linogna-
noma, and hemangioma occur. Varicose dilations of scrotal veins thus pedalis, the foot louse of sheep, can also affect the scrotal
occur in older bulls. They appear as flattened and irregular skin. Cutaneous myiasis and dermatophilosis rarely affects the
thickenings of the scrotal skin. The overlying epithelium scrotum. Draining tracts through the scrotal skin from perior-
usually is normal unless it ulcerates and bleeds. The affected chitis and epididymitis may occasionally occur (Fig. 5-8).
venous channels are irregular in shape, widely dilated, and In bucks, sarcoptic mange, with typical crusted lesions and
have thickened walls; thrombosis occurs in many. thickening of the skin, can involve the scrotum.
In boars, hemangiomas are common. They are multiple In dogs, disease of the scrotum is uncommon. Pyoderma,
exophytic and variegated or papillary lesions that may bleed. both superficial and deep, and folliculitis and furunculosis can
They do not appear to affect fertility. Such lesions are benign affect the scrotum. Brucella canis is reported to cause scrotal
and may not be true neoplasms. Age, altered hemodynamic dermatitis and ulcers, but many cases are the result of licking
forces in the capillary bed of the scrotal dermis, and genetic and self-trauma from the pain and discomfort of epididymitis
predisposition are factors that might be involved in their and periorchitis. Ehrlichia spp and Rickettsia rickettsii may
development. Any cutaneous disease of the pig could poten- cause scrotal edema, infarction, and ulceration from vasculitis.
tially affect the scrotum. Fungal infections of the scrotum occur in dermatophytosis
In the stallion, trauma from the kick of a mare occurs and and infection with Microsporum and Trichophyton spp. Mallas-
the local effects include swelling and edema plus ulceration sezia and other yeasts such as Candida species can affect the
and hemorrhage. Abscessation can occur. The scrotum is often scrotum too, and they produce a superficial intraepidermal
affected in dependent edema from systemic and or intestinal pustular and hyperplastic disease. Blastomycosis (Blastomyces
diseases as an extension from preputial edema. Peritonitis, dermatitidis), sporothricosis (Sporothrix schenckii), and proto-
equine viral arteritis, and other vasculitides including purpura thecosis (Prototheca wickerhamii) cause nodular pyogranulo-
hemorrhagica, and surra, caused by Trypanosoma evansi infec- matous dermatitis. Protozoal infections of the scrotum include
tion, are potential causes. Dourine (Trypanosoma equiperdum) leishmaniasis (Leishmania spp) and have the typical lesions of
Vaginal Tunics 473
a plasma cell–rich or pyogranulomatous nodular-to-diffuse also occur in conditions that cause edema of the scrotum (as
dermatitis. Parasitic diseases of the scrotum of dogs include listed previously).
infection with Cuterebra emasculator, which results in a drain- Hematocele is the accumulation of blood in the vaginal
ing tract from an abscess and local necrosis of the tissue. cavity. It is the result of trauma and is seen in stallions with
Sarcoptes scabiei, Demodex species, and Pelodera strongyloides mating injury and in boars housed together.
affect the scrotum, as they do in other locations. Migration of The visceral tunic is an integral part of the testicular
hookworm larvae can also occur through scrotal skin. Of the capsule. It is composed of inelastic collagen and fibrous tissue,
many other cutaneous diseases seen in dogs, contact irritant and smooth muscle through which the vascular tunic is nor-
and hypersensitivity reactions occur, as does atopy, food mally visible. In spite of the presence of smooth muscle, the
hypersensitivity, fixed drug eruptions, and a plethora of capsule is not significantly contractile; it probably contributes
immune-mediated diseases. The scrotum can be affected by to the flow of semen by maintaining intratesticular pressure.
physicochemical injury including burns, sunburn, abrasions The tunic is thickened and opaque in testicular hypoplasia and
and lacerations from fighting and motor vehicle accidents, and atrophy.
frostbite. Neoplasms of the scrotum include any neoplasm of Inflammatory changes in the vaginal tunic may be part of
skin, and if they are common elsewhere in skin, they are likely disseminated infection, with typical lesions of feline infectious
to occur on the scrotum. Examples include mast cell tumors peritonitis, tuberculosis, caseous lymphadenitis, and diseases
and vascular tumors such as hemangiomas and hemangiosar- causing polyserositis in all species. Suppurative and fibrinous
coma. There does not appear to be any increased susceptibility inflammation also occurs as an extension of scrotal injury or
to a particular neoplasm in this area. from epididymitis. Inflammation of the tunics is often called
In both cats and camelids, bite wounds from other males periorchitis.
occur in the scrotum. Other primary spontaneous scrotal Severe periorchitis is a complication of epididymitis irrespec-
disease is rare. tive of cause, but is particularly found in bulls with Trypano-
soma brucei infection, in rams infected with Brucella ovis or
Actinobacillus seminis (Fig. 5-9), and dogs with Escherichia coli
Further reading epididymitis (Fig. 5-10). Setaria labiatopapillosa causes granu-
Cerundolo R, et al. Review of cutaneous lesions of the canine scrotum. lomatous periorchitis in bulls, and lesions occur particularly
Vet Dermatol 2002;13:63-76. after adults are killed by anthelmintic treatment. A high prev-
Foster RA. Common lesions in the male reproductive tract of cats and alence of eosinophilic, then granulomatous, periorchitis in
dogs. Vet Clin North Am Small Anim Pract 2012;42;527-545. water buffaloes is attributed to Setaria sp. Ectopic parasites,
Nikolopoulos W, et al. Scrotal cooling and its benefits to male fertility: such as migrating equine strongyle larvae (Strongylus edenta-
a systematic review. J Obstet Gynaecol 2013;33:338-342. tus), can be found on the tunics. Periorchitis in rams is very
Raj K, et al. Congenital hypospadia associated with atresia ani et recti common in infectious epididymitis. Pyocele or hemipyocele is
and rectovesical fistula in a kid. J Vet Sci Anim Sci 1994;25:172. reported rarely as a spontaneous condition and is reported in
Smith KC, et al. A survey of congenital reproductive abnormalities the ram with Staphylococcus capitis infection. Cysts of taenid
in rams in abattoirs in south west England. Reprod Dom Anim larvae, mostly Cysticercus tenuicollis, may be found in the
2012;47:740-745. scrotal cavity of rams, without inflammation. In dogs, rare
Teankum K, et al. Capillary haemangiomas of the scrotum and testicle
in boars. J Comp Pathol 2008;139;177-186.
VAGINAL TUNICS
The vaginal tunic is a membrane of dense fibrous tissue over-
laid with a single mesothelial layer continuous with and struc-
turally similar to the peritoneum. The scrotum and intrascrotal
contents are covered by the parietal and visceral layers, which
form the boundaries of the cavity of the vaginal tunic.
The cavity of the vaginal tunics communicates with the
peritoneal cavity and is susceptible to the accumulation of
ascitic fluid. Fluid within the cavity around the scrotal con-
tents is called hydrocele. It forms for exactly the same reasons
as ascites. Hydrocele may lead to severe testicular degenera-
tion on the involved side and to a lesser extent on the opposite
side. Scrotal hydrocele, with diminished sperm quality, is a
herd problem in bulls in some regions. Clinically, the fluctuant
nature of the enlarged scrotum, with a scrotal circumference
up to 60 cm, is indicative of edema, and if affected bulls are
examined at autopsy, there is obvious ascites. If hydrocele
persists, the tunics become increasingly fibrotic. Ostertagiasis
and hemotropic mycoplasma (Mycoplasma wenyonii) infec-
tion are incriminated as causes of this syndrome. Hydrocele
in other species occurs with ascites of heart failure or any Figure 5-9 Periorchitis secondary to epididymitis in a ram. Fibrin
other cause of fluid buildup in the peritoneal cavity. It can and edema fluid are present within the cavity of the vaginal tunics.
473.e1
Further reading
Althouse GC, et al. Episodic scrotal mutilation with concurrent bilateral
sperm granuloma in a dog. J Am Vet Med Assoc 1993;202:
776-777.
Blanchard TL, et al. Identifying, treating, and preventing scrotal skin
disorders of large animals. Vet Med 1990;290-294.
Kambarge DM. Sarcoptic mange infestation in goats. Bull Anim Hlth
Prod Africa 1992;40:239-244.
Rhodes AP. The effect of extensive chorioptic mange of the scrotum
on reproductive function of the ram. Aust Vet J 1976;52:
250-257.
Schoeb TR, et al. Scrotal and testicular changes in canine brucellosis:
a case report. J Am Vet Med Assoc 1978;172:598-599.
474 CHAPTER 5 • Male Genital System Testis and Epididymis
Further reading
Figure 5-10 Severe epididymitis and periorchitis in a dog. The Abbitt B, et al. Scrotal hydrocele secondary to ascites in 28 bulls. J Am
tail of the epididymis is large and edematous, and there is fibrin Vet Med Assoc 1995;207:753-756.
and exudate in the cavity of the vaginal tunic. The testis is necrotic. Brookins MD, et al. Massive visceral pentastomiasis caused by
The ventral scrotum was ulcerated from self-trauma. Porocephalus crotali in a dog. Vet Pathol 2009;46:460-463.
Hagos A, et al. Serological and parasitological survey of dourine in
the arsi-bale highlands of Ethiopia. Trop Anim Health Prod
2010;42:769-776.
peritoneal cestodiasis caused by larvae of Mesocestoides spp. Lacasta D, et al. Unilateral scrotal pyocele in ram caused by Staphylo-
may involve the vaginal tunics, with saccular dilations within coccus capitis. Aust Vet J 2009;87:484-486.
the tunics, thickening of the spermatic cord, and pyogranulo- Vascellari M, et al. Malignant mesothelioma of the vaginal tunic testis
matous inflammation involving the testicular capsule and in a dog: histological and immunohistochemical characterization. J
extending into the testes. There is also a report of pentastome Vet Diagn Invest 2011;23:135-139
larvae of Porocephalus crotali within the testicular capsule of Welles EG, et al. Eperythrozoon infection in young bulls with
a dog. scrotal and hindlimb edema, a herd outbreak. Theriogenol
Adhesions between the visceral and parietal layers of the 1995;43:557-567.
vaginal tunic are common, especially in older animals. Adhe-
sions are at first fibrinous, reflecting acute periorchitis (see Fig.
5-9), but later become fibrous. Fine, thread-like, fibrous adhe-
TESTIS AND EPIDIDYMIS
sions located at the epididymal tail in bulls are normal. Exten-
sive adhesions result from infectious periorchitis secondary to Spermatozoa develop in the seminiferous tubules and pass
epididymitis. Most adhesions are focal and solitary, and do not through the straight tubules into the intratesticular rete within
have lesions in the testis or epididymis; they probably are of the mediastinum testis. They leave the testis via the rete testis
little consequence. and enter the efferent ductules. The efferent ductules number
Cystic lesions of the vaginal tunic may be loculations between 13 and 20, depending on the species. Most join the
within adhesions. Very small cysts, probably of paramesoneph- single duct of the epididymis, but it is common in most species
ric duct origin, are common adjacent to the head of the epi- for one or more to end blindly. The epididymis is long and
didymis in the horse, and are referred to as appendix testis tortuous, and divided into many distinct areas. For this discus-
or Morgagni’s hydatid. In rams they are called inclusion cysts sion, 3 main areas will be referred to: the head, body, and tail.
(see Fig 5-5). The tail terminates in the deferent duct. Disease of one area
Neoplastic disease involving the vaginal tunic is rare, even has effects on other regions.
as secondary extension from the testis or scrotum. Mesothelio- Pathologists often examine the testes or biopsies of indi-
mas with primary involvement of the vaginal tunic occur in vidual animals rather than whole groups of animals. Gross and
the dog and bull (Fig. 5-11). Extension of the tumor into the histologic assessment of reproductive tissues is a valuable tool
peritoneal cavity has been observed in the dog. Ultrastructural if used appropriately. Complete definition of a clinical problem
study or immunohistochemistry is necessary to differentiate often requires collaboration of the cytogeneticist, endocri-
mesotheliomas from metastatic adenocarcinoma. The origin nologist, theriogenologist, and pathologist, who alone may not
of intrascrotal mesothelioma from the paramesonephric duct be able to determine the complete pathogenesis. For the
remnant is suggested. There is a report of a lipoma occupying pathologist to function optimally, appropriate samples must
the right scrotal cavity in a ram, causing compression of, but be collected and processed. For many of the diseases and the
apparently not directly involving, the testis. tissues, routine fixation with 10% formalin is adequate, but for
474.e1
Further reading
Cihak RW, et al. Malignant mesothelioma of the vaginal tunic in a dog.
Vet Pathol 1986;96:460-461.
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Ladds PW, Crane CK. Scrotal mesothelioma in a bull. Aust Vet J
1976;52:534-535.
Shore MD, et al. Outcome of scrotal hydrocele in 26 bulls. J Am Vet
Med Assoc 1995;207:757-760.
Zeman DH, et al. Scrotal cestodiasis in a dog. Cornell Vet
1988;78:273-279.
Testis and Epididymis 475
a detailed assessment of spermatogenesis, or the histologic loop that begins and ends at the mediastinum, and turns
appearance of seminiferous tubules, rapid fixation after death completely at the testicular capsule. In ruminants, the testes
or collection (within minutes in many species) in Bouin’s, are oriented in a dorsoventral plane, the stallion has a more
Zenker’s, or Davidson’s fluid, with paraffin embedding, is nec- craniocaudal orientation, the dog is oblique, and the boar and
essary. Plastic embedding is the method of choice for a detailed cat are inverted oblique. The basic microscopic appearance is
assessment of the spermatogenic cycle. Inadequate fixation or similar—the testis is divided into the interstitial (extratubular)
suboptimal processing of testicular tissues will cause artifacts or intertubular compartment and the seminiferous tubular com-
that cannot be distinguished from degeneration. partment. The interstitial endocrine cells are the major resi-
The normal testis is pale pink or even almost white. This dent of the intertubular compartment; macrophages are
is presumably because of the large quantity of chromatin another important cell type. In the boar, the interstitial endo-
material. Abnormalities that result in a lowering of spermato- crine cells are particularly prominent and numerous (Fig.
genesis result in the dominance of other pigments—especially 5-13). In young horses, there are lipofuscin-containing mac-
lipochrome pigment. The testes of boars become progressively rophages in the interstitium, remnants of gonadal atrophy of
brown with age, and are brown if degenerate. A frequent mis- the fetal gonad (Fig. 5-14). The normal tubular diameter is
diagnosis is made in equine fetal and neonatal gonads. Fetal 270 µm in the bull, 146 µm in the stallion, 180 µm in the
testes undergo hypertrophy because of hyperplasia of the dog, and 236 µm in the boar. It is normal to see spermatogenic
interstitial endocrine cells as they produce precursors for pla- arrest in some seminiferous tubules in some species.
cental hormones. These cells and testicular macrophages
contain lipochrome pigments that are especially noticeable
during the atrophic stage that occurs prior to birth. Many a
practitioner and pathologist are fooled by the apparent brown
discoloration of the testicular parenchyma of the neonatal
equine testis (Fig. 5-12). The testis varies in gross and micro-
scopic appearance among the species. The stallion has promi-
nent fibrous tissue septa; it is less prominent in the dog and
boar, and absent in ruminants.
Sampling of the testis should be planned. Taking a random
sample of any part of the testis is adequate for generalized
disease; however, such a sample may not be representative of
the entire testicular parenchyma. There is species and indi-
vidual variability in the part of the testis initially affected
by degenerative processes, including variations between the
dorsal and ventral parts of the ruminant testis, variations
between seminiferous tubules, and along the length of indi-
vidual seminiferous tubules. Sampling of the testis to maximize
the number of seminiferous tubules examined should be at right Figure 5-13 Normal spermatogenesis within a normal seminifer-
angles to the direction of the tubules. In general, the seminiferous ous tubule of an adult boar. Note the prominent interstitial endo-
tubules run at right angles to the mediastinum. Each forms a crine cells.
Figure 5-12 Equine fetal testis and epididymis (upper) with Figure 5-14 Testis of a neonatal foal with prominent interstitial
physiologic gonadal hypertrophy; testis is dark brown. Testes cells, macrophages containing lipochrome pigment, and immature
undergo atrophy to become the size of the normal neonatal testis seminiferous tubules that have prominent and centrally located
(lower) before passing through the inguinal ring. germ cells.
476 CHAPTER 5 • Male Genital System Testis and Epididymis
Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 224-251.
Russell LD, et al. In: Histological and Histopathological Evaluation of
the Testis. Clearwater FL: Cache River Press; 1990. p. 162-193,
195-295.
Setchell BP. Male reproductive organs and semen. In: Cupps PT, editor.
Reproduction in Domestic Animals. 4th ed. New York: Academic
Press; 1991. p. 221-250.
Further reading
Hemeida NA, et al. Ductuli efferentes in the epididymis of the boar,
goat, ram, bull and stallion. Am J Vet Res 1987;39:1892-1900.
Testis and Epididymis 477
Further reading
Amann RP, Veeramachaneni DN.. Cryptorchidism in common eutherian
mammals. Reproduction 2007;133:541-561.
Bernal-Mansas CM, et al. Proliferation and apoptosis of spermatogonia
in postpuberal boar testes with spontaneous unilateral and bilateral
abdominal cryptorchidism. Acta Histochem 2005;107:365-372.
Gorlov IP, et al. Mutations of the GREAT gene cause cryptorchidism.
Hum Mol Genet 2002;11:2309-2318.
Hayes HM. Epidemiological features of 5009 cases of equine cryptor-
chidism. Equine Vet J 1986;18:467-471.
Kersten W, et al. Bilateral cryptorchidism in a dog with persistent
cranial testis suspensory ligaments and inverted gubernacula: Figure 5-20 Testicular hypoplasia in a cat. Seminiferous tubules
report of a case with implications for understanding normal and contain only Sertoli cells and a few germ cells. There is some
aberrant testis descent. J Anat 1996;189:171-176. degeneration of Sertoli cells with vacuolation. The interstitial
Ladds PW. Congenital abnormalities of the genitalia of cattle, sheep, endocrine cells are very prominent.
goats and pigs. Vet Clin North Am Food Anim Pract 1993;9:
127-144.
Osawa T, et al. Fibrolipoma of a cryptorchid testis in a young bull. J Vet
Med Sci 2011;73:1253-1255. one or more combinations of these (see Figs. 5-14, 5-16, 5-17).
Searle D, et al. Equine castration: review of anatomy, approaches, Germ cells may be absent, or be present but fail to produce
techniques and complications in normal, cryptorchid and monor- enough spermatozoa. Thus germ cells may fail to migrate to
chid horses. Aust Vet J 1999;77:428-434. the genital ridge in utero, fail to migrate in sufficient numbers,
Yates D. Incidence of cryptorchidism in dogs and cats. Vet Rec fail to survive, have arrested development, undergo excessive
2003;152:502-504. apoptosis, or undergo degeneration (Fig. 5-20). The underlying
cause can be abnormal sex chromosomes (thus a sex chromo-
some DSD), a deficiency of gonadotropins, or other altered
Testicular hypoplasia environment of the testis during development.
Hypoplastic testes fail to grow to a normal size. Testicular At the sex chromosome level, testicular hypoplasia is rec-
hypoplasia occurs in sex chromosome DSD, cryptorchidism, and ognized in animals with a condition resembling Klinefelter
as an “uncomplicated” disease. This latter situation is catego- syndrome. Affected, bulls, pigs, horses, sheep, dogs, and cats
rized as an XY SRY+ testicular DSD. It can be unilateral or have an XXY genotype or a mosaicism with XXY chromo-
bilateral, and is confirmed after puberty when an immature somes. The best known of these is the male tortoiseshell or
testis does not develop to its expected normal size. The small calico cat. In Saanen goats with the gene for polledness (PIS),
size is because of a reduction in the amount of seminiferous testicular hypoplasia is seen in individuals that have XX sex
epithelium, thus there are fewer Sertoli cells, spermatogonia, chromosomes but have testes and a male phenotype. A variety
spermatocytes, elongated spermatids, and spermatozoa. An of other sex chromosome abnormalities are identified with
affected testis is grossly similar to a normal prepubertal testis hypoplasia.
in almost every way (see Fig. 5-4). A deficiency of gonadotrophins occurs with hypoplasia
Studies of hypoplasia are mostly observational at the clini- (hypogonadotrophic hypogonadism) in men and mice, but
cal, gross, or microscopic level. Evaluation of mutant mice has studies in domesticated mammals indicate a normal or raised
aided the study of pathogenesis, mostly by identifying the serum concentration of FSH and LH. Testosterone concentra-
effects of lack of cytokines and growth factors. Research indi- tion was lower than normal in some bulls with hypoplasia;
cates there is an alteration of control of spermatogenesis, so in sheep, testosterone and inhibin concentration may be
there are many similarities with testicular degeneration (see normal.
later). From a pathogenetic point of view, hypoplasia occurs Microscopic abnormalities include a total lack of germ
when spermatogenesis is affected prior to or at the time of cells, arrested spermatogenesis in all tubules, or arrested sper-
puberty, and degeneration occurs from a similar cause after matogenesis that varies from tubule to tubule (see Fig. 5-20).
puberty. Hypoplastic testes with a total lack of germ cells are very small
Hypoplasia is known or suspected to be hereditary in the and fail to enlarge from their size at birth (see Fig. 5-4). Those
bull, ram, and buck. The exact genetic abnormality is often testes with arrested development of all tubules fail to progress
not established. There are few studies of hypoplasia in domes- beyond a certain stage of spermatogenesis. It is common to
ticated animals, but there are some special features of the see some hypoplastic tubules in a normal testis.
disease in selected species discussed later.
Hypoplasia is the potential outcome of a large number of
different abnormalities that may operate at a systemic or local Further reading
level. The small size of the testis is theoretically because of an Borel N, et al. Testicular hypoplasia in a bull persistently infested with
abnormally small number, length, or diameter of tubules, or bovine diarrhoea virus. J Comp Pathol 2007;137:169-173.
478.e1
Further reading
Claxton JH, Yeates NTM. The inheritance of cryptorchidism in a small
crossbred flock of sheep. J Hered 1972;63:141-144.
Dolling CHS, Brooker MG. Cryptorchidism in Australian Merino sheep.
Nature 1964;203:49-50.
Hayes HM, et al. Canine cryptorchidism and subsequent testicular neo-
plasia: case control study with epidemiological update. Teratol
1985;32:51-56.
Humphrey JD, Ladds PW. Pathology of the bovine testis and epididymis.
Vet Bull 1975;45:787-797.
Kawakami E, et al. Peripheral plasma levels of LH, testosterone, and
estradiol-17 β before and after orchiopexy in unilaterally cryptorchid
dogs. Nippon Juigaku Asshi 1990;52:179-181.
Marshall LS, et al. Persistent Müllerian duct syndrome in miniature
Schnauzers. J Am Vet Med Assoc 1982;181:798-801.
Millis DL, et al. Cryptorchidism and monorchidism in cats: 25 cases
(1980-1989). J Am Vet Med Assoc 1992;200:1128-1130.
Romagnoli SE. Canine cryptorchidism. Vet Clin North Am Small Anim
Pract 1991;21:533-544.
Rothschild MF, et al. Evidence for multigene control of cryptorchidism
in swine. J Hered 1988;79:313-314.
Soller M, et al. Cytogenetics of Saanen goats showing abnormal devel-
opment of the reproductive tract associated with the dominant
gene for polledness. Cytogenetics 1969;8:51-67.
St. Jean G, et al. Cryptorchidism in North American cattle: breed pre-
disposition and clinical findings. Theriogenol 1992;38:951-958.
Tarigan S, et al. Genital pathology of feral male goats. Aust Vet J
1990;67:286-290.
Watt DA. Testicular pathology of Merino rams. Aust Vet J 1978;54:
473-478.
478.e2
Further reading
Centerwall WR, Benirschke K. An animal model for the XXY Klinefel-
ter’s syndrome in man: tortoiseshell and calico male cats. Am J Vet
Res 1975;36:1275-1280.
Galloway DB, et al. An outbreak of gonadal hypoplasia in a sheep
flock: clinical, pathological and endocrinological features, and aeti-
ological studies. Vet Rec 1992;131:506-512.
Gimbo A, et al. Ram testicular hypoplasia: anatomical and histopatho-
logical observations. Schweiz Arch Tierheilk 1987;129:481-491.
Olson PN. Clinical approach for evaluation dogs with azoospermia or
aspermia. Vet Clin North Am Small Anim Pract 1991;21:591-607.
Sponenberg DP, et al. Unilateral testicular hypoplasia in a goat. Vet
Pathol 1983;20:503-506.
Veeramachaneni D, et al. Pathophysiology of small testes in beef bulls:
relationship between scrotal circumference, histopathologic fea-
tures of testes and epididymides, seminal characteristics, and endo-
crine profiles. Am J Vet Res 1986;47:1988-1999.
Testis and Epididymis 479
Han K, et al. Pathogenesis of type 1 (European genotype) porcine Various degrees of hypoplasia are recognized, and affected
reproductive and respiratory syndrome virus in male gonads of testes may have tubules that, at the extreme are ∼90 µm in
infected boar. Vet Res Commun 2013;37:155-162. diameter (normal 160 µm) and lined by mostly fetal Sertoli
Kay GW, et al. Heritable testicular hypoplasia in Nguni (Bos indicus) cells. There is a report of an outbreak of gonadal hypoplasia
bulls: vascular characteristics and testosterone production. J Reprod of multiple rams born within a short time frame. The affected
Fertil 1992;96:537-547. testes were uniformly small and had a “Sertoli cell-only”
Olson PN, et al. Clinical and laboratory findings associated with actual pattern histologically. An environmental cause was
or suspected azoospermia in dogs: 18 cases (1979-1990). J Am Vet suspected.
Med Assoc 1992;201:478-482. Hypoplasia in bucks. There are several types of hypoplasia
Settergren I, McEntee K. Germ cell weakness as a cause of testicular recorded in bucks. It is a common abnormality in the polled/
hypoplasia in bulls. Acta Vet Scand 1992;33:273-282. intersex (PIS) syndrome of polled Saanen goats, in which the
Smith KC, et al. A survey of congenital reproductive abnormalities in animals have XX sex chromosomes but have testes and are
rams in abattoirs in south west England. Reprod Dom Anim phenotypically male. The testes of affected animals have rudi-
2012;47:740-745. mentary seminiferous tubules. Other sporadic forms of hypo-
plasia occur, and the cause is not known.
Hypoplasia in cats. Testicular hypoplasia is a sporadic
disease of cats. In male cats with a tricolor or calico coloration
Hypoplasia in bulls. Testicular hypoplasia in bulls, and and therefore a XXY sex chromosome complement, there are
especially in some breeds such as the Belgian blue, is very no germ cells and the testes are markedly hypoplastic with
common. Breeding soundness examination and the culling of small diameter tubules. Chimeric animals may be fertile.
bulls with a scrotal circumference below the normal range is Hypoplasia in dogs. About 6% of dogs may have testicular
common and in some breeds exceeds 90% of tested individu- hypoplasia. A diagnosis is usually made after azoospermia is
als. The causes are probably multifactorial. Studies suggest it found during an investigation of infertility. Congenital azo-
is hereditary in the Swedish Highland breed, in which it has ospermia occurs in some lines of dogs. This suggests a familial
a recessive inheritance with incomplete penetrance. Animals or hereditary basis, implicating inbreeding. Confirmation of
with white body and ears are particularly likely to have hypo- congenital azoospermia because of testicular hypoplasia
plasia. The majority of unilateral hypoplastic testes are on the requires historical information or testicular biopsy after the
left side. In one Bos indicus breed, heritable hypoplasia is expected date of puberty.
linked to branching of the testicular artery near the aorta of Hypoplasia occurs in animals with failure of testicular
the same side, suggesting that reduced blood flow may descent and in sex chromosome abnormalities such as those
be responsible. Testosterone secretion was reduced in the with XX or XXY sex chromosome DSD. Offspring of bitches
affected testis. treated with diethylstilbestrol may have hypoplastic testes.
Microscopic changes of hypoplasia include cessation of
spermatogenesis at some stage, with either degeneration or Other testicular disorders of development
excessive apoptosis of the germinal epithelium. The most Monorchia is the presence of only one testis. As a general
severe cases of hypoplasia have a Sertoli cell-only pattern or term, monorchism is the result of cryptorchidism, severe uni-
they have some normal and abnormal tubules intermixed, lateral testicular degeneration, or agenesis. True agenesis occurs
often with affected tubules being in the more dorsal part of when there is a failure of one testis to develop. The differentia-
the testis. tion between true agenesis and a cryptorchid with total tes-
Persistent infection of bulls with bovine viral diarrhea virus ticular degeneration is impossible, but true agenesis is
(BVDV) may affect testicular development. considered to be very rare. Likewise, supernumerary testes
Hypoplasia in boars. Most research on boar fertility and (polyorchidism) or fusion of abdominal testes is very rare.
altered spermatogenesis has focused on chromosomal abnor- The presence of testicular tissue outside the testis is
malities, including abnormal complement of sex chromo- reported in pigs, in which nodules of tissue were found
somes, translocations of parts of the X chromosome, and other throughout the peritoneal cavity. In the dog and cat, Sertoli
disorders. These result in abnormal spermatogenesis or inabil- cell tumors and interstitial cell tumors can arise from ectopic
ity to produce an appropriate litter size in the face of normal testicular tissue in the scrotal skin or spermatic cord. Previous
semen parameters. Porcine reproductive and respiratory syn- surgical implantation of normal cells is suspected. In the cat,
drome virus (PRRSV) infection of the testis and increased heterotopic interstitial endocrine cells occur in the epididy-
apoptosis of germ cells is reported and may contribute to mis, and neoplasia of this tissue is reported.
infertility of infected boars. Fusion of the testes to abdominal organs such as the spleen
Hypoplasia in stallions. Testicular hypoplasia of horses is and variations in the shape of testes are described. “Hour-glass”
not well studied and prevalence is not available, partly because shaped, round, and horizontally placed testes of ruminants are
most male horses are gelded. It occurs with sex chromosome all reported.
DSD and as a sporadic condition. Many cases are mild and Accessory or ectopic adrenal tissue is reported in horses
unilateral—one testis is smaller than the other. and rams, and rarely in other species. Most are located in the
Hypoplasia in rams. Testicular hypoplasia of rams is con- region of the head of the epididymis and distal spermatic cord
sistently the most commonly reported DSD of the male (Fig. 5-21).
reproductive tract. It is usually a sporadic disease that is either A variety of cystic structures have been described in and
bilateral or unilateral. The disease is not well studied. A condi- around the testis and epididymis. Some arise from the rete
tion resembling Klinefelter syndrome, with an XXY genotype, testis and others are remnants of mesonephric ducts or duct-
is reported. Zinc deficiency is implicated in some cases. ules, or paramesonephric ducts.
480 CHAPTER 5 • Male Genital System Testis and Epididymis
Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 230-231.
Parks AH, et al. Monorchidism in the horse. Equine Vet J
1989;21:215-217.
Testis and Epididymis 481
Further reading
Campero CM, et al. Lesions of presumed congenital origin in the acces-
sory sex glands of bulls. Aust Vet J 1989;66:80-85.
Humphrey JD, Ladds PW. Pathology of the bovine testis and epididymis.
Vet Bull 1975;45:787-797.
Ladds PW, et al. Epididymal aplasia in two rams. Aust Vet J
1990;67:457-458.
Wrobel KH, Hees H. Heterotopic Leydig cells in the cat. Anat Histol
Embryol 1987;16:289-292.
482 CHAPTER 5 • Male Genital System Testis and Epididymis
BOX • 5-1
Causes of testicular degeneration
• Advancing age
• Chemicals
1. Chemotherapy
2. Chlorinated naphthalenes
3. Halogenated compounds, including hexachlorophene
4. Nitrogen-containing compounds, including
benzimidazoles, nitrofurans
5. Metal compound toxicosis
• Epididymitis
• Heat
• Hormones
1. Dexamethasone
2. Estrogen
3. Testosterone
4. Zearalenone
• Neoplasia
1. Pituitary tumors
• Nutritional disorders
1. Negative energy balance Figure 5-25 Unilateral testicular atrophy in a ram. The epididy-
2. Fatty acid deficiency mis of the atrophic testis appears disproportionately large.
3. Hypovitaminosis A
4. Hypervitaminosis A
5. Hypovitaminosis B
6. Hypovitaminosis C
7. Hypovitaminosis E
8. Protein and amino acid deficiency
9. Zinc deficiency
• Plants
1. Locoweed (Astragalus)
2. Lysine seeds (gossypol)
• Radiation
• Stress/corticosteroid therapy
• Trauma
• Ultrasound
• Viral infection
1. Porcine reproductive and respiratory syndrome virus
2. Canine distemper virus
3. Bovine viral diarrhea virus
although in rodents, ethyl glycol alkyl ethers affect spermato- Occlusion of the efferent ductules can lead to dilation of the
cytes, nitroimidazoles affect spermatids, and compounds that rete and mediastinum testis and appear as testicular enlarge-
impinge on energy metabolism affect spermatozoa. Damage ment, although the thickness and fibrous nature of the testicu-
to various stages causes apoptosis, with a rapid uptake of the lar capsule makes sudden enlargement of the testis less likely.
detritus by Sertoli cells. Within 48 hours, there may no longer Adhesions and thickenings of the vaginal tunic can also appear
be evidence of apoptosis—just the appearance of “maturation clinically as testicular enlargement. To the unsuspecting,
arrest.” lesions of the scrotum or its contents are mistaken as testicular
Toxicants can also affect the efferent ductules and epididy- enlargement; hydrocele, epididymitis, or the presence of sper-
mis and/or the spermatozoa in transit. The difficulty with matic granulomas are examples.
investigating efferent ductular toxicosis is separating the effect
caused by alteration in testosterone concentration, and direct
toxic effects. Substances that affect the efferent ductules Further reading
include cyclophosphamide, methyl chloride, and reserpine. Lunstra DD, et al. Sertoli cells in the boar testis: changes during devel-
Such toxicants decrease spermatozoal concentration and opment and compensatory hypertrophy after hemicastration at
cause spermiostasis, spermatic granuloma formation, and different ages. Biol Reprod 2003;68:140-150.
necrotic and degenerative changes to the epithelium. Several Putra DKH, Blackshaw AW. Quantitative studies of compensatory tes-
have direct effects on spermatozoa in the ducts. ticular hypertrophy following unilateral castration in the boar. Aust
There are few reports of direct viral infection and their J Biol Sci 1985;38:429-434.
effects on spermatogenesis. However, porcine reproductive
and respiratory syndrome virus replicates in germ cells, alters
spermatogenesis, and induces apoptosis. Bovine viral diarrhea Inflammation of the testis and epididymis
virus is implicated in infertility. Canine distemper virus infec- Orchitis
tion of dogs can cause testicular degeneration. Apart from bulls in areas endemic for Brucella abortus or
tuberculosis, and in some cases of canine epididymitis, orchitis
is a rare and sporadic disease in domesticated animals. The vast
Further reading majority of cases diagnosed clinically as orchitis are actually
Creasy DM. Pathogenesis of male reproductive toxicology. Toxicol epididymitis (see later). Focal accumulations of lymphocytes
Pathol 2001;29:64-76. are occasionally seen in the testes of most species as incidental
Creasy DM, et al. Proliferate and nonproliferate lesions of the rat and findings. Lymphocytic (or nonsuppurative) inflammation is
mouse male reproductive system. Toxicol Pathol 2012;40:40-121. seen in some infertile animals; an immunologic pathogenesis
De Coster S, van Larebeke N. Endocrine-disrupting chemicals: associ- is invoked as immunization of guinea pigs and bulls with
ated disorders and mechanisms of action. J Environ Public Health spermatozoa induced inflammation of the rete testes espe-
2012;2012:713696. cially. Efferent ductules are also involved experimentally.
Fukuda T, et al. Age related changes in the testes of horses. Equine Orchitis as the primary and severe disease has historically
Vet J 2011;33:20-25. been attributed to brucellosis or tuberculosis. Tuberculous
Sur JH, et al. Evidence for the localization of porcine reproductive and orchitis is a multifocal granulomatous disease that is much less
respiratory syndrome virus (PRRSV) antigen and RNA in ovarian common now because of eradication in many countries. Bru-
follicles in gilts. Vet Pathol 2001;38:58-66. cellosis is similarly reduced in prevalence. Brucella abortus
Turner RM, et al. The emerging pathophysiology of age-related testicu- (bulls), Brucella suis (pigs), Brucella canis (dogs), and Brucella
lar degeneration with a focus on the stallion and an update on melitensis (goats) can cause orchitis as a dominant change.
potential therapies. Reprod Dom Anim 2012;47:178-186. However, epididymitis is often the main manifestation.
Vandenberg LN, et al. Hormones and endocrine-disrupting chemicals: Orchitis is traditionally divided into 3 major categories:
low dose effects and nonmonotonic dose responses. Endocr Rev interstitial orchitis, intratubular or granulomatous orchitis, and
2012;33:378-455. necrotizing orchitis.
Further reading
Boekelheide K, et al. The Sertoli cell cytoskeleton: a target for toxicant-
induced germ cell loss. Toxicol Appl Pharmacol 1989;101:
373-389.
Chapin RE, Williams J. Mechanistic approaches in the study of testicular
toxicity: toxicants that affect the endocrine regulation of the testis.
Toxicol Pathol 1989;17:446-451.
Creasy DM, Foster PMD. The male reproductive system. In: Haschek
WM, Rousseaux CG, editors. Handbook of Toxicologic Pathology.
San Diego, CA: Academic Press; 1991. p. 860-874.
Hess RA. Effects of environmental toxicants on the efferent ducts,
epididymis and fertility. J Reprod Fertil Suppl 1998;53:247-259.
Lowseth LA, et al. Age-related changes in the prostate and testes of
the beagle dog. Vet Pathol 1990;27:347-353.
Pera I, et al. Body temperature (37 C) specifically down-regulates the
messenger ribonucleic acid for the major sperm surface antigen
CD52 in epididymal cell culture. Endocrinol 1996;137:4451-4459.
485.e2
Further reading
Boockfor FR, et al. Effects of unilateral castration and unilateral crypt-
orchidism of the Holstein bull on plasma gonadotropins, testoster-
one and testis anatomy. J Anim Sci 1983;56:1376-1385.
Cox JE. Factors affecting testis weight in normal and cryptorchid
horses. J Reprod Fertil Suppl 1982;32:129-134.
Schanbacher BD, et al. Testicular compensatory hypertrophy in the
hemicastrated calf: effects of exogenous estradiol. Biol Reprod
1987;36:1142-1148.
485.e3
Further reading
Aubry P, et al. Septic orchitis in an alpaca. Can Vet J 2000;41:
704-706.
Fritz TE, et al. Pathology and familial incidence of orchitis and its rela-
tion to thyroiditis in a closed beagle colony. Exp Mol Pathol
1976;24:142-158.
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Lewis KM, et al. Abdominal ultrasonographic findings associated with
feline infectious peritonitis: A retrospective review of 16 cases.
J Am Anim Hosp Assoc 2010;46:152-160.
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 224-358.
Njenga MJ, et al. Semen characteristics of goats with subacute, acute
and chronic besnoitiosis. J S Afr Vet Assoc 1999;70:18-20.
Van Camp SD. Common causes of infertility in the bull. Vet Clin North
Am Food Anim Pract 1997;13:203-231.
486 CHAPTER 5 • Male Genital System Testis and Epididymis
Interstitial orchitis. Interstitial orchitis may not be recog- and inflammation of spermatic arteries occur in bovine malig-
nized macroscopically, but histologically there are lympho- nant catarrhal fever (alcelaphine herpesvirus 1 and ovine her-
cytes in the interstitial stroma, with concurrent or subsequent pesvirus 2). In experimental bluetongue virus infection in
fibrosis. In bulls, small clusters of lymphocytes are frequently bulls, interstitial orchitis accompanies arteritis. Clinical orchi-
observed adjacent to seminiferous or rete tubules or efferent tis and aspermatogenesis were listed as findings in bovine
ductules of otherwise normal testes. In stallions, interstitial enterovirus 1 infection, but lesions are not described. A focal
perivascular lymphocytic foci are particularly common and nodular orchitis is reported in lumpy skin disease (lumpy skin
occur in areas of degeneration. Lymphoid aggregates are fre- disease virus) of bulls.
quently seen in Beagle dogs used as laboratory animals. Foci Orchitis in bulls is similar grossly and histologically, regard-
of lymphocytes in cats are considered an age-associated less of the causative bacterium. The best descriptions are of
change. Brucella abortus infection in endemic regions. In most instances
Intratubular orchitis. Intratubular orchitis is inflammation the orchitis is acute and severe. It may be unilateral but
focused on the seminiferous tubules. Some cases result from affected animals are sterile. The scrotum swells and is hot and
ascending infection but in others there is no epididymitis to doughy as a result of inflammatory changes in the tunics and
confirm this. Alternative explanations include a breakdown of to a lesser extent in the epididymis. Swelling of the testis is
the blood-testis barrier allowing agents into the tubules, or limited by the inability of the testicular capsule to stretch, and
spermatozoal antigens leaking into the interstitium. Macro- any swelling constricts venous and then arterial flow causing
scopically, there are solitary or multiple white-yellow foci of infarction. The cavity of the vaginal tunics distends with fibri-
up to 1 cm diameter. Histologically, the tubule outline is nopurulent exudate. Scattered yellow foci of necrosis coalesce
retained in the affected area, but the seminiferous epithelium to produce total testicular necrosis. Sequestration by inflam-
is either degenerate or obliterated and replaced by macro- mation and thickening of the tunics follows. Sometimes the
phages and multinucleated giant cells that surround neutro- necrotic parenchyma liquefies and the organ then is a pus-
phils and debris (Fig. 5-32). In some cases, the reaction is filled cavity surrounded by a thick connective-tissue capsule.
predominantly lymphocytic, suggesting an autoimmune Rupture may occur but is unusual.
pathogenesis. The pathogenesis of the granulomatous orchitis Microscopically, the inflammation of the tunics results in
is comparable to spermatic granuloma formation in the epi- extremely dense adhesions between the parietal and visceral
didymis. Sertoli cell hyperplasia and mineralization may layers. Within the testes, the infection appears to progress
accompany these changes. along the lumen of the seminiferous tubules. The seminal
Necrotic orchitis. Necrotizing orchitis is characteristic of epithelium becomes necrotic and desquamates. Large numbers
brucellosis but may result from other infections, or conditions of the organisms are visible in the lumen. At the early stage,
causing severe trauma or ischemia of the testis. Severe perior- neutrophils, macrophages, and lymphoid cells are in the inter-
chitis may reduce blood supply to the testis so that it becomes stitial tissues and form cuffs about the tubules. The tubules
a necrotic mass encased within the markedly thickened tunics. and the interstitial tissues then become necrotic. There is often
Necrotic areas are dry, yellow, often laminated, and slightly focal necrotizing epididymitis complicated by the develop-
mineralized. The histologic picture is coagulative necrosis bor- ment of spermatic granulomas.
dered by fibrosis and inflammatory cells. Abscessation and Tuberculous orchitis in bulls is an uncommon lesion,
fistulation through the scrotum may accompany necrotizing even in areas of endemic infection. The granulomatous
or other forms of orchitis. response to the tubercle bacilli is similar to the granulomas
Orchitis in bulls. In bulls, many viruses have been isolated that occur to spermatozoa. Involvement of the testis may be
from testes or semen. Histologic changes are seldom found. either miliary or regional. In the miliary form, small or large
Persistent infection with bovine viral diarrhea virus results in caseous and mineralized foci are irregularly scattered through-
spermatozoal defects but no distinct histologic lesions in the out the testes but may spare the epididymis entirely. The
testis. Severe interstitial orchitis and testicular degeneration path of infection is probably intratubular from a primary
epididymal lesion.
Other bacteria causing orchitis in bulls, sometimes with
overt abscessation, include streptococci, staphylococci, True-
perella pyogenes, Escherichia coli, Histophilus spp., Salmonella
spp., Actinomyces bovis, Actinobacillus spp., and Nocardia spp.
In nocardiosis especially, the lesions are at first nodular but
ultimately transform the whole testis into an abscess, the
capsule of which is the vaginal tunic.
Infection of bulls with Chlamydophila spp. causes orchitis,
and in field cases, focal granulomatous lesions are observed.
The spontaneous occurrence of orchitis and epididymitis
caused by Mycoplasma spp. infection is reported.
Orchitis in boars. Viral infection of the testis and shedding
in the semen of boars is identified in many, but inflammation
in natural disease is not well documented, or is not reported.
Intratesticular inoculation is used in an experimental setting,
and this overwhelms natural defences and adds local trauma
as a complication. Experimental orchitis and epididymitis is
Figure 5-32 Severe intra-tubular neutrophilic necrotizing orchi- reported in porcine rubulavirus (a paramyxovirus responsible
tis in a dog. for the disease “blue eye”) infection. The virus targets the head
Testis and Epididymis 487
of the epididymis, where it causes interstitial inflammation of epididymitis. Sporadic testicular abscesses result from
and spermatic granulomas. Interstitial fibrosis is seen in animals infection with Trueperella pyogenes and Corynebacterium
that recover. Suid herpesvirus 1 infection (pseudorabies, pseudotuberculosis.
Aujeszky’s disease) may cause edema of the scrotal region; In bucks, caprine arthritis-encephalitis virus is found in
intratesticular inoculation results in exudative periorchitis. semen and in the testis and epididymis but without lesions.
Porcine parvovirus 1, porcine reproductive and respiratory Orchitis may result from infection with Brucella melitensis. It
syndrome virus, and porcine circovirus 2 replicate in the can be severe enough to induce a fibrinonecrotic disease.
reproductive tract and may cause testicular degeneration. Orchitis also occurs in breeding goats as a component of
Orchitis caused by Brucella suis results in multiple abscesses besnoitiosis.
rather than confluent necrosis. Some cases have fibrinopuru- Orchitis in dogs and cats. Dogs with canine distemper
lent and hemorrhagic periorchitis. Abscessation develops in virus infection develop intranuclear and cytoplasmic inclu-
the epididymis as well as in the testis; there is central caseation sions in Sertoli cells. The majority of seminiferous tubules
surrounded by a zone of epithelioid macrophages, and these degenerate, and inflammation occurs in some tubules.
in turn by a broad connective-tissue capsule and lymphocytes Orchitis is seen with bacterial epididymitis, where there is
and plasma cells. retrograde spread from the epididymis. Escherichia coli, Proteus
In some tropical countries, orchitis caused by infection vulgaris, and other coliforms are usually responsible. An acute
with Burkholderia pseudomallei occurs in boars and other inflammatory response in either the epididymis or testis is
domestic mammals. Lesions can occur in the vesicular glands, usually necrosuppurative, with the formation of one or more
prostate, and other organs. Extreme enlargement of the testis abscesses (see Fig. 5-32). The vaginal tunic is involved by
caused by purulent inflammation may occur. The main histo- extension, and fistulation through the scrotal skin to the exte-
logic lesion is multifocal necrosis with marked lymphocytic rior may occur. Dogs will traumatize their scrotum and
inflammation and encapsulation by much fibrous connective produce a fistula. Acute inflammation usually is centered on
tissue. Severe testicular degeneration accompanies orchitis. the ducts, with degeneration and desquamation of the epithe-
Other organisms isolated from boars with orchitis include lium, and edema and neutrophils in the surrounding stroma.
Trueperella pyogenes, Streptococcus zooepidemicus, Streptococcus Healing occurs by scarring. With time, the affected testis
equisimilis, and Salmonella spp. becomes firm, small, and irregular. Lymphocytes and plasma
An inbred strain of Duroc boars developed a high preva- cells predominate and fibrosis is well developed.
lence of lymphocytic interstitial orchitis suggesting a genetic Other bacterial causes of orchitis in dogs include Brucella
predisposition. The orchitis caused degeneration of the semi- canis and Burkholderia pseudomallei, both of which cause epi-
niferous tubules and predominantly unilateral testicular didymitis (see later). A familial occurrence of interstitial, lym-
atrophy. phocytic orchitis, associated with testicular atrophy and
Orchitis in stallions. In stallions, mild interstitial orchitis reduced fertility, was observed in inbred Beagle dogs with
is common and incidental. Similar lesions may be part of lymphocytic thyroiditis; immune factors were implicated.
generalized vascular involvement in equine viral arteritis. Fungi such as Blastomyces dermatitidis can cause orchitis as
Infarcts may also occur in equine infectious anemia. Orchitis part of systemic disease. Protozoal orchitis caused by Leishma-
can occur as part of systemic disease, and is reported in glan- nia spp. is reported in dogs. Penetrating wounds of the scrotum
ders (Burkholderia mallei), and as an acute suppurative, some- affect the scrotal contents including the testis.
times abscess-forming orchitis in infection with Salmonella Orchitis in cats is very rare. Feline infectious peritonitis
abortus-equi, Streptococcus equi, and Streptococcus zooepi- virus can induce a primary orchitis (Fig. 5-33); however, peri-
demicus. Focal lesions attributed to the migrating larvae of orchitis is the usual manifestation. Orchitis can be a sequel to
Strongylus edentatus are reported in the testis, tunics, and traumatic injury to the scrotum.
epididymis, especially of young horses. Cryptorchid testes are Orchitis in camelids. Orchitis is uncommon in camelids.
more commonly affected. Hemorrhagic 2-mm wide tracts Septic orchitis from Streptococcus equi subsp. zooepidemicus is
containing the migrating larvae are seen. The histologic lesions reported in an alpaca. Camels are susceptible to Brucella
are initially hemorrhagic and then become eosinophilic. Hali- abortus and Brucella melitensis, and some develop orchitis.
cephalobus gingivalis can cause granulomatous orchitis as a
consequence of systemic spread. A pseudocyst is reported in Epididymitis
a horse as a sequel to fibrinonecrotic orchitis. The lesion was Inflammation of the epididymis is very common. Regardless of
associated with trauma, and secondary infection with Strepto- cause, damage to the epididymal duct results in a response to
coccus zooepidemicus occurred. spermatozoa and other luminal contents, spermatic granulo-
Testicular rupture, hemorrhage, and orchitis can occur with mas, and subsequent development of chronic epididymitis.
trauma to the testis, such as when a stallion is kicked while The exception is in prepubertal animals in which there are no
mating a mare. Spermatic granulomas in the testis occur spermatozoa; in these cases, true abscesses occur. Epididymitis
secondarily. in the absence of sperm granulomas is possible in adults, but
Periorchitis in horses occurs as part of generalized septic it usually is a subclinical or early event.
disease, peritonitis, and as a complication of trauma, penetrat- Epididymitis is usually infectious, and infectious disease
ing injury, or surgery. frequently causes a spectrum of lesions, including inflamma-
Orchitis in small ruminants. In rams, nodular orchitis tion of the accessory genital glands. The effects of epididymitis
occurs in sheep pox in a similar fashion to lumpy skin disease are usually more dramatic than prostatitis, vesicular adenitis,
in bulls. Chronic interstitial orchitis is reported in rams or ampullitis, and these are often overlooked. Sterile epididy-
infected with the ovine lentivirus maedi-visna virus. The most mitis with spermatic granulomas does occur in congenital
common causes of orchitis are bacteria that also cause epi- ductal disorders of sexual development, adenomyosis, trauma,
didymitis. It is unusual to find orchitis in the absence and reflux of urine.
488 CHAPTER 5 • Male Genital System Testis and Epididymis
Figure 5-33 Pyogranulomatous orchitis from feline infectious Figure 5-35 Chronic epididymitis in a ram, with marked epi-
peritonitis virus infection in a cat. didymal enlargement, fibrosis of the tunics, and testicular atrophy.
Brucella ovis.
Further reading
Blue MG, McEntee K. Epididymal spermatic granuloma in a stallion.
Equine Vet J 1985;17:246-251.
Constable PD, Webber JJ. Escherichia coli epididymitis in rams. Aust
Vet J 1987;64:123.
Held JP, et al. Bacterial epididymitis in two stallions. J Am Vet Med
Assoc 1990;197:602-604.
Holzmann A, et al. Orchiepididymitis in a bull with Mycoplasma in its
ejaculate. Zbl Vet Med A 1983;30:760-766.
Kadota K, et al. Granulomatous epididymitis related to Rhodotorula
glutinis infection in a dog. Vet Pathol 1995;32:716-718.
Saravanamuthu V, et al. T and B lymphocyte subsets in spermatic
granuloma in the ram. Vet Pathol 1991;28:482-491.
Vermeulen SO, et al. Brucella ovis as a possible cause of epididymitis
in an Angora goat. J S Afr Vet Assoc 1988;54:177-179.
490 CHAPTER 5 • Male Genital System Testis and Epididymis
Brucella abortus rarely causes epididymitis in the absence result and testicular degeneration increases. Unlike brucellosis
of orchitis. Actinobacillus seminis, a frequent cause of epididy- in the bull, there is seldom a primary orchitis. Lesions in the
mitis in rams, has been isolated from the semen of a bull with deferent duct similar to those in the epididymis may occur,
bilateral epididymitis. Epididymitis is observed in bulls with but there is no sperm stasis or leakage. There is pronounced
vesicular adenitis induced by inoculation of Mycoplasma bovi- epithelial hyperplasia, with thickening and folding of the wall,
genitalium, but the role of mycoplasmas and chlamydias in and the lamina propria contains many lymphocytes, plasma
causing epididymitis awaits clarification. Epididymitis may cells, and histiocytes. Many rams do not develop detectable
accompany orchitis, periorchitis, and testicular degeneration gross lesions or they develop them only late in the course of
in cattle, horses, sheep, goats, and dogs infected with Trypano- the disease. Identification of B. ovis in histologic sections is
soma brucei. difficult, but is aided by immunohistochemistry.
Epididymitis in boars. Brucella suis infection is a classical Actinobacillus seminis and related strains of the so-called
cause of epididymitis, and the lesions are variable. Single or gram-negative pleomorphic organisms also induce epididymi-
multiple “abscesses” are frequent in the epididymis, but less tis. Both H. somni and A. seminis are temporarily resident in
so in the testes, which may be enlarged or atrophic. Enlarge- the prepuce and become opportunistic pathogens by ascend-
ment of the vesicular glands caused by localization of B. suis ing infection. This usually occurs at puberty, when there are
may also occur, and abscessation, perhaps seen only micro- elevated levels of gonadotrophin releasing hormones. The
scopically, occurs in the vesicular glands and prostate and pathogenesis of E. coli epididymitis in rams probably is similar.
bulbourethral glands. Typically, these are severe infections in young rams, and there
Epididymitis in stallions. In the stallion, migrating stron- may be severe and diffuse periorchitis. In epididymitis caused
gyle larvae are implicated as a cause of epididymitis and by Actinobacillus seminis, there is fibrinosuppurative and
spermatic granuloma of the epididymis; adenomyosis is a necrotic inflammation of one or both epididymides, and these
further cause. Rare sporadic cases of bacterial epididymitis are may fistulate through the scrotal wall. Histologically, the
reported with Streptococcus zooepidemicus isolated from such initial epididymal lesion is similar to that of Brucella ovis. In
cases. the chronic form of the disease seen in older rams, the epi-
Epididymitis in small ruminants. Epididymitis is of par- didymides are large and fibrotic, and the testes are atrophic
ticular importance in rams, in which it is a frequent and (see Fig. 5-35). The vesicular glands also may be affected.
serious cause of reduced fertility. Although either Brucella ovis Experimental inoculation of rams by various routes with Acti-
or Actinobacillus seminis are usually responsible, many other nobacillus seminis has shown that part of or the entire genital
bacteria, such as Histophilus somni, Mannheimia haemolytica, tract may become infected, but that the epididymis is most
Escherichia coli, and Trueperella pyogenes, are isolated from constantly involved.
sporadic cases of epididymitis. Whereas Brucella ovis is a cause Epididymitis is less studied in bucks than in rams. Brucella
of epididymitis in mature rams, other gram-negative pleomor- melitensis, Actinobacillus seminis, Staphylococcus aureus, Esche-
phic organisms are commonly cultured from epididymitis in richia coli, or Pseudomonas spp. may be isolated from lesions,
virgin rams, suggesting the existence of two separate disease and there is a report of possible Brucella ovis epididymitis in
entities. an Angora goat.
Ovine epididymitis caused by Brucella ovis is an important Epididymitis in dogs and cats. Viral epididymitis is rare
cause of reduced fertility in many countries and is studied but it reported in canine distemper virus infection. Cytoplas-
extensively. Progression of the infection is very slow, from a mic and intranuclear inclusions are present in the epithelial
local infection persisting in the exposed mucus surface for 1 cells and there is a lymphocytic interstitial epididymitis. Eosin-
month, to a regional one involving adjacent lymph nodes, ophilic cytoplasmic bodies are normally present in the head
leading to bacteremia. The bacteremic stage subsides after of the epididymis and should not be confused with viral inclu-
about 2 months, but organisms localize in the genital tract, sion bodies; immunohistochemistry will differentiate these
spleen, kidney, and liver, where they persist for an indefinite inclusions.
period. Following experimental infection, neither gross nor In male dogs infected with Brucella canis, there is epididy-
microscopic lesions are seen in organs other than genitalia. mitis, prostatitis, scrotal dermatitis, and testicular atrophy.
In the vast majority of epididymides with lesions caused These changes can be unilateral. Infected animals are bacte-
by Brucella ovis, the epididymal tail is involved, and lesions in remic and the organism can persist in tissues (e.g., the pros-
this location probably occur in all epididymides infected with tate) for many months. Recovery can eventually occur and
this organism. Initial localization of the bacteria produces recovered dogs are immune to reinfection. Venereal transmis-
edema, and lymphocytes and macrophages appear. Later, neu- sion to females by infected males can occur, although the
trophils appear. Early epithelial changes include degeneration organism is not consistently isolated from semen. Scrotal
and then hyperplasia, with the formation of intraepithelial swelling is apparent 1-2 weeks after experimental intravenous
lumina (see Fig. 5-37). At the same time there is increasing inoculation, or 3-5 weeks after oral infection. Such swelling is
fibrosis in interstitial areas (see Figs. 5-37, 5-38). The combina- from fibrinopurulent exudate in the cavity of the vaginal
tion of inflammation, fibrosis, and epithelial hyperplasia tunics. Scrotal ulceration is the result of persistent licking of
obstructs the lumen and causes spermiostasis. These changes the scrotum caused by the pain of epididymitis. Testicular
can develop over many months, and large numbers of organ- lesions are seldom if ever observed but testicular necrosis (as
isms are in the ejaculate. Subsequent events depend on the observed in the bull) may occur rarely, and there is concurrent
extravasation of spermatozoa and formation of spermatic marked fibrous thickening of tunics.
granulomas. The tail of the epididymis in these cases may be Microscopically there is coagulative necrosis from necrotiz-
enlarged 4-5 times (see Fig. 5-35), and the lesion is often ing vasculitis and associated thrombosis, and a predominantly
bilateral. If the inflammatory reaction and extravasated sper- lymphoid response peripherally. More frequently, however,
matozoa enter the cavity of the vaginal tunic, adhesions will there is interstitial epididymitis and prostatitis, and testicular
Testis and Epididymis 491
atrophy. Lymphocytic inflammation of epididymal stroma is the precise cause of this lesion is not clear. In old dogs, arteries
variable. Fibrosis may be extensive but, in contrast to brucel- and arterioles in regions of testicular degeneration have thick-
losis in other species, obliteration or stricture of ducts is ened hyaline walls. Initial lesions occur in the testicular capsule
unusual. Neutrophils and macrophages are present in the and parenchyma, but the artery in the spermatic cord is
epididymal duct. In chronic cases, there is marked enlarge- affected too. Focal areas of ischemia and infarction may occur
ment of the epididymis, especially the tail, with involvement with severe vascular lesions. Atheromatous change is rare; in
of the deferent duct. The ejaculate of male dogs with chronic dogs this change may indicate hypothyroidism or diabetes
brucellosis contains inflammatory cells, abnormal spermato- mellitus.
zoa, and spermatozoa agglutinins. The resulting infertility may Thrombosis of testicular arteries, usually of unknown cause,
be mediated by isoimmune reactions resulting from the is seen occasionally in bulls. Such thrombi are present in both
heightened nonspecific phagocytic activity of cells attracted the parenchyma and tunics and may be partially mineralized
to the sites of bacterial growth in the epididymis. Brucella suis and sometimes occluding. The degenerative changes in semi-
also may cause spontaneous granulomatous epididymitis and niferous tubules are usually mild, however. In experimental
prostatitis in the dog. Trypanosoma vivax infection in sheep, thrombosis of testicular
Escherichia coli or other gram-negative bacteria cause most vessels probably contributes to testicular degeneration. Sub-
sporadic cases of canine epididymitis (see Fig. 5-36). The sequent infarction and necrosis may sometimes occur. Venous
epididymitis often has concurrent severe systemic disease thrombosis was observed in the testes of rams in isolated
from endotoxemia. Scrotal swelling and mutilation are accounts. The thrombi were solitary and laminated. Some
common. The range of lesions is similar to those of canine affected rams had a concurrent varicocele; testicular degenera-
brucellosis, although the lesions are usually more severe. tion was mild.
Following infection with Burkholderia pseudomallei, dogs Inflammation of the testicular artery occurs in the horse.
develop pyrexia, lethargy, scrotal swelling, edema of one or The known causes are migrating strongyle larvae and equine
more limbs, and lameness. Macroscopically, the epididymides arteritis virus infection, but a cause was not found in many
are enlarged 3-4 times normal, are firm and hemorrhagic, and cases. The usual lesions in testicular tissue include focal
may contain small necrotic foci. The testis and deferent duct aggregates of lymphocytes and degeneration of seminiferous
may also be involved. tubules adjacent to the inflamed arteries and arterioles. The
Mycoplasma canis can cause urinary tract infection in dogs, inflammatory reaction is rarely severe enough to cause throm-
with subsequent purulent epididymitis and prostatitis. bosis and infarction. Horses infected with equine arteritis
Mycotic epididymitis caused by Rhodotorula glutinis or Blas- virus may have acute necrotic vasculitis, edema, and hemor-
tomyces dermatitidis produces granulomatous epididymitis rhage. Chronic cases will have lymphocytic vasculitis and
with a reaction pattern similar to disease in other tissues. The perivasculitis.
complication of spermatic granulomas adds to the granuloma- A striking vasculitis with marked interstitial epididymitis,
tous nature of the disease. orchitis, and testicular degeneration occurs in malignant
Ascending epididymitis is exceedingly rare in cats. Epididy- catarrhal fever in buffaloes and bulls. Dogs may develop vas-
mitis can occur in feline infectious peritonitis. culitis as part of a localized or generalized polyarteritis, and it
Camelids develop epididymitis rarely. Camels are suscep- may occur in juvenile systemic necrotizing polyarteritis/
tible to Brucella abortus and Brucella melitensis, and develop vasculitis (“Beagle pain syndrome”).
orchitis and epididymitis. Occlusion of the testicular artery with resulting ischemia of
the testis may result from torsion (see Figs. 5-18, 5-19), contu-
Circulatory disturbances sion of the spermatic cord, inappropriate placement and/or
The spermatic artery is long because of the coiled portions of hypotension during surgery, or the use of an emasculatome
the pampiniform plexus proximal to the testis. The degree of for castrating young lambs and calves. Experimentally, destruc-
coiling is marked in ungulates and the spermatic artery is tion of germinal epithelium can be demonstrated after isch-
several meters long. Testicular blood flow is low in relation to emia of more than 1 hour. Necrosis of testicular parenchyma
metabolic needs, and hypoxia and oxidative stress develops follows after 4-6 hours, although spermatozoa are relatively
quickly if increasing testicular temperature increases meta- resistant to lysis and may retain their staining characteristics
bolic demand or if blood flow is impaired. By the time the for weeks or months. The outermost part of the testis may
artery penetrates the testicular capsule, pulsatile flow is almost survive with diffusion of oxygen and nutrients from the
eliminated and the structure of the vessel changes. The diam- vaginal tunics. Islets of seminiferous tubules at the capsule
eter enlarges, the wall becomes thinner, and the elastic fibers (Moskoff’s islets) may survive, and regeneration occurs during
are reduced. Increased intratesticular pressure will reduce the ensuing months. As the regenerated tubules lack a normal
blood flow dramatically. drainage system, there is spermiostasis and ultimately degen-
The interstitial tissue of the testis has abundant lymphatics. eration. In addition and following ligation of the spermatic
In addition to the usual role in fluid exchange, they probably artery in prepubertal rams, revascularization of the testicular
assist in transportation of hormones between interstitial endo- capsule occurred by penetration of capillaries from the epi-
crine cells and the tubules. Edema of the testis occurs after didymal arteries.
trauma and is a frequent early change in orchitis. Although Torsion of the testis is rare unless there is incomplete descent.
the testicular capsule is relatively indistensible, some enlarge- The stallion appears to be the exception, as spontaneous
ment can occur. With edema, there is separation and dilation torsion of an intrascrotal testis is a recognized cause of “colic.”
of tubules, diffuse vacuolation of germinal epithelium, and In other species, such as cats, there are individual reports. In
dilation of lymphatics. dogs especially, testicular neoplasia is often also present, to
The walls of arterioles become thicker and hyaline in provide sufficient weight to maintain the torsion. The usual
wedge-shaped areas of fibrosis in the testes of old bulls, but clinical presentation is acute abdominal pain, and the testis is
492 CHAPTER 5 • Male Genital System Testis and Epididymis
Further reading
Holyoak GR, et al. Pathological changes associated with equine arteritis
virus infection of the reproductive tract in prepubertal and peripu-
bertal colts. J Comp Pathol 1993;109:281-293.
Nguyen L, et al. Effect of unilateral testicular torsion on blood flow and
histology of contralateral testes. J Pediatr Surg 1999;34:680-683.
Parker JE, Rakestraw PC. Intra-abdominal testicular torsion in a horse
without signs of colic. J Am Vet Med Assoc 1997;210:375-357.
Turner TT, et al. Acute testicular ischemia results in germ cell specific
apoptosis in the rat. Biol Reprod 1997;57:1267-1274.
Testis and Epididymis 493
size—either related to the size of the diameter of seminiferous multinodular. The consistency is soft, there being little stroma,
tubules or in centimeters. Such a separation is artificial. and the cut surface is slightly greasy.
In the dog, interstitial cell tumors occur in older animals. Interstitial cell tumors grow slowly and expansively with
They also occur in the bovine testis, in the older age groups, surrounding compression atrophy. They are not notably inva-
and mainly in Guernseys. There are very few reports of tes- sive. In bulls with interstitial cell tumors, semen production
ticular neoplasia in boars, but interstitial endocrine cell hyper- and fertility may be reduced.
plasia and tumor are more common than others. In horses, the The cells in the dog are well differentiated interstitial endo-
tumor develops almost exclusively in a cryptorchid testis. Cats crine cells, being round or polyhedral, with abundant cyto-
develop interstitial cell tumors rarely; ectopic tumors are plasm that may be granular or vacuolar and that often contains
reported, especially in previously castrated animals. yellow or brown lipochrome pigment (Fig. 5-41). The neo-
Some interstitial cell tumors of dogs produce excess andro- plastic cells in the bull are not vacuolated and contain very
gen, but most tumors do not cause signs of hyperandrogenism. little lipid. Sometimes and in some tumors the cells have a
Signs of hyperestrogenism were observed in a few dogs with more mesenchymal appearance, being spindle-shaped with an
interstitial cell tumors and estradiol concentration in testicular indistinct cytoplasmic outline and a streaming arrangement. It
venous blood of affected dogs may be elevated. The condition is in such tumors especially that necrosis and cyst formation
is corrected by removal of the neoplasm. Multiple perianal occur. The nuclei are regular in size and stain affinity, and
hepatoid adenomas, tail gland hyperplasia, and prostatic mitoses are rare. The stroma is scant, and vessels may resemble
enlargement may also be found. sinusoids, as occurs in endocrine organs.
Nodular hyperplasia may be a preneoplastic change in the Intranuclear cytoplasmic invaginations or inclusions occur in
dog. Hyperplastic nodules occur especially in testes that have up to 15% of neoplastic cells in canine interstitial cell tumors.
undergone senile atrophy and, although they may be macro- The inclusions, which are strongly PAS-positive and composed
scopically visible, the nodules are small, nonencapsulated, and of smooth and rough endoplasmic reticulum, vesicles and lipid
consist of an increased number of interstitial endocrine cells vacuoles, myelin figures, and disrupted membranous profiles,
in the intertubular stroma. Hyperplastic cells are regular in were not found in other testicular tumors. Nuclei containing
form and size with increased acidophilia of the cytoplasm; these invaginations are larger. Except where invaginations are
mitoses are not seen. present, the ultrastructural appearances of neoplastic and
Interstitial cell tumors in the dog are often multiple, but normal interstitial endocrine cells in the dog are similar.
may be solitary and unilateral or bilateral (Fig. 5-40). Most are Immunohistochemistry of canine interstitial cell tumors is
from 1 mm to 2 cm diameter; only exceptionally are they usually not required because the histologic findings are char-
large enough to increase the size of the organ. They may make acteristic. A variety of antibodies were used on interstitial cell
the organ irregular in contour with the rounded bulge of the tumors and GATA4 appears to be consistently positive.
tumor being visible in an otherwise small, soft, atrophic testis. A high incidence of telangiectasis of the liver, thyroid C
On cut surface, the tumors are well demarcated, spheroidal, (parafollicular) cell tumors, and infertility was observed in
and yellow. They are prone to hemorrhage, which causes dark Guernsey bulls with interstitial cell tumors, but a cause and
discoloration and cyst formation. Large tumors are often effect was not proven.
Interstitial cell tumors in stallions occur most often in
undescended testes. They contain 2 cell types; the first is
essentially a hypertrophic interstitial endocrine cell but the
other is a pleomorphic fusiform cell with fibrillar, vacuolated
cytoplasm and indistinct borders. Increased hormone
contribute to a tubular pattern, and the neoplastic cells tend (see Fig. 5-17), but their potential to develop into neoplasms
to palisade. In smaller tubules they stretch from one side of seems unlikely, given the rarity of the tumors.
the tubule to the other (Fig. 5-43B). Some form cystic struc- Sertoli cell tumors in other species, including camelids, are
tures that may be confused with carcinoma. In the well- very rare.
differentiated tumors, the cells resemble normal Sertoli cells,
being elongate with foamy acidophilic cytoplasm and small, Germ cell tumors
basally located, nuclei. In less differentiated varieties, the cells Seminomas. Seminomas are common in canine testes and
are still elongate, have eosinophilic cytoplasm, but the nuclei are reported in the bull, boar, stallion and mule, ram, buck,
are oval and pleomorphic, and are no longer basally located tomcat, and bull camelids. They occur in older animals and are
against the trabecular pole. In the less common form of the disproportionately common in cryptorchid testes. Their phe-
tumor, the cells show little or no tendency to palisade but are notype is usually spermatocytic, and there is subclassification
discrete and spherical with well-defined eosinophilic cyto- into classical and spermatocytic types based on periodic acid
plasm and anisokaryosis. Mitoses are sparse in most. Lipids are Schiff (PAS) and placental alkaline phosphatase (PLAP) stain-
demonstrable in the neoplastic cells as large droplets and ing. Classical seminoma is positive for both. Although a soli-
globules in more differentiated tumors, and as fine droplets in tary tumor is observed macroscopically, they are histologically
the least differentiated tumors. There is little correlation multifocal in the affected testes. These tumors typically do not
between histologic type and metastasis. produce hormones; if there is evidence of a hyperestrogenism
It is not possible to generalize about the detailed immuno- syndrome, other possibilities must be completely excluded.
histochemical staining characteristics of Sertoli cell tumors They are usually benign, but metastatic examples are reported.
because of variable results. Neoplastic cells should be positive There are no known factors to predict the metastatic potential
for vimentin (as are interstitial endocrine cells) and negative of seminomas.
for cytokeratin stains (but not always). There are varied The main presenting sign is testicular enlargement. Sudden
reports of staining for many different antigens including S100, enlargement of the testis and pain caused by hemorrhage and
melan A, GATA4, inhibin, and anti-Müllerian hormone necrosis in the tumor, can occur. In all species, the cut surface
(AMH) to name a few. If inhibin and AMH staining are is coarsely lobulated by a few fine trabeculae. The color is
present, a diagnosis is made with greater confidence. usually white or gray-white, except in stallions in which they
Canine Sertoli cell tumors have characteristic electron are often tan (Fig. 5-44), and the texture is soft; they usually
microscopic structures including intercellular junctions and bulge from the cut testicular surface (see Fig. 5-44). If lightly
crystals of Charcot-Bottcher. If these are not visible, Sertoli squeezed, a milky fluid may exude from them. The texture
cell tumors have abundant organelles that allow differentia- and color closely resemble that of neoplastic lymphoid tissue.
tion from interstitial cell tumors and seminomas. Microscopically, intratubular and diffuse types are recognized.
Extratesticular Sertoli cell tumors occur in dogs. They are The earliest development of the tumor is intratubular and
located in the prescrotal and scrotal region or spermatic cord even in some large examples, intratubular growth is still
of neutered dogs. They presumably develop from remnants evident elsewhere (Fig. 5-45A). Rupture of the tubules soon
implanted at castration. Prolonged stimulation of testicular occurs and the growth becomes confluent, forming broad
remnants eventually allows transition from hyperplasia to sheets of closely packed cells with scant supporting stroma.
neoplasia. The tumors are identical to Sertoli cell tumors The cells are large and round or polyhedral, with a rim of
within the testis, and some produce a hyperestrogenism syn- visible cytoplasm that may be basophilic or eosinophilic (Fig.
drome. No metastases are documented. 5-45B). The nuclei are large, round, and hyperchromatic, with
In general, the gross and microscopic appearance of Sertoli one or more large acidophilic nucleoli. In some tumors, the
cell tumors in the bull resembles those in the dog. Early age nuclei are larger and vesicular but still regular in shape. In
of slaughter of most food animals precludes studies on true many seminomas, it is possible to find scattered mono- or
tumor occurrence with increasing age. In one study in which multinucleated giant cells with abundant granular acidophilic
bulls and buffaloes were kept until 9-14 years for draft pur- cytoplasm. A useful distinguishing feature is the presence of
poses, 20 of 161 testes examined contained neoplasms; all but focal nodules of, or diffuse, CD8+ lymphocytes. Whereas
one were Sertoli cell tumors. Seven tumors were in unde- degeneration of tubules at the edge of the tumor is normally
scended testes. In contrast to dogs, bovine Sertoli cell tumors
are often in newborn or young calves, suggesting altered
embryogenesis. They sometimes have laminated intratubular
concretions resembling those seen in bovine testicular hypo-
plasia and cryptorchidism. A simultaneous occurrence of
Sertoli cell tumor and epididymal aplasia was observed. One
bovine Sertoli cell tumor was in a testis of an animal in which
castration by the burdizzo method was attempted 5 years
previously. Metastasis of Sertoli cell tumor to the pampini-
form plexus is reported in a bull; there is no clear evidence of
a hyperestrogenism syndrome.
One case of Sertoli cell tumor in a stallion involved the
single descended testis; a ductal pattern of neoplastic Sertoli
cells, which contained clusters of distinct hyaline bodies, was
evident. Figure 5-44 Multinodular and yellow tan appearance of a semi-
Sertoli cell tumors in the ram are comparable to those in noma in a horse. In other species, the neoplastic tissue varies from
the bull. Hyperplastic Sertoli cells occur in cryptorchid rams white to tan and is friable.
496 CHAPTER 5 • Male Genital System Testis and Epididymis
Reports of mesenchymal tumors of the testis are mostly occurs in virtually every species; it is not reported yet in
individual cases. They include leiomyoma and leiomyosar- the cat.
coma, hemangioma, hemangiosarcoma, lymphangioma, and Adenomyosis of the mesonephric ducts is a histologic
peripheral nerve sheath tumor. Mast cell tumor and histiocytic finding in which diverticula of the epithelium of the epididymis
sarcoma are also reported. or deferent duct protrude through the muscular wall. Spermato-
Neoplasia of the epididymis is a very rare event. Any tissue zoa may become entrapped and incite an inflammatory reac-
may transform, and carcinoma is reported. Metastases from tion. Hyperestrogenism may be an inciting cause. Adenomyosis
elsewhere occur too, and lymphoma may occur. Interstitial cell is the suspected underlying defect when a sperm granuloma
tumor of the epididymis of the cat is a recognized disease and is found in a location apart from where blind-ending efferent
arises from ectopic interstitial endocrine cells. ductules would be expected. Virtually every species develops
adenomyosis of the mesonephric duct.
The rete testis is a series of interconnected channels that
Further reading join the seminiferous tubules to the efferent ductules. It has
Ali A, et al. Unilateral seminoma in a dromedary camel. Reprod Dom intratesticular and extratesticular segments. Spermatophagia
Anim 2013;48:17-19. occurs in this area, and immune reactions to spermatozoa may
Banco B, et al. Immunohistochemical evaluation of the expression of be manifested by inflammation. There are 2 main primary
anti-mullerian hormone in mature, immature and neoplastic canine diseases of the rete: neoplasia and cyst formation. The epithelial
Sertoli cells. J Comp Pathol 2012;146:18-23. cells are the origin of adenomas and adenocarcinomas in
Dreimanis U, et al. Evaluation of preputial cytology in diagnosing oes- horses, dogs, and other species. Cysts of this region occur in
trogen producing testicular tumours in dogs. J Sm Anim Pract the stallion, dogs, and cats. Secondary dilation of the rete testis
2012;53:536-541. occurs with obstruction of the efferent ductules or
Grieco V, et al. Canine testicular tumours: a study on 232 dogs. J Comp epididymis.
Pathol 2008;138:86-89.
Jensen KL, et al. Malignant Sertoli cell tumour in a young Simmenthal
SPERMATIC CORD
bull—clinical and pathological observations. Reprod Dom Anim
2008;43:760-763. The spermatic cord is composed of the 3 arteries, veins, lymphatics,
Kennedy PC, et al. Histological classification of tumors of the genital 3 nerves, and deferent duct. It is covered by 3 layers, including
system of domestic animals. WHO International Histological Clas- the cremaster muscle and fascias. These are critical structures
sification of Tumors of Domestic Animals, Series 2, vol III. Washing- for the function of the testis and epididymis. Scrotal hernia
ton, DC: AFIP, ARP; 1998. and varices of the pampiniform plexus are the most com-
Marino G, et al. Activins and inhibins: expression and role in normal monly recognized diseases of the spermatic cord. Most of the
and pathological canine reproductive organs: a review. J Vet Med other diseases become differential diagnoses for these.
2013;42:1-8.
McEntee MC. Reproductive oncology. Clin Tech Small Anim Pract Varicocele
2002;17:133-149. A varicocele is a dilation and tortuosity of the veins of the pampi-
Mischke R, et al. Blood plasma concentrations of oestradiol-17β, niform plexus. Varices of the spermatic veins are most common
testosterone and testosterone/oestradiol ratio in dogs with in old rams (Fig. 5-46). They occur sporadically in others,
neoplastic and degenerative testicular diseases. Res Vet Sci such as the bull, stallion, and dog, as an incidental finding or
2002;73:267-272. secondarily to conditions in which there is constriction of
Nodtvedt A, et al. Breed differences in the proportional morbidity of the veins of the spermatic cord. Experimental induction
testicular tumours and distribution of histopathologic types in a is achieved by generating partial obstruction of the left
population-based canine cancer registry. Vet Comp Oncol renal vein.
2011;9:45-54. Varices are seldom recognized unless they are thrombosed.
Peters MA, et al. Use of antibodies against LH receptor, 3β-hydroxysteroid There is no concrete evidence that small varicoceles are det-
dehydrogenase and vimentin to characterize different types of tes- rimental. Large ones are, because of their size and the reduced
ticular tumour in dogs. Reproduction 2001;121:287-296. ability of the animal to raise the testis to maintain thermo-
Quartuccio M, et al. Sertoli cell tumors associated with feminizing regulation, or because of alteration of blood flow and changed
syndrome and spermatic cord torsion in two cryptorchid dogs. J Vet testicular oxidant/antioxidant balance. The pathogenesis of
Sci 2012;13:207-209. varicocele is poorly understood. In humans, the left unilateral
Ramos-Vara JA, Miller MA. Immunohistochemical evaluation of GATA-4 location is the result of altered hemodynamics from insertion
in canine testicular tumors. Vet Pathol 2009;46:893-896. of the testicular vein to the renal vein rather than directly to
Reis-Filho JS, et al. Bilateral gonadoblastomas in a dog with mixed the vena cava. Evidence in humans with varicose veins of the
gonadal dysgenesis. J Comp Pathol 2004;130:229-233. legs suggests that the elastic properties of the walls of the
Yu C-H, et al. Comparative immunohistochemical characterization veins, arterial flow, and valves in veins are major factors. It is
of canine seminomas and Sertoli cell tumours. J Vet Sci difficult to implicate intimal sclerosis of the spermatic vessels
2009;10:1-7. as older animals of all species develop this, but so few develop
varicocele.
Varicoceles appear as dark red, up to 3-cm diameter,
Miscellaneous diseases of the testis nodules enclosed in fascia of the spermatic cord proximal to
and epididymis the testis. Varicoceles may have large organizing laminated
Spermatic granulomas occur at any location. The most recog- thrombi, typical of venous thrombi. Differential diagnoses of
nized syndrome is spermatic granuloma of the epididymal head, varicocele include neoplasia (mesothelioma), scrotal hernia,
a condition resulting from blind-ending efferent ductules. It scrotal lymphadenitis, spermatic granuloma of the epididymal
497.e1
Further reading
Banco B, et al. An immunohistochemical study of normal and neoplas-
tic canine Sertoli cells. J Comp Pathol 2010;143:239-247.
Bazzo R, et al. Sertoli cell tumour with Call-Exner-like bodies in a dog.
J Vet Med A Physiol Pathol Clin Med 2002;49:535-537.
Brinsko SP. Neoplasia of the male reproductive tract. Vet Clin North Am
Equine Pract 1998;14:517-533.
Doxsee AL, et al. Extratesticular interstitial and Sertoli cell tumors in
previously neutered dogs and cats: a report of 17 cases. Can Vet J
2006;47:763-766.
Grieco V, et al. Classical and spermatocytic seminoma in the dog:
histochemical and immunohistochemical findings. J Comp Pathol
2007;137:41-46.
Grieco V, et al. Inhibin-alpha immunohistochemical expression in
mature and immature canine Sertoli and Leydig cells. Reprod Dom
Anim 2011;46:920-923.
Luby CD, et al. Theriogenology question of the month. J Am Vet Med
Assoc 2007;231:10.
McEntee K. Reproductive Pathology of Domestic Mammals. London:
Academic Press; 1990. p. 230-231.
Murakami Y, et al. Immunohistochemical analysis of cyclins in canine
normal testes and testicular tumors. J Vet Med Sci 2001;63:
909-912.
Owsten MA, et al. Histologic and immunohistochemical characteriza-
tion of a testicular mixed germ cell sex cord-stromal tumor and a
Leydig cell tumor in a dog. Vet Pathol 2007;44:936-943.
Patnaik AK, Mostofi FK. A clinicopathologic, histologic and immuno-
histochemical study of mixed germ cell-stromal tumors of the testis
in 16 dogs. Vet Pathol 1993;30:287-295.
Peters MA, et al. Ageing, testicular tumours and the pituitary-testis axis
in dogs. J Endocrinol 2000;166:153-161.
Radi ZA, et al. Rete testis mucinous adenocarcinoma in a dog. Vet
Pathol 2004;41:75-78.
Taniyama H, et al. Immunohistochemical detection of inhibin-α, -βB,
and -βA chains and 3β-hydroxysteroid dehydrogenase in canine
testicular tumors and normal testes. Vet Pathol 2001;38:661-666.
Weaver DM, et al. Bilateral testicular interstitial cell tumour in an aged
boar. Vet Rec 2000;146:224.
498 CHAPTER 5 • Male Genital System Spermatic Cord
Further reading
McEntee K. Reproductive Pathology of Domestic Mammals. Academic
Press.1990, p281.
Smith KC, et al. A survey of congenital reproductive abnormalities in
rams in abattoirs in south west England. Reprod Dom Anim
2012;47:740-745.
Turner TT. The study of varicocele through the use of animal models.
Hum Reprod Update 2001;7:78-84.
van der Velden MA, van der Harst MR. Inguinal herniation in foals.
Literature review and a case report. Tijdschr Diergeneeskd
2004;129:286-292.
Zhao X, et al. Association of HOXA10, ZFPM2 and MMP2 genes with
scrotal hernias evaluated via biological candidate gene analysis in
pigs. Am J Vet Res 2009;70:1006-1011.
Further reading
Ezzi A, et al. Pathology of varicocele in the ram. Aust Vet J
1988;65:11-15.
Nistal M, Paniagia R. Testicular and Epididymal Pathology. New York:
Thieme and Stratton; 1984.
Perkins NR, Frazer GS. Reproductive emergencies in the stallion. Vet
Clin North Am Equine Pract 1994;10:671-683.
Roberts SJ. Scrotal hernia in rams: a case report. Cornell Vet
1988;78:351-352.
500 CHAPTER 5 • Male Genital System Accessory Genital Glands
granuloma formation is rarely observed. Tuberculous vesicular including cryptorchidism. A prostatic appendage is reported
adenitis causes an increased size of vesicular glands with char- in the bull where a polyp-like protrusion of prostatic tissue
acteristic caseation and granulomas. bulged into the urethral lumen. Congenital retention cysts
Several viruses, including the virus of infectious bovine occur in the bull and a cryptorchid boar. In some dogs, the
rhinotracheitis-infectious pustular vulvovaginitis (bovine her- dorsal median groove of the prostate may be indistinct so the
pesvirus 1), may infect the accessory genital glands of the bull. bilobed structure is not evident.
Clinical signs of vesicular adenitis in such cases are reported Prostatic cysts and pseudocysts in the dog may be congeni-
to be mild and transitory. The vesicular glands and prostate tal or secondary to hyperplasia, neoplasia, or inflammation
are the most productive sites for viral replication in bovine (see later). Cysts within the prostate may be multiple cysts in
viral diarrhea virus infection in bulls, but neither gross nor prostatic hyperplasia, retention cysts, and cysts with squamous
microscopic lesions are observed. Mycoplasma bovis, Myco- metaplasia. Those outside the prostate are called paraprostatic
plasma bovigenitalium, and ureaplasmas were isolated from cysts or pseudocysts (Fig. 5-49). Those lined by epithelium are
bulls with vesicular adenitis, and unequivocal lesions have true cysts (Fig. 5-50) and those without epithelium are pseu-
resulted from experimental infection. Apart from variable docysts. The precise origin of paraprostatic cysts is not clear.
numbers of eosinophils in these lesions, they are nonspecific. Most cysts attach to the prostate at a small localized area. The
Mycoplasma bovigenitalium, however, was isolated from vesic- cysts are up to 30 cm long and 14 cm in diameter, and have
ular gland secretions from a large proportion of normal pubes- a wall of compressed collagen and even bone (see Fig. 5-50).
cent bulls. As with the mycoplasmas, Chlamydophila spp. are Fibrin may be present on the inner aspect of the larger cysts,
isolated from the semen and epididymides of bulls, and their as well as polypoid bony extensions into the lumen. Cysts
possible role in vesicular adenitis is unknown. The vesicular become infected to form a prostatic abscess, although most
glands may also be an important site for localization of Lep-
tospira spp. Leptospira interrogans serovar hardjo was isolated
with equal frequency from vesicular glands and kidneys of
naturally infected bulls, thereby suggesting the possibility of
venereal transmission.
The pathogenesis of bovine vesicular adenitis is unresolved.
Hematogenous infection of the glands seems probable in some
cases, but ascending infection from the urethra is probable.
Stress, reflux of urine or semen into the vesicular glands, and
congenital defects in the mesonephric duct system predispose
to infection.
In pigs, sheep, and goats, vesicular adenitis is of less impor-
tance than in the bull. It occurs in brucellosis caused by
Brucella suis, Brucella ovis, and Brucella melitensis, respectively.
The characteristic lesion is chronic, and resembles the chronic
interstitial form seen in the bull (see Fig. 5-48). In boars,
abscessation of the vesicular glands and prostate may accom-
pany orchitis caused by Burkholderia pseudomallei. Abscesses
in the vesicular glands of barrows may be the result of infec-
tion at the time of castration.
In the stallion, purulent, abscessating vesicular adenitis is Figure 5-49 Paraprostatic cyst (upper) distorting the contour of
described, but appears to be uncommon. Virus is shed for the prostate (lower) in a dog. The bladder is to the right.
months in the semen of stallions infected experimentally with
equine arteritis virus. The ampullae and bulbourethral glands
are predilection sites. It is unclear whether there are lesions
in infected tissues, or associated spermatozoal abnormalities.
Bacterial vesicular adenitis and ampullitis occur sporadically
and may be a cause of “colic.”
A marbled cut surface. They may also contain cysts that are large
enough to cause fluctuant swelling of the perineal region.
These are filled with urine and cellular detritus because they
communicate with the urethra via the ducts of the gland. The
epithelial hyperplasia may obstruct the urethra. Cystic uterus
masculinus develops too, and there may be mammary devel-
opment (for effect on females, see Vol. 3, Female genital
system). Prolapse of the rectum also occurs. The prostatic
changes are visible as chalky or yellow streaks and flecks on
the dorsal surface of the urethra. Microscopically, there is
squamous metaplasia with central keratinization.
Marked squamous metaplasia, especially of the vesicular
glands, of bulls follows ingestion of chlorinated naphthalenes.
Nodular hyperplasia of the bulbourethral glands of rams
occurs occasionally as an incidental finding.
Prostatic hyperplasia is very common in dogs, and is tes-
tosterone dependent (Fig. 5-54). It also occurs in the bull. The
B entire prostate is larger; nodular hyperplasia is very rare. The
Figure 5-53 A. Histologic appearance of suppurative prostatitis prevalence and degree of hyperplasia increases with advancing
with destruction of glandular lumina with predominantly neutro- years, such that 80% or more of mature or old dogs have an
phils, lesser numbers of macrophages, and interstitial edema. enlarged prostate.
B. Lymphocytic prostatitis with lymphocytes, plasma cells, and Enlargement of the prostate frequently causes obstipation.
abundant fibrous tissue in the interstitium of the prostate of The colon is obstructed when the prostate is forced into the
a dog. pelvic inlet as the dog assumes the position for defecation and
increases abdominal pressure. Less common is interference with
urination. Urinary retention occurs. It is impossible to demon-
Prostatitis is a constant feature of Brucella canis infection. strate compression of the urethra, the urethra is not sur-
Typically, involvement is extensive but lobular in distribution, rounded by the prostate gland, and in the living animal,
and consists of many lymphocytes in the interstitium. There incontinence is common and urine can be expressed easily.
is often fibrosis and atrophy or loss of adjacent epithelium. Pressure of the enlarged gland on the sacral parasympathetic
Apart from bacterial prostatitis, systemic fungal infections nerves may be responsible, as is attenuation of the urethral
caused by Blastomyces dermatitidis, Cryptococcus neoformans, lumen by longitudinal stretching when the prostatic enlarge-
and Coccidioides immitis may involve the prostate. There are ment is sufficient to cause displacement forward into the
reports of prostatitis with Mycoplasma canis and Leishmania abdomen. Acute infections of the urinary tract and hydrone-
spp. recovered from the lesion or seminal fluid. phrosis often complicate urinary retention.
Prostatitis in bulls, boars, stallions, rams, bucks, and tomcats A higher estrogen:testosterone ratio underlies prostatic hyper-
is very rare, but when present, has a similar range of changes plasia in dogs. Prolactin may also be involved. Hyperplasia
as occurs in the dog. does not occur in castrated dogs, and castration causes a reduc-
tion in size. The exception is extremely rare, that is, when a
Hyperplasia and metaplasia of the prostate and castrated dog has an estrogen-secreting tumor. At puberty,
bulbourethral gland epithelial hyperplasia is coincidental with normal testicular
Hyperplasia or metaplasia of the bulbourethral glands is rare. development and hormone production. Throughout life, the
Reversible enlargement of the bulbourethral glands with squa- testosterone and dihydrotestosterone concentration in serum
mous metaplasia, hyperplasia, and cystic dilation occurs in is unchanged, but it increases in prostatic secretion with age.
wethers ingesting strains of clover with high estrogenic potency, Testosterone receptor content in each cell is not changed. The
such as Trifolium pratense, T. repens, T. subterraneum. In wethers, 17β estradiol:testosterone ratio is increased in those dogs with
but not in rams, grazing potent green clover pastures induces prostatic hyperplasia. Estrogens act synergistically with andro-
the bulbourethral glands to become large and firm with a gens to potentiate hyperplasia of the epithelium. It is unclear
Accessory Genital Glands 503
in spontaneous prostatic hyperplasia, however, whether and estrogens. The metaplastic change may involve acini in all parts
to what extent estrogen induces accompanying stromal of the gland as well as the prostatic urethra, uterus masculinus,
changes. and ducts. Affected epithelium becomes stratified squamous
The hyperplastic gland is large and the surface is either in type, with keratin squames in the lumen. Neutrophils and
smooth and regular or irregularly nodular (see Fig. 5-54). macrophages are often in the lumina too. There is no evidence
Larger prostates have a less obvious bilobed appearance. Fluc- that squamous metaplasia of the canine prostate is a preneo-
tuating cysts and venous and lymphatic ectasias may be plastic change.
present beneath the capsule. The appearance of the cut surface Squamous metaplasia occurs in swine exposed to estro-
depends on the degree of acinar and stromal hyperplasia and genic mycotoxins such as zearalenone. In cats, prostatic
on the presence and size of cysts. The lobules vary in size and enlargement with epithelial hyperplasia and cystic dilation of
may be poorly defined, or well defined if there is a prominent glands follows estrogen administration. Metaplastic cornifica-
increase in amount of the interlobular stroma. tion is restricted to urethral epithelium.
The glandular elements are often sponge-like in appear-
ance because there are numerous small cysts containing milky Neoplasms of the prostate and bulbourethral gland
fluid. The cysts are irregularly distributed, but the largest ones Neoplasia of the accessory genital glands is rare in all domestic
tend to be located beneath the capsule. The prostatic urethra mammals, although carcinoma of the prostate in dogs is a
may have small yellow elevations of the mucosa correspond- well-known and intensely studied disease used in comparison
ing to the papillae of the excretory ducts. Microscopically with human prostatic carcinoma. The original site of develop-
there is lobular hyperplasia, stromal hyperplasia and conden- ment and the classification of carcinomas is debated and opin-
sation, and cyst formation variously interspersed. The acinar ions vary. Neoplasms may arise from the pelvic urethra,
hyperplasia consists of hyperplasia and hypertrophy of the prostatic ducts, or glandular acini, and the phenotypes vary
epithelial cells often with papillae, but there is always a single from adenocarcinoma to transitional cell carcinoma to squa-
layer of epithelial cells on an intact basement membrane. mous cell carcinoma and mixtures of several types. The major-
Within the same lobule, some acini may be cystic, and these ity are poorly differentiated and a mixture of types. Because
are of irregular size, round, and lined by epithelium that is dogs castrated prior to puberty develop carcinoma with equal
attenuated (Fig. 5-55). There may be secretion in the lumen. frequency to nonneutered males, a urothelial phenotype is
The interlobular connective tissue is increased in amount to often suggested, given that about half of cases will express
various degrees and density, and may exist as broad sheets with urothelial phenotypic markers (such as uroplakin). Immuno-
some extension into the intralobular stroma. In most instances, histochemical and proteomic studies have failed to adequately
this interstitial tissue contains some lymphocytes and plasma classify these tumors accurately or to show a prognostic
cells but the epithelium or acinar lumen is not affected. difference.
There is no clear distinction between a normal prostate and The prostate and urethra arises embryologically from endo-
one that is in the early stages of hyperplasia, although arbitrary dermal epithelium, so separation of the different types is
decisions are based on the weight or size of the gland relative fundamentally difficult. Studies so far have failed to conclu-
to body weight and for a specific age. The relative weight cor- sively indicate a prognostic difference between the types. It is
rected for age is fairly consistent, except in Scottish Terriers better to group the neoplasms as carcinoma of the prostate,
in which the relative weight of the prostate is about 4 times and to avoid classification without ironclad outcome-based
that of any other breed. Although estrogen is therapeutically data.
effective in causing temporary regression of an enlarged pros- The cause of prostatic carcinoma is unknown. The prevalence
tate, rapid enlargement of the gland follows. of hyperplasia of the prostate and the rarity of neoplasia
Squamous metaplasia of the epithelium may occur in dogs suggest they are not linked. Low-grade prostatic intraepithelial
with Sertoli cell tumors, or following the administration of neoplasia (PIN), as occurs in human males, does not occur as
a solitary lesion in dogs except in very rare situations. Even
then, separation of PIN from squamous metaplasia or other
change in prostatitis is difficult. High-grade PIN does occur in
prostates with carcinoma.
The high relative prevalence in previously neutered dogs
suggests that hormonal influences are not involved, at least
not in those animals. Prostatic neoplasia is not causally related
to testicular neoplasia.
Prostatic carcinoma occurs mostly in old dogs, especially
those older than 10 years. Clinical signs mimic those of
prostatic disease generally, and fall into 2 main categories.
Many dogs develop dysuria, stranguria, and obstruction. Some
have fecal obstipation, whereas others have emaciation and
hindlimb locomotory disturbances, apparently a result of
metastasis to the lower lumbar vertebrae, bones of the pelvis,
and long bones of the rear limbs. Spread of neoplastic cells to
bone is via the vertebral venous plexus, systemic circulation,
or direct extension.
Figure 5-55 Microscopic appearance of prostatic hyperplasia. Enlargement of the prostate with carcinoma is more likely
The acinar epithelial cells are tall columnar with prominent eosin- to be asymmetric and irregular than in hyperplasia (Figs. 5-56,
ophilic granules in their apical cytoplasm, and the acini are cystic. 5-57). A severe fibrosing reaction with neoplastic cells may
504 CHAPTER 5 • Male Genital System Accessory Genital Glands
lining of the concretion cavity varies from normal to pseu- fertilization. The number and complexity of the disorders of
dostratified. Their structure is amorphous eosinophilic debris development is great, so only the more common and or impor-
with occasional clumps of enmeshed nuclear material. Con- tant are listed here.
cretions are composed of organic components, phosphates, Penile and preputial hypoplasia results from a lack of testos-
carbonates, and spermatozoa—so-called “semen stones.” Micro- terone at critical time periods—from development of the
concretions are common in the vesicular glands of rams, unas- penis to puberty. This occurs in early castration and in many
sociated with inflammation. DSD. Bulls have a form of hypoplasia described as congenital
In dogs, the occurrence of prostatic concretions or calculi short penis, possibly associated with shortening of the retractor
is extremely rare and such calculi may be confused with penis muscle. Penile protrusion (penile tip to preputial orifice)
urinary calculi. One report of a 30 × 20 × 10 mm laminated is 10-22 cm as opposed to 25-42 cm in normal matched con-
prostatic calculus composed of calcium carbonate and struvite trols. Partial or complete lack of the sigmoid flexure of the penis
suggested that it resulted from reflux of urine. Calculi are occurs in bulls and rams. Hypoplasia of the head of the penis
normally 1-5 mm in diameter, hard, white, and spherical, and only is reported. Other rare disorders of sexual development
consist of phosphates and carbonates of calcium as well as in the bull include abnormal insertion of the retractor penis
urates and oxalates. These form around a crystallization point muscle, with stretching of the skin cranial to the testis during
of organic material—mostly desquamated gland epithelium. erection, partial or complete duplication of the penis, super-
Calculi seldom elicit clinical signs. Prostatic calculi are reported numerary ectopic penis, and detached urethral process in
in sheep. which the free end of the penis has a bifid appearance resem-
Metaplastic ossification of prostatic stroma occurs in the bling diphallia. Diphallia is reported in several species, includ-
dog, usually with neoplasia. Foci of mineralized bone could ing the bull, ram, and tomcat.
be mistaken for calculi on radiographic examination. Defects of the urogenital system may have a penile urethral
Intraductal foreign (plant) material and chronic adenitis component. Congenital dilation of the penile urethra is
affected the bulbourethral gland of a bull. described in the goat.
Directional deviations of the erect penis occur with persis-
tence of balanopreputial folds—regions in which the prepuce
Further reading failed to separate from the penile epithelium. A well-known
Caney SMA, et al. Prostatic carcinoma in two cats. J Small Anim Pract fold is the persistent penile frenulum, which occurs when the
1998;39:140-143. penile frenulum fails to separate from the prepuce. Persistent
Cornell KK, et al. Clinical and pathologic aspects of spontaneous penile frenulum is reported in the bull, boar, buck, dog, and
canine prostate carcinoma: a retrospective analysis of 76 cases. tomcat. Although studies in the boar have indicated some
Prostate 2000;45:173-183. breed susceptibility for persistent frenulum, there is no defi-
Grieco V, et al. Cytokeratin and vimentin expression in normal and nite evidence for inheritance of this trait in any domestic
neoplastic canine prostate. J Comp Pathol 2003;129:78-84. species. Deviation of the penis occurs with asymmetrical devel-
Kirchof N, et al. Prostatic calculus in a dog. Praktische Tiearzt opment of the cavernosum of the penis in the horse and
1996;77:113-116. donkey, malfunction of the apical ligament in the bull and
Lai C-L, et al. Histopathological and immunohistochemical character- ram, and congenital curvature of the os penis in the dog.
ization of canine prostate cancer. Prostate 2008;68:477-488. Erectile dysfunction, failure of erection of the penis, is rare.
LeRoy BE, Northrup N. Prostate cancer in dogs: comparative and clinical Erection requires central nervous system control, local nervous
aspects. Vet J 2009;180:149-162. control with contraction of the ischiocavernosus muscles, and
Teske E, et al. Canine prostate carcinoma: epidemiological evidence of vasoconstriction of veins. This allows arterial input to the
an increased risk in castrated dogs. Mol Cell Endocrinol erectile tissue of the cavernosum and spongiosum but occludes
2002;197:251-255. venous drainage. Vascular defects of the penis that cause
failure of erection are studied in the bull and boar, but their
precise diagnosis antemortem or postmortem requires injec-
tion of contrast material and radiography, or injection of
PENIS AND PREPUCE
plastic into vessels to form casts. Vascular shunts from the
The penis and prepuce develop from the urogenital tubercle. cavernosum to the spongiosum of the penis or to peripenile
The preputial cavity only forms when the epithelial recess vasculature prevent effective erection. Congenital shunts from
separates just before puberty. The penis attaches to the the cavernosum to neighboring veins in boars can be inherited.
ischium and ends with the head of the penis. In all species Immunohistochemical studies of impotence in the boar pro-
except the dog, the intrapreputial component of the penis vided evidence that defective innervation contributes, with
includes the head and a short part of the body of the penis. depletion of vasointestinal polypeptide (VIP) reactivity in
The head of the penis is longest in the dog, where it includes penile nerves.
the erectile bulbs of the penis and is the only intrapreputial Penetrating injuries and traumatic fistulas of the erectile
part. The penile urethra forms ventrally. Small ruminants have tissue and the urethra or external tissues leads to hemorrhage
a urethral process, and in the cat, the penile spines or barbs are that can be life threatening. This, in the bull, includes forced
testosterone dependent. The stallion has a sebaceous secretion deviation and rupture of the penis with subsequent hematoma
in its prepuce that is smegma. In the other species, the internal formation. Penile hematoma resulting from forced deviation
prepuce is a mucous membrane. of the penis occurs in bulls and rams at the distal bend of the
Disorders of development of the penis are many, and are sigmoid flexure, but sometimes proximal to it (Fig. 5-59). In
part of the myriad disorders of sexual development (DSD). stallions, rupture of the cavernosum outside an intact tunic
Some are surgically correctable, others are functional abnor- (tunica albuginea) of the penis is more frequent; trauma is the
malities, and others prevent intromission and or do not allow likely cause. Other vascular lesions include varicosities of
505.e1
Further reading
Ahmad N, et al. Seminal vesiculitis and epididymitis in an Anglo-Nubian
buck. Vet Rec 1993;133:322-323.
Girard C, Despots J. Mineralised paraprostatic cyst in a dog. Can Vet J
1995;36:573-574.
Hayden DW, et al. Prostatic leiomyosarcoma in a dog. J Vet Diagn
Invest 1999;11:283-286.
Kirkland PD, et al. Replication of bovine viral diarrhoea virus in the
bovine reproductive tract and excretion of virus in semen during
acute and chronic infections. Vet Rec 1991;128:587-590.
LeRoy BE, et al. Canine prostate carcinomas express markers of uro-
thelial and prostatic differentiation. Vet Pathol 2004;41:131-140.
Randles JL. Clinical, pathological and histopathological findings in
lambs implanted with a growth promoting product containing pro-
gesterone and oestradiol. J S Afr Vet Assoc 1990;61:126-127.
Rohleder JJ, Jones JC. Emphysematous prostatitis and carcinoma in a
dog. J Am Anim Hosp Assoc 2002;38:478-481.
Schoofs S, et al. Streptococcus pneumoniae in a prostatic abscess in a
dog. Vlaams Diergeneeskundig Tijdschrift 1997;66:229-230.
506 CHAPTER 5 • Male Genital System Penis and Prepuce
of necrosis on the penis. These may form confluent and flat posthitis, and as animals on a high plane of nutrition are pre-
efflorescences. In severe cases, edema of the penis and prepuce disposed, a parallel of this condition with ovine posthitis is
may occur. The foci of necrotic mucosa exist for 1-2 days only, suggested. However, it is not clear why steers are infrequently
then the surface sloughs and sharp erosions remain, especially affected. Mild to severe erosions and ulceration with edema
in the area of the head of the penis. Many erosions are sur- are confined to the preputial orifice and cranioventral area of
rounded by a red zone of hyperemia. In uncomplicated cases, the prepuce. Lesions begin as small raised areas of necrosis
healing is complete in 2 weeks. As with any infection of the that leave shallow erosions. The ulcers are irregular in shape,
prepuce, lymphoid follicles develop and are pale to dark red may be several centimeters in diameter, are sharply defined
1-2 mm nodules that raise the mucosal surface. and frequently bleed. The histologic appearance of lesions is
The microscopic lesions are foci of dead cells within the nonspecific, with superficial necrosis, reactive epithelial hyper-
epithelium and spongiosis. Intranuclear inclusion bodies may plasia, and underlying granulation tissue. Causal organisms
appear in epithelial cells. Dead cells slough and shallow ulcers cannot be demonstrated histologically in the lesions that
form. Neutrophils migrate into the affected epithelium and precede ulceration. In more severe forms there is increasing
lymphocytes appear in the submucosa. As with other herpes- edema, abscessation, and even myiasis. Deformity of the pre-
viral infections, latency occurs and viral production is reacti- putial orifice and phimosis may occur following healing of
vated naturally or following treatment with corticosteroids. ulcers.
Although orchitis is reported in bulls, it is exceptional. Traumatic injury with subsequent infection by such organ-
The pathogenesis of equine coital exanthema, caused by isms as Trueperella pyogenes, Escherichia coli, streptococci, and
equid herpesvirus 3, are comparable to BoHV-1 in cattle, staphylococci is common in bulls. Less common lesions
although the penile and preputial lesions and subsequent ero- include balanoposthitis from infection with the larvae of
sions are larger, being up to 15 mm in diameter. Lesions in the Strongyloides papillosus. Tuberculous balanoposthitis, with
stallion tend to involve the body of the penis more frequently characteristic granulomas involving the penis or prepuce, is
than the head. They first appear 2-5 days post exposure as seen occasionally in bulls from infected herds, sometimes as
vesicles, but rapidly progress to circumscribed yellow pustules the only lesion. Genital transmission is possible. The presence
with raised borders and depressed centers. Resolution usually of Campylobacter fetus subsp. venerealis in the preputial sac
occurs within a few weeks, leaving depigmented spots. does not produce gross or histologic changes. Likewise, specific
Herpesviral infection of male goats (CapHV-1) causes similar lesions do not accompany preputial infection in bulls by Tri
lesions that can progress to extensive suppurative and necro- trichomonas foetus. Microscopic examination of infected penile
tizing phaloposthitis involving the head of the penis, fornix, and preputial epithelium may reveal cells and debris in crypts,
and entire urethral process. and a typical lymphocytic submucosal reaction. Rarely can
In dogs, the genital lesions of canid herpesvirus 1 infection trichomonads be demonstrated in histologic sections. Recogni-
consist of hyperemia, petechial hemorrhages, and the develop- tion of the carrier state in bulls in the absence of lesions in
ment of lymphoid nodules, especially over the base of the both campylobacteriosis and trichomoniasis emphasizes the
penis and the preputial reflection. There is a serous discharge need for diagnosis by culture or molecular techniques.
from the preputial orifice. Lesions appear about 3 days after Preputial diverticulitis occurs in swine, and the character-
experimental infection, but are self-limiting, and regress 4-5 istic plaques and ulcers occur in the preputial diverticula of
days subsequently, with no apparent sequelae. Simultaneous 25-40% or more of castrated and entire male pigs. The lesions
conjunctivitis may occur. Recurrence of lesions, an important begin as foci of hyperkeratosis and progress to distinct white-
feature of the disease in bitches, seems to be less common in gray plaques 2-4 mm in diameter with obvious para- and
the male. Pustule formation and ulceration do not appear to dyskeratosis. Yellow-brown ulcers up to ~10 mm in diameter
be a feature of genital herpesvirus infection in the male dog with raised borders form (Fig. 5-61) following central necrosis,
even though virus can be isolated from the penis of infected sloughing of epithelium, and infiltrating neutrophils. Such
dogs following immunosuppression with prednisolone. lesions may become confluent, and hemorrhage from them is
A mild balanoposthitis, not associated with herpesvirus common. Calculi may be present in the diverticulum. The
infection and presumed to be bacterial in origin, is common precise cause of preputial diverticulitis in pigs is unclear, but
in dogs. Depending on duration, there is intense hyperemia of
the epithelium, erosion, and mucopurulent exudate. Lym-
phoid follicles become enlarged and prominent. Hemolytic
strains of Escherichia coli are most frequently isolated from
such cases, other common isolates being Proteus vulgaris and
hemolytic streptococci.
Multiple pale dome-shaped papules up to ∼3 mm in diam-
eter on hairless parts of the equine prepuce, and on the
muzzle, may result from infection with the molluscum con-
tagiosum virus (Molluscipoxvirus) (for details see Vol. 1,
Integumentary system). Histologically, discrete epithelial
hypertrophy and hyperplasia with characteristic “molluscum
bodies” are present.
Outbreaks of ulcerative posthitis in bulls occur occasion-
ally, but these are less severe than in sheep (see later). The
cause and pathogenesis of this condition is unknown. Coryne-
bacterium renale, an inhabitant of the prepuce of apparently
healthy bulls, is frequently isolated from bulls with ulcerative Figure 5-61 Ulcers of the preputial diverticulum of a boar.
508 CHAPTER 5 • Male Genital System Penis and Prepuce
accumulation and decomposition of urine is important. Acti- The lesion in wethers begins as a small yellow area of
nobaculum suis, a cause of pyelonephritis and cystitis in sows, epithelial necrosis at the orifice of the prepuce, often dorsally.
may be isolated from the prepuce of boars with diverticulitis This ulcerates and there is slow expansion of the lesion and
and healthy boars alike; the likelihood of venereal transfer granulation that results in stenosis and occlusion of the pre-
exists. Other bacteria frequently present in the diverticulum putial orifice. Secondary lesions occur when the prepuce
include Proteus spp. and staphylococci. There is no correlation becomes swollen from the accumulation of urine or pus.
between types of bacteria present and boar performance. Extensive internal ulceration of the prepuce develops, the
Older pigs are more likely to develop ulcers. An age-related urethral process is destroyed, and the head of the penis ulcer-
change in the bacterial flora of the diverticulum occurs, Acti- ates. The common name applied is pizzle rot.
nobaculum suis being generally more common in pigs >4 A severe ulcerative balanitis, distinct from the aforemen-
months of age and in adult boars than in younger animals. tioned condition, occurs in border Leicester rams and in
Spirochetes also colonize the preputial diverticulum and may Dorper sheep. Ewes mated to them develop vulvovaginitis.
contribute to inflammation. Outbreaks occur in a flock. Deep ulcers up to several centi-
Marked and apparently selective infestation of muscles of meters in diameter occur on the ventral surface of the penis.
the penile urethra in pigs may occur several months after Excessive granulation tissue and variable hemorrhage follows.
infection with Sarcocystis miescheriana from dogs. Microscopi- Necrotic and purulent material covers the head of the penis
cally, there is degeneration of muscle fibers; eosinophils with and urethral process. Adhesions of the penis and prepuce
fewer lymphocytes and macrophages are present. result. Ewes in contact with affected rams have shallow ulcers
Balanoposthitis is an uncommon lesion in the stallion but on the ventral commissure of the labia and posterior vagina.
occurs in dourine, caused by Trypanosoma equiperdum (see The causative agent(s) is not known, and it is not clear why
also Vol. 3, Female genital system). Primary infection in these rams are predisposed.
dourine occurs in the genitalia, following transmission by Traumatic injury by the cocklebur (Xanthium strumarium)
coitus. There is marked edema of the prepuce and adjacent may cause outbreaks of severe “acroposthitis” in rams with
areas, and phimosis may result. In many cases, yellow-red subsequent suppurative vaginitis in ewes mated to them.
nodules up to ∼8 mm in diameter may subsequently appear Proliferative lesions of the penis and prepuce occur in dogs
on the penis especially near the urethral orifice. These later with leishmaniasis, and misdiagnosed as transmissible vene-
transform to shallow ulcers, which after healing may leave real tumor. The lesions, which develop over a period of several
distinct nonpigmented foci on the skin of the penis, prepuce, months, are multiple ulcerated nodules up to ∼1 cm in diam-
scrotum, and perineum. In cutaneous habronemiasis (for eter located on the penile tip and preputial mucosa, as well
detailed discussion, see Vol. 1, Integumentary system) the as other organs. Histologically, macrophages containing amas-
lesions may affect the penis, especially around the urethral tigotes of Leishmania infantum dominate the lesions.
meatus, and or the preputial mucosa at about the point of its Miscellaneous conditions causing variable inflammation of
contact with the end of the retracted penis. The lesions are the penis and prepuce include intrapreputial foreign bodies
elevated, ulcerated, and bleed; they consist of exuberant such as sand, and “hair ring” in the bull, ram, buck, and cat, in
fibrous tissue enclosing few or many larvae of Habronema spp. which hairs encircle and may constrict the penis.
and may be sufficiently large to cause paraphimosis. There are
large numbers of eosinophils that form small eosinophilic Neoplasms of the penis and prepuce
“abscesses” around immobilized and dead larvae; they corre- The important primary tumors are fibropapilloma in the bull,
late to small yellow foci on the cut surface. The lesion devel- squamous papilloma and squamous cell carcinoma in the
ops during the summer months. These larvae often infect horse, and papillomas and transmissible venereal tumor of
squamous cell carcinomas, so lesions should be examined for dogs. Additional details on bovine fibropapillomas and canine
neoplasia. Nodules in the prepuce of the stallion are also transmissible venereal tumor are in Vol. 3, Female genital
caused by adults, larvae, and ova of Halicephalobus spp., or by system.
mycotic infection, particularly pythiosis. Geldings develop a Fibropapillomas in bulls caused by bovine papillomavirus
nonspecific posthitis with accumulation of smegma and detri- 1 occur on the head of the penis. They are most common in
tus, presumably because of reduced penile extrusion. young bulls, 1-2 years of age, and are noticed after mating,
In sheep, ulcerative posthitis of wethers, and occasionally when hemorrhage occurs. They are usually multiple and up
of rams, is common and important. Vulvitis may occur in ewes to several centimeters in diameter (Fig. 5-62). Tumors are pink
in affected flocks. Wethers are particularly susceptible, sug- or gray-white on section and are composed mainly of fibrous
gesting incomplete development of the prepuce and penis, tissue with an epithelial covering (Fig. 5-63). Histologically,
and/or the tendency of wethers to urinate within their sheath. there are differences between tumors in young and old bulls,
Development of the primary lesion depends on the occur- those in young bulls being more cellular with frequent mitoses.
rence of a transmissible, urea-hydrolyzing bacterium such as Although benign, large fibropapillomas in bulls interfere
Corynebacterium renale, and on the excretion of urine rich in with free movement of the penis through the preputial orifice
urea. In one outbreak, Rhodococcus equi and Corynebacterium and prevent retraction of the head of the penis. In such cases,
hofmanni, both of which produce urease, were isolated from preputial hairs may surround the prolapsed penis and cause
lesions. Other factors in urine, possibly hormonal in origin, strangulation. Alternatively, continued growth of the mass
may also be involved. High protein and especially leguminous within the preputial cavity may prevent penile protrusion.
diets predispose to the disease and the incidence is lowest The urethra can become obstructed and rupture, causing
during the summer. It is presumed that wethers are infected extensive cellulitis.
by the transmission of material on contaminated bedding, A transmissible genital papilloma occurs in swine and the
herbage, or by flies. Venereal transmission from rams to ewes virus is likely a Sus scrofa papillomavirus. Both the natural and
also occurs. experimental papillomas regress with time. The tumors are
Penis and Prepuce 509
Further reading
Axner E, et al. Reproductive disorders in 10 domestic male cats. J Small
Anim Pract 1996;37:394-401.
Bleier T, et al. Canine osteosarcoma of the penile bone. J Vet Med A
Physiol Pathol Clin Med 2003;50:397-398.
Johnston SD, et al. Ovarian and testicular function in the domestic cat:
clinical management of spontaneous reproductive disease. Anim
Reprod Sci 1996;42:261-274.
Kidanemariam A, et al. Ulcerative balanitis and vulvitis of Dorper sheep
Figure 5-65 Canine transmissible venereal tumor on the penis of
in South Africa: a study on its aetiology and clinical features. J S
a dog.
Afr Vet Assoc 2005;76:197-203.
Knight CG, et al. Equine penile squamous cell carcinomas are associ-
they have a common origin. The DNA of the CTVT has ated with the presence of equinepapillomavirus type 2 DNA
closely related DNA of wolves and East Asian dog breeds. sequences. Vet Pathol 2011;48:1190-1194.
The cells of a CTVT avoid detection by immune cells. They Mukaratirwa S, Gruys E. Canine transmissible venereal tumour: cyto-
downregulate MHC I molecules and there is no MHC II activ- genetic origin, immunophenotype, and immunobiology. A review.
ity, because they secrete inhibitory cytokines (TGFβ1 and IL Vet Q 2003;25:101-111.
6). In the initial proliferative phase of CTVT, they express Murgia C, et al. Clonal origin and evolution of a transmissible cancer.
little MHC class 1 or 2. After about 12 weeks in an experi- Cell 2006;126:477-487.
mental model, MHC expression increased dramatically and Musser JM, et al. Penile hematoma in bulls: 60 cases (1979-1990). J
lymphocytes appear; at the same time, the masses stopped Am Vet Med Assoc 1992;201:1416-1418.
growing. It appeared that the lymphocytes stimulated MHC Newkirk KM, et al. Detection of papillomavirus in equine periocular
expression and are responsible for regression of the tumors. and penile squamous cell carcinoma. J Vet Diagn Invest
The phenotype of the cells was the subject of considerable 2014;26:131-135.
debate. Immunohistochemical staining characteristics suggest Trichard CJ, et al. The identification of Mycoplasma mycoides mycoides
they are of histiocytic origin, as they are positive when stained LC as the aetiological agent of balanoposthitis and vulvovaginitis
with vimentin, often positive with α1-antitrypsin and lyso- in sheep in South Africa. Onderstepoort J Vet Res 1993;60:29-37.
zyme, and negative for CD3, immunoglobulins, and cytokera- van der Harst MR, et al. Priapism in the stallion. Tijdschr Diergeneeskd
tin (for more detail, see Vol. 3, Female genital system). 2002;127:746-751.
Less common tumors of the penis or prepuce in dogs include Vogel FS, et al. Intrapreputial infection of young bulls with bovine
the epithelial, mesenchymal, round cell and other tumors herpesvirus type 1.2 (BHV-1.2): acute balanoposthitis, latent infec-
(such as melanoma) found in other parts of the body. Of the tion and detection of viral DNA in regional neural and non-neural
epithelial tumors, apocrine sweat gland adenocarcinoma is tissues 50 days after experimental reactivation. Vet Microbiol
reported. Mesenchymal tumors include lipoma, hemangioma, 2004;98:185-196.
hemangiosarcoma, soft tissue sarcoma, mesenchymoma, and
osteosarcoma, chondrosarcoma, and ossifying fibroma of the
os penis of the dog. Sarcoids are found in the penis and For more information, please visit the companion site:
prepuce of the horse. Round cell tumors include lymphoma, PathologyofDomesticAnimals.com
510.e1
Further reading
Bolton LA, et al. Aberrant migration of Ancylostoma caninum to the
os penis of a dog. J S Afr Vet Assoc 1996;67:161-162.
Chafin MK, et al. Multicentric cutaneous pythiosis in a foal. J Am Vet
Med Assoc 1992;201:310-312.
Dalin AM, Rodriguez-Martinez H. Vasointestinal polypeptide (VIP)—
immunoreactive nerves in the boar penis. J Vet Med 1992;39:
792-797.
Dunn DG, et al. Nodular granulomatous posthitis caused by Halicepha-
lobus (syn. Micronema) sp. in a horse. Vet Pathol 1993;30:
207-208.
Felleisen RSJ, et al. Detection of Tritrichomonas foetus by PCR and DNA
enzyme immunoassay based on rRNA gene unit sequences. J Clin
Microbiol 1998;36:513-519.
Font A, et al. Canine mucosal leishmaniasis. J Am Anim Hosp Assoc
1996;32:131-137.
Ghanem M, et al. Atresia ani with diphallus and separate scrota in a
calf: a case report. Theriogenol 2004;61:1205-1213.
Gilbert RO, et al. Communication between the corpus cavernosum
penis and the corpus spongiosum penis in a bull diagnosed by
modified contrast cavernosography: a case report. Theriogenol
1990;33:577-581.
Lobetti RG, et al. Suspected corpus cavernosum trauma in three dogs.
Vet Rec 1995;137:492.
MacDonald RK. Urethral prolapse in a Yorkshire terrier. Compend
Contin Educ Pract Vet 1989;11:682-683.
Mair TS, et al. Surgical treatment of 45 horses affected by squamous
cell carcinoma of the penis and prepuce. Equine Vet J 2000;32:
406-410.
Mirkovic TK, et al. Urinary obstruction secondary to an ossifying
fibroma of the os penis in a dog. J Am Anim Hosp Assoc
2004;40:152-156.
Nasir L, Saveria Campo M. Bovine papillomaviruses: their role in the
aetiology of cutaneous tumours of bovids and equids. Vet Dermatol
2008;16:243-254.
Payan-Carreira R et al. Priapism associated with lumbar stenosis in a
dog. Reprod Dom Anim 2013;48:e58-e64.
Pritchard G, et al. Infectious pustular vulvovaginitis/infectious pustular
balanoposthitis in cattle. Vet Rec 1997;140:587.
I NDEX
Entries followed by “f,” “b,” and “t” refer to figures and tables, respectively. The volume number of the entry is indicated in italics at the beginning
of the page number.
511
512 Index
Australian Kelpie dogs, globoid cell Bacterial infections (Continued) B-cells (Continued)
leukodystrophy in, 1:339 liver, 2:314-318 diffuse large B-cell lymphomas, 3:220-222,
Australian Shepherd dogs lungs and, 2:472-473 3:221f
choroidal hypoplasia, 1:413 myocarditis, 3:42 follicular-derived B-cell lymphomas,
cobalamin deficiency, 3:127 pneumonia, 2:562-563, 2:562f 3:222-226, 3:223f
cochleosaccular degeneration, 1:492 respiratory system, 2:531-532, 2:531f lymphoid hyperplasia, 3:201
spindle cell tumor, 1:486 cats, 2:589 in masticatory myositis, 1:226-227
Autoimmune dermatoses, 1:600-607 cattle, 2:542-551 Reed-Sternberg cell, 3:219
pemphigus complex, 1:518, 1:600-603 dogs, 2:577-579 T-cell-rich B-cell lymphoma, 3:221-222,
Autolytic changes in retina after death, horses, 2:569-573 3:222f
1:467 pigs, 2:531-533 Beagle dogs
Autopsy. See Gross and histologic sheep and goats, 2:562-563 chondrodysplasia, 1:44, 1:45f
examinations skin, 1:629-646 cobalamin deficiency, 3:127
Autopsy-in-a-jar pathology, 1:2 lesions in, 1:645-646 Factor VII deficiency, 3:264
Autosomal recessive congenital ichthyoses teeth, 2:9 globoid cell leukodystrophy, 1:339
(ARCI), 1:530, 1:531f Bacterial osteomyelitis, 1:98-103, 1:98f-99f hypertrophy type 1 and 2, 1:225
Autosomal recessive PKD (ARPKD), cats, 1:99-100 iatrogenic acromegaly, 3:286f
2:396 cattle, 1:99 lymphomas, 3:238
Autosomal recessive severe combined dogs, 1:99-100 osteogenesis imperfecta, 1:50
immunodeficiency, 3:140-141 horses, 1:99, 1:99f, 1:101f osteoporosis, 1:67
Avascular chorion, 3:397 Bacterial overgrowth, small intestine, 2:364 pain syndrome, 1:158, 3:70
Avipoxvirus, 1:616 Bacterial pododermatitis of horses and peripheral vestibular disease, 1:494
AV node, 3:2 ruminants, 1:642-645 selective deficiencies of immunoglobulins,
heart examination and, 3:13-14 Bacterial pseudomycetoma, 1:642, 1:642f 3:139
impulse formation disturbances, 3:5 Bacterial septicemia, 3:289, 3:290f Beagle pain syndrome. See Steroid-responsive
Avocado poisoning, 3:38 Bacteriology, 1:10-11 meningitis-arteritis
Axillary nodular necrosis, 1:695 Bacteroides fragilis, 2:113, 2:199 Beauceron dogs, canine atopic dermatitis in,
Axonal dystrophy, 1:257-258, 1:258f, Bacteroides spp., 2:9 1:591
1:324-325 Balanoposthitis, 3:507 Bedlington Terriers, 2:303, 2:303.e1f
Axonopathy, 1:256, 1:318-334 Balantidium, 2:243-244, 2:244f Belgian Blue cattle
distal, 1:257 Baldy calf syndrome, 1:538 dermatosparaxis, 1:48
peripheral, 1:334-336 Bali cattle, Jembrana disease in, 3:195-196, osteopetrosis, 1:51-52
proximal, 1:257, 1:257f 3:195f Belgian Gorenendael Shepherd dogs, canine
Axons, 1:255-258, 1:256f Balloon cell malignant melanomas, 1:722 X-linked muscular dystrophy in, 1:192
growth disorders, 1:268-269 Ballooning degeneration of epidermis, 1:519, Belgian Malinois dogs, vitiligo in, 1:556.e1f
Ayrshire cattle, cropped and notched pinnae 1:519f Belgian Tervuren dogs
in, 1:502 Bandera’s neonatal ataxia, 1:318-319 canine atopic dermatitis, 1:591
Banzi virus, 1:281 vitiligo, 1:555-556
B Barbados Blackbelly sheep, osteogenesis Benign bone cysts, 1:126
Babesia bigemina, 3:119 imperfecta in, 1:50 Benign cortical fibromas, 2:447
Babesia bovis, 3:118 Bartholin’s glands, 3:442 Benign epithelial neoplasms, 2:478-479,
Babesia caballi, 3:119-120 Bartonella, 1:646 2:479f
Babesia canis, 1:665, 3:119, 3:119.e1f endocarditits and, 3:30-31 Benign mammary neoplasms, 3:460
Babesia divergens, 3:119 liver and, 2:318 Benign melanocytic tumors, 1:721
Babesia felis, 3:120 Bartonella berkhoffi, 1:646 Benign spindle cell tumors, 1:722-723
Babesia gibsoni, 1:665, 2:412 Bartonella henselae, 3:42 Benign tumors of joints, 1:160-162
Babesia major, 3:119 Bartonella vinsonii, 1:99-100, 1:646 Bergmann’s glia, 1:261
Babesia rossi, 3:119 Basal cell carcinomas, 1:714 Bergmeister’s papilla, 1:417-419, 1:418f
Babesia spp., 1:611, 3:117-120, 3:117f Basement membrane zone (BMZ), 1:513-514 Bernese Mountain dogs
differential diagnosis, 3:119 Basic multicellular unit (BMU), 1:26 afibrinogenemia, 3:265
splenic babesiosis, 3:161, 3:161f Basidiobolomycosis, 1:660 Alexander disease, 1:341
Baccharis cordifolia, 2:89 granulomatous rhinitis and, 2:476 canine hypomyelinogenesis, 1:338
Baccharis megapotamica, 2:89 Basilar membrane, 1:489-490 degenerative radiculomyelopathy,
Baccharis pteronioides, 2:89 Basophilia, 3:111 1:330
Bacillary angiomatosis, 1:646 Basophilic intranuclear viral inclusions, 2:22 vasculitis, 3:70
Bacillary hemoglobinuria, 2:317, 2:317f Basosquamous carcinomas, 1:714 Besnoitiosis, 1:661-663, 1:662f
Bacillus anthracis, 3:171-174 Basset Hound dogs granulomatous rhinitis and, 2:476
Bacillus fragilis, 2:113 canine atopic dermatitis, 1:591 Besnoitia spp., 2:239
Bacillus piliformis, 3:42 degenerative diseases of cartilaginous B-cells, endocrine pancreas, 2:368
Bacterial arthritis, 1:148-154 joints, 1:143-144 β-glucuronidase-deficient MPS, 1:290
Bacterial diseases, tooth surface, 2:9 globoid cell leukodystrophy, 1:339 β-Mannosidosis, 1:289, 1:492
Bacterial endophthalmitis, 1:449 granulomatous hepatitis, 2:318 B2-microglobulin, 2:385
Bacterial enterotoxin, 2:71 platelet dysfunction, 3:259 Betaherpesviruses, 2:537
Bacterial granulomas, 1:637-642 seborrhea, 1:548 Bibersteinia trehalosi, 2:543, 2:562-563
Bacterial hemolysins, 3:126 severe combined immunodeficiency Bichon Frise dogs, canine atopic dermatitis,
Bacterial infections (SCID), 3:139 1:591
abortion and stillbirth due to, 3:398, Baylisascaris procyonis, 1:390-391 Bilateral extraocular muscle myositis of dogs,
3:399b, 3:402-417 B-cells 1:228
alimentary tract, 2:158-201 chronic lymphocytic leukemia/small Bilateral hypoplasia, 2:392
central nervous system, 1:353-365 lymphocytic lymphoma (B-CLL/SLL), Bile cast nephropathy, 2:430
endocarditis, 3:30-33, 3:31f 3:219-220 Bile peritonitis, 2:250
Bovine necrotizing meningoencephalitis, Brachycephalic type dwarfism, 1:39, 1:39f Bronchial arteries, 2:467-468, 2:468f
1:381-382, 1:381f-382f Brachydont teeth, 2:5 Bronchial atresia, 2:485
Bovine ovarian lymphosarcoma, 3:378, Brachygnathia inferior, 1:56, 1:56f, 2:3 Bronchial gland carcinoma, 2:497
3:379f Brachygnathia superior, 1:56, 2:3 Bronchiectasis, 2:503-504, 2:503f, 2:503.e3f,
Bovine papillomaviruses, 1:706-707, 1:707f, Brachyspina, 1:57 2:501.e1f
2:22 Brachyspira pilosicoli, 2:182 Bronchiolar necrosis and inflammation,
Bovine papular stomatitis virus (BPSV), Brachyspira hyodysenteriae, 2:182 2:504-506, 2:504f
1:616, 1:618-619, 2:39-40, 2:139-140, Brachyspira spp., 2:98 Bronchioles, 2:469
2:140f Bracken fern, 1:471, 2:461 Bronchiolitis obliterans, 2:504, 2:504f,
Bovine parainfluenza virus 3 (BPIV-3), Brain. See also Spinal cord 2:504.e2f
2:541 age changes in, 1:304 Bronchioloalveolar hyperplasia, 2:505,
Bovine paramyxoviral atrophy, 1:304-305 2:504.e2f
meningoencephalomyelitis, 1:382 cerebellar hypoplasia, 1:275f Bronchitis, 2:500-504
Bovine parvovirus (BPV), 2:157-158, cerebellum cats, 2:502-503
3:429-430 agenesis, hypoplasia, and dysplasia, chronic, 2:501-503, 2:502.e1f
–induced papilloma, 2:44 1:275-276, 1:275f Bronchogenic cysts, 2:484-485
Bovine respiratory syncytial virus (BRSV), Arnold-Chiari malformation, 1:276-277, Bronchointerstitial pneumonia, 2:511-512,
2:539-541, 2:540f, 2:540.e2f, 2:540.e1f 1:277f 2:514.e2f
Bovine rhinitis virus (BRAV), 2:542 atrophy, 1:276, 1:276f foals, 2:514
Bovine rotaviral infection, 2:151-152, 2:152f Dandy-Walker syndrome, 1:277 Bronchopneumonia, 2:506-509, 2:506f,
Bovine spongiform encephalopathy (BSE), development, 1:274-277 2:507t
1:349 hypoplasia, 1:275f bacterial, in cattle, 2:542-546, 2:545f
Bovine torovirus, 2:112 intracranial arachnoid cyst, 1:280f caseonecrotic, 2:553f
Bovine trypanosomiasis, 3:122-124 vascular leakage, 1:298f chronic suppurative, 2:508, 2:508.e1f
Bovine tuberculosis, 2:547-551, 2:549f cerebrum, 1:266-274 death from, 2:507-508
Bovine viral diarrhea virus (BVDV), 1:104, cerebral aplasia, anencephaly, 1:266-267, morphology, 2:507
1:105f, 1:281-283, 2:112, 2:114, 1:266f opportunistic bacterial pathogens and,
2:122-128, 2:123f-125f, 2:542, 2:542.e3f defects in cerebral corticogenesis, 2:532-533
esophageal lesions, 2:124, 2:124f 1:268 reduced lung function, 2:508
fetal infections, 2:122 disorders of axonal growth, 1:268-269 resolution and sequelae, 2:507-508
mucosal disease, 2:123 encephalocele, meningocele, 1:267, sequestrum, 2:508
-negative cattle, 2:413 1:267f Bronchopneumopathy, eosinophilic,
noncytopathic (NCP), 2:122-128 holoprosencephaly, 1:269-270, 1:269f 2:501-502, 2:502f, 2:501.e1f
PI calves, 2:122 hydranencephaly, porencephaly, Bronchopulmonary dysplasia, 2:516
pregnant uterus, 3:425-426 1:272-274, 1:272f Bronchopulmonary segment, 2:467
secondary infections, 2:127 hydrocephalus, 1:270-272, 1:271f Bronchus-associated lymphoid tissue (BALT),
severe acute, 2:122-123 periventricular leukomalacia of neonates, 2:472
thymic atrophy and, 3:145 1:274 Brown recluse spider, 1:568
Bowie, 1:90-91 edema, 1:293-295, 1:295f Brown Swiss cattle, progressive
Bowman’s capsules, 2:406-407, 2:437-438, embolism, 2:490 myeloencephalopathy of, 1:325
2:407.e1f increased intracranial pressure, 1:293-295 Brucella abortus, 3:402-406, 3:485-487,
thickening and lamination, 2:407.e1f lesions of blood vessels and circulatory 3:490
Bowman’s space, 2:406-407 disturbances, 1:296-301, 1:296f Brucella canis, 1:449, 3:490
Boxer dogs hemorrhagic, 1:300-301 abortion and, 3:403-404, 3:404f,
acne, 1:549 ischemic, 1:297-300, 1:297f 3:406
canine atopic dermatitis, 1:591 microcirculation of, 1:263-264, 1:264f, Brucella melitensis, 3:406
canine leproid granuloma, 1:503, 1:641 1:263.e1f Brucella ovis, 3:405-406, 3:405f
canine persistent (recurrent) ulcer traumatic injuries, 1:301-303 abortion and, 3:473-474, 3:490
syndrome, 1:434, 1:435f tumors, 1:296f Brucella suis, 3:490
chondrosarcoma, 1:118 Branched-chain α-ketoacid decarboxylase abortion and, 3:404-405
congenital myotonia, 1:201 deficiency, 1:344, 1:345f Bruch’s membrane, 1:445
degenerative radiculomyelopathy, 1:330 Brangus cattle, Chediak-Higashi syndrome in, Brugia, 3:98
diffuse fibrous hyperplasia, 2:21-22 3:259 Brunn nests, 2:449
dilated cardiomyopathy, 3:48 Brassica rapa, 2:342 Brush cells, 2:469
factor VII deficiency, 3:264 Braunvieh x Brown Swiss cattle, congenital Bubalus arnee, 2:117-118
hyperadrenocorticism, 1:588 myopathy in, 1:199-200 Buccal cavity, 2:12-19
hyperestrogenism, 1:589 Braxy, 2:53, 2:53f circulatory disturbances, 2:12-13
hypothyroidism, 1:587, 3:315 Braxy-like clostridial abomasitis, 2:53f foreign bodies in, 2:13
immune-mediated myositis, 1:228 Brazilian Terrier dogs, Sly syndrome in, 1:58 inflammation of, 2:13-19
intestinal lymphomas, 3:239 Breda virus, 2:112 parasitic diseases, 2:19
lymphomas, 3:238 Breed-related nephropathies, 2:388t-390t pigmentation, 2:12
malignant lymphoma, 1:123-124 in domestic species, 2:388t-390t salivary glands, 2:28-30
malignant oral tumors, 2:21 Brick inclusions, 2:430 tonsil diseases, 2:19-20
myotonic dystrophy-like disorder, Brittany Spaniel dogs Buccal mucosal bleeding time (BMBT),
1:202-203 canine X-linked muscular dystrophy, 3:257
progressive axonopathy, 1:329-330 1:192 Bucked shins, 1:36
recurrent flank alopecia, 1:590 hypothyroidism, 1:587 Budd-Chiari syndrome, 2:298
spongy encephalomyelopathies, 1:346 late-onset progressive spinocerebellar Budgerigars, 3:286
typhlocolitis, 2:97-98, 2:98f degeneration, 1:319 Bufadienolide cardiac glycoside-containing
Brachycephalic airway syndrome, 2:482, Brodie’s abscess, 1:98, 1:98f plants, 3:35
2:482f Bronchi, 2:468-469 Buffalopox virus, 1:620-621
Bulbourethral gland, 3:500-504, 3:500f Calcium (Continued) Canine dietary factors, 2:457
disorders of sexual development, 3:500- crystal-associated arthropathy Canine distemper virus (CDV), 1:104-105,
501, 3:500f (pseudogout), 1:156-157 1:384-385, 1:474, 2:116-117, 2:574-576,
hyperplasia and metaplasia, 3:502-503, dogs, 1:156-157 2:575.e1f
3:502f deficiency, 2:8. See also Hypocalcemia acquired deafness and, 1:493
inflammation, 3:501-502, 3:501f odontodystrophy, 2:8 lymph nodes and, 3:207f
neoplasms, 3:503-504, 3:504f osteoporosis, 1:61, 1:65-66 thymic atrophy and, 3:145
Bullae, 1:524 rickets, 1:61, 1:66, 1:69 Canine dynamin 1 (DNM1) gene, 1:198
pneumothorax and, 2:487, 2:487f vitamin D, 1:61 Canine ehrlichiosis, 1:474-475
Bullmastiff dogs functions, 3:291-292 Canine eosinophilic granuloma, 1:694
acne, 1:549 hypercalcemia, 3:305-310, 3:305f Canine epitrichical ductular adenomas,
calvarial hyperostosis of, 1:92 hypocalcemia, 3:299 1:718-719
canine leproid granuloma, 1:503, 1:641 malabsorption, 2:70 Canine exertional rhabdomyolysis, 1:223
spongy encephalomyelopathies, 1:346-347 muscle necrosis and, 1:181-182, 1:181f Canine familial glomerulonephritides, 2:412
Bullous immune skin diseases, 2:14 oxalate, 2:457 Canine familial nephropathies, 2:391
Bullous pemphigoid (BP), 1:603-604, 2:15 phosphate, 2:458 Canine hepacivirus, 2:577
Bull Terrier dogs, 2:416-417 phosphorus homeostasis and, 1:61-63 Canine hepatozoonosis, 1:94, 1:94f
autosomal recessive acrodermatitis, 3:141 -regulating hormones, 3:291-310, 3:291f Canine herpesvirus-1 (CaHV-1), 2:577,
canine atopic dermatitis, 1:591 salts, deposition of, 1:443, 1:519 3:431-432, 3:432f, 3:434f
cochleosaccular degeneration, 1:492 Calculi, 2:452 encephalitis, 1:383
lethal acrodermatitis, 1:533, 1:533.e1f salivary, 2:29 Canine hypomeylinogenesis, 1:337-338
melanocytopenic hypomelanosis, 1:555 urinary, 2:453t Canine immune-mediated hemolytic anemia,
subvalvular aortic stenosis, 3:20 Calf diphtheria, 2:17 3:265
Bully Whippets, 1:191, 1:191f Calicium pyrophosphate dihydrate, Canine infectious respiratory disease (CIRD)
Büngner’s bands, 1:256 1:156-157 complex, 2:574
Bunina bodies, 1:255 Calicivirus, 1:154, 1:628, 2:117 Canine influenza, 2:577
Burkholderia mallei, 2:573 California encephalitis virus Canine juvenile cellulitis, 1:690-691, 1:691f
Burkholderia pseudomallei, 1:637, 3:491 meningoencephalomyelitis, 1:383 Canine juvenile pancreatic atrophy, 2:363,
respiratory system and, 2:563 Call-Exner body, 3:376 2:363f
splenic abscesses, 3:183-184 Calliphorine myiasis, 1:669 Canine kidneys, 2:378
splenic lesions, 3:188-189, 3:188f Callipyge phenotype in sheep, 1:191 Canine leproid granuloma, 1:503, 1:641,
Burkitt-like lymphoma (BKL), 3:226 Calluses, 1:524, 1:559-560 1:641f
Burmese cats, primary endocardial Calodium hepaticum, 2:320 Canine lymphomas, 3:238-239, 3:239f,
fibroelastosis in, 3:22 Calvarial hyperostosis of Bullmastiffs, 1:92 3:239.e1f, 3:239.e2f, 3:238.e2f
Burns, 1:564-566, 1:565f Camelostrongylus, 2:54-55 Canine minute virus (CnMV), 2:157, 3:430
Bursitis, 1:155-156 Camelpox virus, 1:616, 1:621 Canine monocytotropic ehrlichiosis, 3:111
sheep, 1:155f Campylobacter fetus, 3:406-408, 3:408f, Canine multifocal retinopathy, 1:469
Butterfly vertebrae, 1:57 3:424, 3:507 Canine nasodigital hyperkeratosis, 1:549-550
liver and, 2:314-315 Canine necrotizing meningoencephalitis
C Campylobacter spp., 2:98, 2:117 (NME), 1:392-393, 1:392f
Cabugi breed sheep, 1:42 enteritis associated with, 2:180-181 Canine panosteitis, 1:106-107, 1:107f
Cachectic atrophy, lymph node, Canalicular domain, liver, 2:262 Canine papillomavirus 1 (CPV1), 2:22, 2:22f
3:198-199 Canalicular stage of lung growth, 2:484 Canine parainfluenza (CPIV), 2:576
Cache valley virus (CVV), 1:280, Canal of Hering, 2:262 Canine parvovirus, 2:116-117
3:438-439 Cancrum oris, 2:18 thymic atrophy, 3:145
Cachexia, atrophy resulting from, 1:177, Candida albicans, 1:647, 2:32, 2:202, Canine parvovirus 2 infection (CPV-2),
1:177f 2:459 2:156-157, 2:156f-157f
Cadmium, 1:67 Candida parapsilosis, 3:30-31 Canine perivascular wall tumors (PWTs),
Caffey’s disease, 1:53 granulomatous rhinitis and, 2:476 1:723, 1:724f
Cairn Terrier dogs Candida tropicalis, 2:202 Canine persistent (recurrent) ulcer syndrome,
canine atopic dermatitis, 1:591 Candidiasis, 2:202 1:434, 1:435f
diabetes mellitus, 2:373 Canid herpesvirus 1, 3:507 Canine pigmented plaques, 1:710-711,
globoid cell leukodystrophy, 1:339 Canine acanthosis nigricans, 1:555 1:711f
hyperestrogenism, 1:589 Canine adenovirus 1 (CAV-1), 1:105, Canine pneumovirus, 2:577
polycystic kidney and liver disease, 1:452-453, 2:410 Canine pseudoplacentational endometrial
2:265 hepatitis, 2:310-312, 2:311.e1f hyperplasia, 3:383, 3:384f
primary portal vein hypoplasia, Canine adenovirus 2 (CAV-2), 2:577 Canine pulmonary veno-occlusive disease
2:267-268 Canine atopic dermatitis, 1:591-593 (PVOD), 2:493, 2:493f, 2:493.e1f
progressive neuronopathy, 1:332-333 Canine blastomycosis, 2:459 Canine reactive histiocytosis, 3:247-250,
Calcinosis circumscripta, 1:563, 1:563f Canine bocavirus, 2:577 3:248f, 3:247.e1f
Calcinosis cutis, 1:562, 1:588, 1:589f Canine cardiomyopathies, 3:48-49, 3:48f cutaneous, 3:247-249, 3:248f, 3:249.e1f,
Calcinosis universalis, 1:562-563 Canine colitis, 2:94 3:247.e1f
Calcitonin, 1:62, 3:296-297 Canine congenital myasthenia, 1:209 systemic, 1:729, 3:249-250, 3:249f
biological actions, 3:297 Canine coronavirus (CCoV), 2:116, 2:150 Canine recurrent flank alopecia, 1:590,
biosynthessis and secretion, 3:297 Canine cutaneous histiocytoma (CCH), 1:590f, 1:590.e1f
in physis, 1:25t 1:728-729, 3:243-245, 3:244f-245f, Canine respiratory coronavirus (CRCoV),
Calcitriol 3:244.e1f, 3:243.e1f 2:576
biological action, 3:295-296 Canine cutaneous Langerhans cell Canine transmissible veneral tumor (CTVT),
biosynthesis, 3:295 histiocytosis, 1:729, 3:245-246, 3:246f 3:448-449, 3:449f, 3:509, 3:510f
Calcium Canine cyclic hematopoiesis, 3:110 Canine tubulointerstitium, 2:382f
carbonate, 1:562, 2:458 Canine demodicosis, 1:679-682, 1:679f Canine urothelial cell carcinomas, 2:462-463
chelation, 2:426 Canine dermatomyositis, 1:198, 1:541-542, Canine uveodermatologic syndrome, 1:557,
chloride, 1:562 1:542f-543f 1:557f-558f, 1:613
Index 519
Canine X-linked muscular dystrophy, Cardigan Welsh Corgi dogs, severe combined Caudal regression syndrome, 1:56-57
1:192-194, 1:193f-195f, 3:49 immunodeficiency (SCID) in, 3:139 Cauliflower-like growths, 2:103-104
Capillaries, 3:54 Cardiomyopathies, 3:44-51, 3:45.e1f Cavalier King Charles Spaniel dogs, 2:457
Capillarization, liver, 2:288 cats, 3:46-48, 3:46.e2f caudal fossa, 1:277
Capped elbow, 1:155 cattle, 3:50-51, 3:50f ichthyosis, 1:531-532
Capped hocks, 1:155 dogs, 3:48-49, 3:48f, 3:48.e2f inherited thrombocytopenia, 3:258
pigs, 1:156 Cardiovascular system, 3:1-101. See also muscle hypertonicity, 1:203
Capillarization of sinusoids, 2:260 Circulatory disturbances myxomatous valvular degeneration, 3:27
Caprine arthritis-encephalitis virus (CAEV), conduction system diseases, 3:51 oral eosinophilic granuloma, 2:16
1:154, 1:154f, 1:378-380, 1:379f, endocardial disease, 3:27-33 otitis media with effusion, 1:498
2:558-560, 2:559.e1f heart Cavitating leukodystrophy, 1:339-340
mastitis with, 3:458 congenital abnormalities, 3:14-24 CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-
Caprine besnoitiosis, 1:662 diseases, 3:2-54 nitrosourea), 2:329
Caprine herpesvirus 2, 1:625-627 examination, 3:12-14 CD8+ T-cells
Caprine herpesvirus 3, 2:132 failure, 3:6-12 in masticatory myositis, 1:226-227
Caprine lymphomas, 3:237 neoplasms, 3:52-54, 3:52f in polymyositis, 1:228-229
Capripoxvirus, 1:616, 1:622-624 lymphatics, 3:94-98 CD4+ T-cells in masticatory myositis,
Capsular pseudocysts, 2:396f myocardial disease, 3:33-51 1:226-227
Capsular sclerosis, 3:339 pericardial disease, 3:24-27 Cebocephaly, 1:270
Capture myopathy, 1:223 vascular system diseases, 3:54-101 Cecal dilation, 2:78
Cara inchada, 2:12 veins, 3:88-94 Cecocolic intussusception, 2:84f
Carbadox, 3:343 Cardiovirus, 3:43 in horse, 2:84
Carbohydrate overload, 2:40-43 Caries, dental, 2:9-11, 2:10f Cell-mediated immunity, 2:548-549
Carbolic dips, 2:519 Caroli disease, 2:265 Cellular crescent, 2:406.e1f
Carbon dioxide excretion, 2:381 Carotid body adenoma and carcinoma, Cellular elements of bone, 1:17-19, 1:17f
Carbon monoxide poisoning, 1:306 3:355-356 Cellularity, of glomerular tuft, 2:405
Carboxyterminal telopeptide of type I Carpal hygromas, 1:154 Cellular swelling, acute, 2:421-422
collagen (ICTP), 1:27 Carprofen, 2:329 Cellulitis, 1:636-637
Carcinoids, 2:497-498 Cartilage, articular, 1:129 canine juvenile, 1:690-691, 1:691f
hepatic, 2:349, 2:350f response to injury, 1:131-132 Celomic epithelium tumors, 3:377, 3:377f
Carcinomas/adenocarcinomas, 2:30, 2:463. Cartilage-forming tumors, 1:116-121 Cementing lines, 1:27, 1:27f
See also Neoplasia; Tumors Cartilaginous emboli, 1:299f Cementum, 2:5-6
adrenal gland, 3:345-346, 3:346f Cartilaginous end plates, 1:128-129 hyperplasia, 2:6
aortic body, 3:354-355, 3:354f Cartilaginous joints, 1:128-129 hypertrophy, 2:6-8
carotid body, 3:355-356 degenerative diseases of, 1:143-145 Central and peripheral neuronopathies,
derived from apocrine glands of the anal dogs, 1:143-144 1:326-334
sac, 3:307f-308f, 3:308 Caruncles, 3:400 Central chromatolysis, 1:252f-253f, 1:314,
endometrium and cervix, 3:449-450, Caryospora spp., 1:664 1:333f
3:450f Case coordination, 1:12 Central nervous system (CNS). See also
exocrine pancreatic, 2:366-367, Case interpretation and client service in Nervous system
2:367f postmortem examinations, 1:12-14, anoxia and, 1:305-307
feline pulmonary, 2:497.e1f 1:13f degeneration, 1:303-350
gastrointestinal, 2:101-104 Casein clot formation, 2:38 fixed macrophage system, 1:262
of gland of the third eyelid, 1:482 Caseonecrotic bronchopneumonia, 2:553f inflammation, 1:350-396, 1:351t-352t
hepatocellular, 2:346, 2:346.e1f Caseous lymphadenitis (CLA), 2:562, bacterial and pyogenic infections,
lower urinary tract, 2:462 3:204-208, 3:207f-208f, 2:562.e1f, 1:353-365
mammary, 3:460-463, 3:462f, 3:463t 3:205.e1f chlamydia disease, 1:391-392
nasal, 2:478, 2:478f-479f Caseous tuberculosis, 3:389 helminth and arthropod infections,
ovine pulmonary, 2:560-562, 2:561f, Cassia occidentalis, 1:220, 1:220f 1:389-391
2:561.e1f myocardial necrosis and, 3:36 idiopathic inflammatory diseases,
pulmonary, 1:736, 2:495-500, 2:496t, Castor beans, 2:117 1:392-396, 1:392f
2:497f-498f, 2:495.e2f Catagen phase, hair, 1:516 microsporidian infections, 1:385-386
rectal, 2:103f Cataract, 1:442-444, 1:442f parasitic infections, 1:386-391
splenic, 3:194, 3:194f congenital, 1:422 viral infections, 1:365-385
testicular, 3:496 deposition of calcium salts in, 1:443 injury and myocardial necrosis, 3:39
thymic, 3:156-157, 3:157f diabetic, 1:443 malformations, 1:264-284
thyroid, 3:329-332, 3:330f galactose-induced, 1:443 with BVDV, 3:426-427
tracheal, 2:483 megavoltage X-radiation, 1:444 viral causes, 1:280-284
Carcinosarcoma, 2:497 Soemmering ring, 1:444, 1:444f microcirculation, 1:263-264, 1:264f,
Cardenolide cardiac glycoside, 3:35 sunlight-induced, 1:443-444 1:263.e1f
Cardiac dilation, 3:7-9, 3:7f uveitis and, 1:447-448 muscular defects, 1:187-189
Cardiac fibrosis, 2:298 Catarrhal bronchitis, 2:501 neoplastic diseases, 1:396-406
Cardiac gland mucosa, 2:44, 2:46 Catarrhal stomatitis, 2:14 oligodendrocytes in, 1:258
Cardiac hypertrophy, 3:7-9 Catecholamine, 3:271 spinal cord, 1:277-279
Cardiac myocytes, 3:3 hormone biosynthesis, 3:348-349, arachnoid cysts, 1:279
Cardiac output no-reflow phenomenon, 3:350f diplomyelia, 1:278f
2:398 Caterpillar cells, 3:37 dysraphism, 1:278f
Cardiac rhabdomyomas, 1:241 Cat fur mite, 1:683 embolism, 2:490
Cardiac rhabdomyosarcomas, 1:243 Cattle, epidermolysis bullosa in, 1:534-535 lymphoma, 3:240f
Cardiac skeleton, 3:2 Cauda equina, neuritis of, 1:394-395 myelodysplasia, 1:277-279, 1:278f
Cardiac syncope, 3:10 Caudal fossa, 1:274-277 segmental hypoplasia of, 1:277f
Central nervous system (CNS) (Continued) Chabertia spp., 2:215-216 Chlamydophila psittaci, 2:551, 2:590
spina bifida, 1:57, 1:279 Chagas disease, 3:44, 3:44f Chlamydophila spp., 2:53, 2:113
subdural hemorrhage of, 1:303f Chain-of-custody, 1:2 Chlorella algae, 1:665
subdural/intradural abscess, 1:354f Chalazion, 1:423, 1:423f Choanal atresia, 2:473
syringomyelia, 1:278f Channel Island cattle, spontaneous rupture of Cholangiocarcinomas, 2:348, 2:349f
storage diseases, 1:284-293 gastrocnemius muscle, 1:211 Cholangiocellular tumors, 2:348-349, 2:348f
traumatic injuries, 1:301-303 Channelopathies, 1:200 mixed hepatocellular and, 2:349, 2:349.e1f
Wallerian-like degeneration, 1:256-257 Characteristic granular pattern, 2:407-408 Cholangiocytes, 2:262
Central osteosarcomas, 1:110 Charolais cattle Cholangiohepatitis, 2:301, 2:307-308,
Centrilobular liver hip dysplasia in, 1:135-136 2:307.e1f
fibrosis, 2:289, 2:289f progressive ataxia, 1:341, 1:341f Cholangitis, 2:301, 2:307-308, 2:308f
necrosis, 2:282 Chediak-Higashi syndrome (CHS), 1:556, Cholecalciferol, 3:295-296
Centronuclear myopathy of Labrador 3:110, 3:259 -25-hydroxylase, 3:295
Retrievers, 1:197, 1:197f Chemical abomasitis, 2:52 Cholestasis, 3:265
Cercopithifilaria spp., 1:690 Chemical gastritis, 2:52 Cholecystitis, 2:301, 2:306-307
Cerebellar atrophy, 1:276, 1:276f Chemical injury Choledochal cysts, 2:265-266
Cerebellar cortical degeneration, 1:318-320 lungs, 2:518-520 Choledochitis, 2:301
Cerebellum parathyroid glands, 3:298 Cholelithiasis, 2:308-309, 2:309f
agenesis, hypoplasia, and dysplasia, rodenticide intoxication, 3:264 Cholestasis, 2:292-294, 2:292f
1:275-276, 1:275f to skin, 1:566-575 Cholestatis injury, 2:327
Arnold-Chiari malformation, 1:276-277, Chemical peritonitis, 2:250 Cholesteatoma, 1:499, 1:499f
1:277f Chemodectomas, 3:354-356 Cholesteatosis of choroid plexus, 1:304,
atrophy, 1:276, 1:276f aortic body adenoma and carcinoma, 1:304f
Dandy-Walker syndrome, 1:277 3:354-355, 3:354f Cholesterol granuloma, 1:304f
development, 1:274-277 carotid body adenoma and carcinoma, middle ear and, 1:497
hypoplasia, 1:275f 3:355-356 Chondritis, laryngeal, 2:481-482, 2:481.e2f
intracranial arachnoid cyst, 1:280f development, structure, and function, Chondroblastic osteosarcomas, 1:113-114,
vascular leakage, 1:298f 3:354 1:113f
Cerebral abscess, 1:360f extra-adrenal paragangliomas, 3:356 Chondrocytes, 1:22-24
Cerebral aplasia, 1:266-267, 1:266f heart-base tumors derived from ectopic Chondrodysplasias, 1:37-46, 1:37t
Cerebral corticogenesis defects, 1:268 thyroid, 3:356 cats, 1:45-46, 1:46f
Cerebral edema, 1:295f Chemokines, 2:408 cattle, 1:38-39, 1:38f
Cerebral swelling, 1:293-295 Chemosensory cells, 2:469 dogs, 1:37-46, 1:43f-44f
Cerebrocortical necrosis, 1:5f Chemotactic cytokines, 2:408 horses, 1:42, 1:43f
Cerebrocortical atrophy, 1:7f Chesapeake Bay Retriever dogs pigs, 1:42
Cerebrospinal angiopathy, 1:298, 1:298f, 3:60 degenerative radiculomyelopathy, 1:330 sheep, 1:40-42, 1:40f-42f
Cerebrospinal fluid (CSF), 1:270-272 follicular dysplasia, 1:540-541, 1:540.e1f Chondrodystrophy, 1:37
Cerebrospinal vasculitis, 1:298-299, 1:298f Cheyletiellosis, 1:678 dogs, 1:143-144
Cerebrum, 1:266-274 Chief cell adenoma, 3:302, 3:303f manganese deficiency in, 1:80
cerebral aplasia, anencephaly, 1:266-267, Chief cells, 2:45 Chondroid bone, 1:21
1:266f Chihuahua dogs Chondromas, 1:116
defects in cerebral corticogenesis, 1:268 axonal dystrophy, 1:325 laryngeal, 2:482, 2:482.e1f
disorders of axonal growth, 1:268-269 color dilution alopecia, 1:539-540 Chondromatosis, synovial, 1:162, 1:162f
encephalocele, meningocele, 1:267, corneal edema in, 1:429 Chondrosarcomas, 1:118-121, 3:52
1:267f corneal endothelial dystrophy, 1:433 dogs, 1:118, 1:119f
holoprosencephaly, 1:269-270, 1:269f myxomatous valvular degeneration, nasal, 2:480, 2:480.e1f
hydranencephaly, porencephaly, 1:272-274, 3:27 Chordoma, 1:404, 1:404f
1:272f Chimerism, 3:363 Chorioallantoic membranes, 3:400
hydrocephalus, 1:270-272, 1:271f Chinaberry tree, 2:89 Chorioptic mange, 1:676-677, 1:677f
periventricular leukomalacia of neonates, Chinese Crested dogs Chorioretinitis, 1:446
1:274 congenital hypotrichosis, 1:538-539 Choristoma, 1:520
Ceroid/lipofuscin, 1:254 hereditary striatonigral and cerebello- Choroidal hypoplasia, 1:413, 1:414f
Ceroid-lipofuscinoses, 1:290-292, 1:291f olivary degeneration, 1:319 Choroidal melanocytomas, 1:483
Ceroid lipofuscinosis, 1:291f Chinese Shar Pei dogs Choroiditis, 1:357f
Certification of pathologists, 1:14 canine atopic dermatitis, 1:591 Choroid of uvea, 1:445
Ceruminous glands cobalamin deficiency, 3:127 Choroid plexus, 1:262
cysts and tumors, 1:719 cutaneous mucinosis, 1:546 age changes, 1:304, 1:304f
neoplasms, 1:507-508 demodectic mange, 1:679 carcinoma, 1:401f
Cervical vertebral malformation- familial AA amyloidosis, 2:278-279 papilloma, 1:401, 1:401f
malarticulation, 1:136, 1:136f familial Chinese Shar Pei fever, 1:158 Chow Chow dogs
dogs, 1:136, 1:136f intestinal lymphomas, 3:239 alopecia X, 1:589-590
horses, 1:136, 1:136f seborrhea, 1:548 canine hypomyelinogenesis, 1:337
Cervicitis, 3:441-442 selective deficiencies of immunoglobulins, color dilution alopecia, 1:539-540
Cervicovaginitis, bovine, 3:443 3:139 congenital myotonia, 1:200f, 1:201
Cervix vasculitis, 3:70 early onset diabetes mellitus, 2:373
carcinoma, 3:449-450, 3:450f Chlamydia, 2:53 hypothyroidism, 1:587
dilations and diverticula, 3:369 abortion and, 3:414, 3:415f malignant melanoma, 2:26
hypoplasia, 3:368-369 arthritis, 1:152-153 Chromatolysis, 1:252f, 1:314
pathology, 3:441-442 central nervous system and, 1:391-392 central, 1:252f-253f, 1:314, 1:333-334,
Cestodes, 2:221-223, 2:319-320 respiratory system and, 2:551, 2:563, 1:333f
central nervous system and, 1:389 2:590 peripheral, 1:253
Cestrum spp., 2:331 Chlamydia abortus, 3:414, 3:415f Chromoblastomycosis, 1:654-655
Chabertia ovina, 2:215-216 Chlamydophila felis, 1:425, 2:590 Chromogranin A, 3:294
Index 521
Chromomycosis, 1:654-655, 1:655f Circulation, micro-, 1:263-264 Clostridium septicum, 2:53, 2:183-194
Chromosomes Circulatory disturbances, 2:51-52 Clotting times, 3:263
disorders of sexual development and, brain, 1:296-301, 1:296f Club cells, 2:469, 2:469.e1f
3:469 buccal cavity and mucosa, 2:12-13 Coagulase-positive staphylococci, 2:456
sex circulatory failure, 3:6, 3:10-12 Coagulation
disorders, 3:363-365, 3:363f-365f, 3:469 edema, 2:51 liver disease and, 3:264-265
genotype, 3:360 gastric venous infarction, 2:51 regulation of, 3:265-266
Chronic bronchitis, 2:501-502, 2:502.e1f hyperemia, 2:51 Coagulative myocytolysis, 3:37
cats, 2:503 lung, 2:487-494 Coagulative necrosis, 3:37
Chronic cardiac glycoside poisoning, 3:35 muscle, 1:210-213, 1:211f gastric wall, 2:56
Chronic degenerative joint disease, 1:138- compartment syndrome, 1:211 liver, 2:281
140, 1:140f downer syndrome, 1:212 Coarctation of the aorta, 3:23, 3:23f
Chronic endometritis, 3:389-390 muscle crush syndrome, 1:212 Coat color
Chronic eosinophilic enteritis in horses, 2:96 postanesthethic myopathy in horses, dilution and black hair follicular dysplasia,
Chronic erosive colitis, 2:93f 1:213 1:557
Chronic erysipelas, 1:149-150 vascular occlusive syndrome, 1:212, -linked hair follicle dysplasia, 1:540
Chronic gingivostomatitis, 2:15-16 1:212f Cobalamin
Chronic hepatitis, 2:301-306 nasal cavity, 2:473-474 deficiency, 3:127
cats, 2:305 ovary, 3:381-382 malabsorption, 2:69-70
dogs, 2:302-305, 2:305f spleen, 3:169-171 Coccidioides immitis, 1:449-450, 2:583-584,
horses, 2:305, 2:305.e1f stomach, 2:51-52 2:584f
Chronic hepatotoxic injury, 2:328 testes, 3:491-492 adrenal cortex and, 3:340
Chronic hypertrophic pyloric gastropathy, uremic gastritis, 2:51 Coccidioides posadasii, 2:583-584
2:48 Circumventricular organs (CVOs), 1:263, Coccidioides spp., 1:103-104, 1:104f,
Chronic inflammatory bowel disease, 2:2, 1:263.e1f 2:115-116
2:92 Cirrhosis, 2:289-290 respiratory system and, 2:583-584
Chronic interstitial pancreatitis, 2:360, hepatic fatty, 2:276, 2:276.e1f Coccidiosis, 2:227-235
2:361f hypertrophic hepatic, 2:306 cattle, 2:229-231, 2:230f
Chronic lymphadenitis, 3:203-204, 3:203f, Cisplatin, 1:494 dogs and cats, 2:235-239
3:204.e1f Citrobacter koseri, 3:42 horses, 2:233-234
Chronic lymphocytic leukemia (CLL), 3:136 Classical swine fever virus (CSFV), 1:283, pigs, 2:234-235, 2:234f
Chronic lymphocytic leukemia/small 3:77-79, 3:78f, 3:178-181, 3:179f-180f, sheep and goats, 2:231-233, 2:232f
lymphocytic lymphoma (B-CLL/SLL), 3:77.e1f, 3:78.e1f, 3:79.e1f Cochlear duct, 1:489, 1:489f
3:219-220 pigs, 1:104 Cochleosaccular degeneration, 1:492
Chronic metabolic acidosis, 1:67 pregnant uterus, 3:79, 3:424-425 Cochliomyia hominivorax, 1:669-670, 2:43
Chronic polypoid cystitis, 2:460-461 sheep, 1:104 Cochliomyia macellaria, 1:669-670
Chronic pressure overload, 3:7 thymic atrophy and, 3:145 Cocker Spaniel dogs
Chronic renal disease, 2:16-17 Classic equine viral papillomatosis, 1:707- axonal dystrophy, 1:325
anemia and, 3:127 710, 1:708f, 1:708t dilated cardiomyopathy, 3:48
hyperparathyroidism secondary to, Classic hepatic lobule, 2:261 lymphomas, 3:238
3:300-301, 3:300f Classification of lymphomas, 3:215-243, malignant melanoma, 2:26
hypertension and, 3:59 3:217t malignant oral tumors, 2:21
Chronic renal failure (CRF), 2:377-378, Clear cell basal cell carcinomas, 1:714 multisystem neuronal degeneration,
2:384, 2:413-414 Clear cell epitrichial carcinomas, 1:719 1:320
Chronic rhinitis, 2:475 Cleft palates, 2:3, 2:3f myxomatous valvular degeneration, 3:27
Chronic suppurative bronchopneumonia, primary, 2:3 peripheral vestibular disease, 1:494
2:508, 2:508.e1f secondary, 2:3f seborrhea, 1:548
Chronic suppurative sinusitis, 2:477-478, Clefts, epidermal, 1:519, 1:519f Codman’s triangle, 1:33
2:477.e1f Clonality, 3:215 Coenurus cerebralis, 1:389
Chronic ulcerative paradental syndrome, 2:16 Clonorchis sinensis, 2:323-324 Coffee senna plant, 1:219-220
Chronic ulcerative stomatitis, 2:16 Clostridial myositis, 1:230-233, 1:231f COL4A3 gene, 2:416
Chronic volume overload, 3:7 Clostridium botulinum, 2:77, 2:183-194 COL4A4 gene, 2:416
Chronic wasting disease (CWD), 1:349 Clostridium chauvoei, 2:183-194, 3:42 COL4A5 gene, 2:415-416
Chrysomyia bezziana, 1:669-670 Clostridium difficile, 2:100, 2:183-194, Cold agglutinin disease, 1:608
Chuzan virus (CHUV), 1:281, 3:431 2:192f-194f Cold injury, 1:564
Chylothorax, 2:521, 3:95-96, 2:521.e3f acute necro-hemorrhagic colitis, 2:99f Coliform arthritis, 1:151
Chylous ascites, 3:96 Clostridium haemolyticum, 3:126 Coliform mastitis, 3:454-455, 3:454f-455f
Cicatricial alopecia, 1:698 liver and, 2:317 Colitis. See also Clostridium difficile
Cicuta douglasii, 3:36 Clostridium novyi, 3:126 cats, 2:98-99
Cilia-associated respiratory bacillus (CAR), liver and, 2:316 cystica profunda, 2:97
2:547, 2:547f Clostridium perfringens, 2:53-54, 2:183-194, idiopathic mucosal, 2:92-93
Ciliary body of uvea, 1:445 2:187f, 2:452, 3:126 canine, 2:94
Ciliary dyskinesis, 1:496 gastritis, 2:57 necrotic, 2:99, 2:99f
Ciliated cells, 2:469 type A, 2:113 spirochetal, in pigs, 2:181-183
Circoviruses, 2:116 type C, 2:84, 2:100, 2:113, 2:187, weaner colitis of sheep, 2:180-181
circoviral antigen stains, 2:116 2:187f-188f Collagen dysplasia, 1:543-544
Circovirus postweaning multisystemic type D enterotoxemia, 2:115, 2:188-191, cats, 1:545, 1:545f
wasting syndrome (PMWS), 2:527-529, 2:189f-190f cattle, 1:544
3:210-212, 3:210f-212f, 3:440, 3:440f Clostridium piliforme, 2:98-99, 2:113-114, dogs, 1:544-545, 1:545f
Circulating nonhematopoietic neoplastic 2:183-194, 3:42 horses, 1:544, 1:544.e1f
cells, 3:137-138 liver and, 2:314-315, 2:317, 2:317f-318f sheep, 1:544
Collagen fibers, 1:129 Congenital atelectasis, 2:486 Constrictive pericarditis, 3:26, 3:27f
degeneration, 1:519 Congenital chondrodystrophy of unknown Contact activation pathway, 3:261
dermal, 1:514 origin (CCUO), 1:80 Contact dermatitis
Collagenofibrotic glomerulonephropathy, Congenital colonic aganglionosis, 2:74 allergic, 1:596-597
2:419f, 2:418.e1f Congenital corneal opacities, 1:421-422 irritant, 1:566-568, 1:567f
Collagenous hamartomas, 1:723 Congenital cystic adenomatoid malformation, phytophoto, 1:578-579
Collagenous metaplasia, 1:304 2:485, 2:485.e1f Contagious agalactia, 3:458
Collapse, tracheal, 2:483f, 1:192.e1 Congenital diaphragmatic clefts, 1:191-192 Contagious bovine pleuropneumonia
Collie dogs Congenital dilation of large and segmental (CBPP), 2:551-552
afibrinogenemia, 3:265 bile ducts, 2:265 Contagious caprine pleuropneumonia
axonal dystrophy, 1:324 Congenital duplication cysts, 2:31 (CCPP), 2:563-564
canine dermatomyositis, 1:198 Congenital enzyme defects of adrenal cortex, Contagious equine metritis (CEM), 3:445,
choroidal hypoplasia, 1:413 3:339 3:445f
Collie eye anomaly, 1:413-414, 1:414f Congenital erythropoietic porphyria, 1:59-60, Contagious footrot, 1:643-644
hereditary deafness, 1:492 1:59f Contagious ovine digital dermatitis (CODD),
hyperestrogenism, 1:589 cats, 1:59 1:644
melanocytopenic hypomelanosis, 1:555 cattle, 1:59-60 Contagious pustular dermatitis, 1:617-618,
motor neuron disease, 1:331 pigmentation of teeth in, 2:7 1:617f
retinal folding, 1:419 Congenital flexures, 1:189 Continuing education for pathologists,
Collie eye anomaly (CEA), 1:413-414, Congenital follicular parakeratosis, 1:532 1:14-15
1:414f Congenital hearing impairment, 1:491-492 Contractility disturbances, 3:4-5
Colliquative myocytolysis, 3:37 Congenital heart abnormalities, 3:14-24, Contractures, muscle, 1:213-214
Colloid goiter, 3:322, 3:322f 3:15t, 3:66-67 Contusions, head, 1:302
Colloid mineralization, 3:314, 3:315f Congenital hematomas, 3:22-23 Convulsions, bovine familial, 1:319
Coloboma, 1:412, 1:412f endocardium, 3:30 Coonhound paralysis, 1:394
Colon Congenital hepatic fibrocystic diseases, Cooperia spp., 2:213
adenocarcinoma 2:265 Coopworth sheep, 1:324
cats, 2:103f Congenital hepatic fibrosis, 2:265, Copper
metastasis, 2:102-103 2:265f-266f deficiency, 1:559f, 2:115
bacteria, 2:65 Congenital histiocytosis, 1:730 myocardial necrosis and, 3:34
colonic glands, 2:61-62 Congenital hyperostosis (diaphyseal neonatal, 1:328-329, 1:328f
epithelial cell proliferation, 2:68 dysplasia), 1:53, 1:53f osteochondrosis and, 1:81
impaction, 2:76 Congenital hypothyroidism with osteoporosis and, 1:66
invasive carcinoma, 2:105f dyshormonogenic goiter, 3:314, 3:323f pigmentation and, 1:558, 1:558f
lamina propria, 2:62 Congenital hypotrichosis, 1:538-539 liver toxicity, 2:342-343
left dorsal displacement, 2:78-79, 2:79f associated with pigmentary alteration, staining in liver, 2:303, 2:303f
mesenteric attachments anomaly, 2:74 1:539-541 Corgi dogs
neoplasms, 2:117 cats, 1:539 canine dermatomyositis, 1:198
osmotic overload, 2:71-72 cattle, 1:538-539 degenerative diseases of cartilaginous joints
right dorsal displacement, 2:78 dogs, 1:539, 1:539.e1f in, 1:143-144
tympany, 2:78 Congenital idiopathic megaesophagus (CIM), degenerative radiculomyelopathy,
volvulus, 2:79 2:33-34 1:330
Color dilution alopecia, 1:539-540, 1:540f, Congenital inguinal hernia, 2:80 severe combined immunodeficiency
1:557 Congenital intrahepatic arterioportal fistulae, (SCID), 3:139
Combined ocular and skeletal dysplasia, 1:45 2:266f tongue atrophy, 1:228
Comedo, 1:524 Congenital melanosis, 2:270 Cornea, 1:427-441
Committed myoblasts, 1:167 Congenital myasthenia gravis, 1:209 anomalies, 1:421-422
Compact cell carcinoma of thyroid, 3:330, Congenital spinal stenosis, 1:81 cutaneous metaplasia, 1:429, 1:429f
3:331f Congenital status spongiosus of Gelbvieh- degeneration, 1:434-436
Compartment syndrome, 1:211 cross calves, 1:347 dermoid, 1:421, 1:422f
Complement-leukocyte-dependent Congenital stenosis of pancreatic duct, dystrophies and deposits, 1:433-434
mechanism, 2:408 2:355-356 endothelial dystrophy, 1:433
Complete blood count (CBC), 3:257 Congenital tremor (CT), 1:338 keratitis, 1:436-441
Complex partial cluster seizures with Congenital trigeminal nerve hypoplasia, lipid and crystalline, 1:433
orofacial involvement, 1:307-308 1:187, 1:188f normal, 1:428f
Complex secretory epitrichial adenomas, Congenitally ectopic lenses, 1:422 secondary to injury, 1:434, 1:434f
1:718-719 Congestion, pulmonary, 2:487 secondary to metabolic disease,
Complex vertebral malformation (CVM), Congestive brain swelling, 1:294 1:433-434, 1:433f
1:57 Congestive heart failure, 2:115, 3:6, 3:10-12, wound healing, 1:429-432, 1:430f,
Compositae/asteracae, 2:331 3:11f, 3:9.e1f 1:431t, 1:432f
Compound granular corpuscles, 1:263 Congo red (CR) stain, 2:415 edema, 1:428-429, 1:428f, 2:136f
Compressive atelectasis, 2:486 Conidiobolomycosis, 1:659-660 perforation, 1:437, 1:437f
Compressive optic neuropathy, 1:320 granulomatous rhinitis and, 2:476 sequestrum in horses, 1:435
Computed tomography (CT), 1:30 Conium maculatum, 1:90, 2:3 Corneodesmosomes, 1:513
Concentric cardiac hypertrophy, 3:8, 3:8f Conjunctiva, 1:424-427 Cornified envelope (CE), 1:513
Concussion, 1:302 neoplasms, 1:479-480, 1:479f-480f Coronary embolism, 3:36
Conduction, heart impulse, 3:5 tumors, 1:481-482 Coronavirus, 2:146-151
Conduction hearing loss, 1:496 Conjunctivitis, 1:424-427 cats, 2:117, 2:150-151, 2:587-588
Condylar fractures, 1:36 eosinophilic, 1:426 cattle, 2:112, 2:148-150, 2:149f, 2:541-
Cone dysplasia, 1:469 feline lipogranulomatous, 1:427, 1:427f 542, 2:542.e1f
Congenital absence of the pericardium, immune-mediated, 1:426-427 dogs, 2:150, 2:576
3:22 ligneous, 1:426-427 horses, 2:150
Congenital aneurysm, 3:23 Connective tissue disorders, 1:542-546 pigs, 2:113, 2:115, 2:147-148, 2:529
Index 523
Ehlers-Danlos syndrome (EDS), 1:543-544 Encephalitozoon cuniculi, 1:385-386, 2:431, Endophthalmitis (Continued)
Ehrlichia canis, 2:414, 2:418, 3:111 3:418 parasitic, 1:451-452
platelet dysfunction, 3:260 Encephalocele, 1:267, 1:267f protozoal, 1:451
Ehrlichia platys, 3:260 Encephalomalacia, 1:307 viral, 1:452
Ehrlichia ruminantium, 3:80-82 focal symmetrical, 1:300-301, 1:301f Endothelial cells
Ehrlichiosis, 1:449 pigs, 1:308-309 hepatic, 2:262-263
Eimeria alabamensis, 2:230-231 nigropallidal, 1:314, 1:314f sinusoidal, 2:260
Eimeria apsheronica, 2:233 Encephalomyelopathies, spongy, 1:342f, vascular, 3:55
Eimeria arloingi, 2:232, 2:232f 1:345f, 1:346-347 disorders, 3:255-268
Eimeria auburnensis, 2:230 Encephalomyocarditis virus (EMCV), 3:43 Endothelial protein C receptor (EPCR),
Eimeria bareillyi, 2:231 Enchondromatosis, 1:116 3:265-266
Eimeria bovis, 2:229 Endoarteritis, 2:84 Endothelium-mediated fibrinolysis, 3:266
Eimeria bukidnonensis, 2:230-231 Endocardiosis, 3:27, 3:28f-29f End-stage kidneys, 2:377-378
Eimeria caprina, 2:231 Endocarditis, 3:30-33, 3:31f, 3:31.e1f English Bulldogs
Eimeria christenseni, 2:231-232 Endocardium, 3:3 acne, 1:549
Eimeria crandallis, 2:233 disease, 3:27-33 brachycephalic airway syndrome, 2:482,
Eimeria gilruthi, 2:54-55 degenerative lesions, 3:27-30 2:482f
Eimeria leuckarti, 2:233-234, 2:233f mural and valvular, 3:4 demodectic mange, 1:679
Eimeria ninakohlyakimovae, 2:231 Endochondral ossification, 1:22, 1:22f factor VII deficiency, 3:264
Eimeria ovinoidalis, 2:231 rickets and, 1:71-72 hypothyroidism, 1:587, 3:315
Eimeria zuernii, 2:229 Endocrine cells, 2:45 keratoconjunctivitis sicca, 1:436
Elaeophora bohmi, 3:88 Endocrine pancreas, 2:368-375 recurrent flank alopecia, 1:590
Elaeophora poeli, 3:88, 3:88.e1f diabetes mellitus, 2:370-373, 2:371f English Cocker Spaniel hereditary nephritis,
Elaeophora schneideri, 1:390, 1:451-452, cats, 2:372, 2:373f 2:416
3:88 cattle, 2:372 English Pointer dogs
Elaeophoriasis, 3:88 diabetic cataract, 1:443 chondrodysplasia, 1:44
Elaphostrongylus cervi, 1:390 dogs, 2:373 motor neuron disease, 1:331
Elaphostrongylus panticola, 1:390 horses, 2:372 sensory and autonomic neuropathies,
Elaphostrongylus rangifera, 1:390 retinopathies, 1:472 1:334
Elastic fibers, dermal, 1:514 hyperplastic and neoplastic diseases, English Setter dogs, atopic dermatitis in,
abnormalities of, 1:545 2:373-375, 2:374f 1:591
Elbow hygroma, 1:155, 1:155f Endocrine system, 3:269-357 English Springer Spaniel dogs
Electrical burns, 2:13 adrenal cortex, 3:336-348 canine congenital myasthenia, 1:209
Electrolytes adrenal medulla, 3:348-354 canine hypomyelinogenesis, 1:337
abnormalities and myopathies, 1:225 diseases/disorders, 2:384-385 chronic hepatitis, 2:304
balance, 2:384 atrophy of, 1:178, 1:178f gangliosidosis, 1:58-59
Ellipsoids, 1:256 mechanisms, 3:272-276 lichenoid-psoriasiform dermatosis,
Ellis van Creveld syndrome 2, 1:39, myopathies associated with, 1:224-225 1:552-553
1:39f of skin, 1:587-590 malignant hyperthermia, 1:210
Elokomin fluke fever, 3:149 general considerations, 3:270-276 persistent atrial standstill, 3:51
Embolic pneumonia, 2:520, 2:520.e2f hormones phosphofructokinase (PFK) deficiency,
Embolic suppurative myocarditis, calcium-regulating, 3:291-310, 3:291f 1:204-205
3:42.e1f catecholamine and iodothyronine, 3:271 polymyopathy, 1:198
Embolism steroid, 3:271 prolonged APTT, 3:263
arterial, 3:63-66, 3:63f-64f thyroid, 3:311-312 retinal folding, 1:419
coronary, 3:36 types, 3:270-271 seborrhea, 1:548
pulmonary, 2:489, 2:490f multiple endocrine neoplasia (MEN), sensory and autonomic neuropathy,
fat, 2:490 3:356-357 1:334
septic, 2:490 paragangliomas, 3:354-356 Enrofloxacin, 1:472
septic, 1:358-362, 1:358f parathyroid gland, 3:292-295, 3:292f Entamoeba histolytica, 2:98-99, 2:242
Embryonal carcinoma, 3:496 pituitary gland, 3:276-291 Enteric clostridial infections, 2:183-194
Embryonal rhabdomyosarcoma, 1:241-243, proliferative lesions, 3:271-272 Enteric coronaviral infections,
1:243f thyroid gland, 3:310-336 2:146-151
Embryonal tumors, 1:401-403 tumors, 3:272 Enteric disease, pathophysiology of, 2:69-73,
Embryonic death, 3:395 Endogenous anticoagulants, 3:265-266 2:107
with persistence of membranes, 3:396 Endogenous lipid pneumonia, 2:517 anemia, 2:73
Embryonic stage of lung growth, 2:484 Endogenous protein, 2:72-73 diarrhea, 2:70-72
Emmonsia crescens, 2:584 Endometritis, 3:388-389, 3:388f increased intestinal motility, 2:72
Emmonsia parva, 2:584 Endolymph, 1:489 increased permeability, 2:71
Emphysema Endometrial biopsy, 3:393 large-bowel, 2:71
fetal, 3:396 Endometrial cups, 3:394, 3:394f malabsorptive, 2:71
lymph node, 3:199 Endometrial polyps, 3:385, 3:386f secretory, 2:71
pulmonary, 2:486-487, 2:487f Endometritis, 3:388-389, 3:388f small-bowel, 2:71
Emphysematous cystitis, 2:459, 2:460f chronic, 3:389-390 inappetence/anorexia, 2:69
Emphysematous pyelonephritis, 2:440 Endometrium, 3:382-387, 3:382f malassimilation, 2:69-70
Empyema, 1:353-354 carcinoma, 3:449-450 assimilation of fat, 2:70
of sinus, 2:477, 2:477f cysts, postpartum, 3:440 lipids, malabsorption of, 2:70
Enamel, 2:5 endometritis, 3:388-389, 3:388f polysaccharides, maldigestion of,
hypoplasia, 2:7f Endophthalmitis, 1:446 2:70
loss, 2:10 bacterial, 1:449 protein maldigestion, 2:70
Encephalitozoon, 1:451 mycotic, 1:449-451 protein-energy malnutrition, 2:69
Enteric disease, pathophysiology of Eosinophilic epitheliotropic disease, 2:16 Epidermolytic ichthyosis, 1:531,
(Continued) Eosinophilic folliculitis and furunculosis, 1:531.e1f
protein metabolism, 2:72-73 1:696 Epididymis. See Testes and epididymis
albumin, elevated hepatic synthesis of, Eosinophilic gastroenteritis, 2:96 Epididymitis, 3:473-474, 3:474f, 3:487-491,
2:73 Eosinophilic granuloma 3:488f-489f
anorexia, 2:72 complex (EGC), feline, 1:693-694, boars, 3:490
decreased protein intake, 2:72 1:693f-694f bulls, 3:489-490
peptides/amino acids, malabsorption of, dogs, 1:694 dogs and cats, 3:490-491
2:72 horses, 1:694-695, 1:695f infectious bovine, 3:443
protein-losing gastroenteropathy, Eosinophilic interstitial pneumonia, 2:513.e1 small ruminants, 3:490
2:72 Eosinophilic meningoencephalitis, 1:396 stallions, 3:490
Enteric nervous system, 2:62 Eosinophilic myocarditis, 3:43 Epidural/subdural abscess, 1:353-354, 1:354f
Enteritis Eosinophilic myositis, 1:236-237, 1:236f- Epilepsy, familial myoclonic, 1:205
adenoviral, 2:143, 2:143f-144f, 2:542, 237f, 2:34 Epinephrine, 3:348, 3:350f
2:568 Eosinophilic pulmonary granulomatosis, Epiphyseal arteries, 1:27
Campylobacter spp., 2:180-181 2:513.e1 Epiphysiolysis, 1:31
Enterococcus spp., 2:198-199 Eosinophilic pustulosis, 1:696 Epiphysis, slipped, 1:31
eosinophilic, 2:96 Eosinophilic rhinitis, 2:476, 2:476.e1f Epiploic foramen, herniation through,
granulomatous, 2:97 Eosinophilic sialoadenitis, 2:29-30 2:79
necrotizing, 2:187, 2:187f-188f Eosinophilic ulcers, 2:16 Episclerokeratitis, 1:476
parvoviral, 2:153-158 Eosinophilic vascular infiltrates, 1:611 Epistaxis, 2:473-474
Enteroaggregative E. coli heat stabile toxin Eosinophilic vasculitis, 1:526 Epithelial cells, 2:61-62
(EAST1), 2:160, 2:160f-161f Eosinophils, 1:527 of neonate, 2:63
Enterococcus durans, 2:113-114 Ependymal cells, 1:262 Epithelial cysts, 1:500
Enterococcus spp. enteritis, 2:198-199 Ependymoma, 1:400-401, 1:401f Epithelial hyperplasia, 1:442-443, 3:151,
Enterocolitis, protothecal, 2:203-204 Epicardium, 3:3 3:151f
Enterocytes, 2:60-61 Epicauta spp., 2:52 Epithelial inclusions, 3:22
invasion and salmonellosis, 2:168 Epidermal collarette, 1:524 Epithelial integrity, restoration of, 2:67
Enteroendocrine cells, 2:60 Epidermal growth factor (EGF), 2:46, 3:257, Epithelial neoplasia, middle ear, 1:500
Enterohemorrhagic colibacillosis, 2:112, 3:257f Epithelial regeneration, 2:422-423
2:162f Epidermal hamartomas, 1:705 Epithelial renewal
Enterohemorrhagic E. coli (EHEC), Epidermal inclusion cysts, 2:478 large intestine, 2:68-69
2:162 Epidermal mast cells, 1:519 small intestine, 2:66-67
Enteroinvasive E. coli, 2:166 Epidermal vesicles, 2:118 villus atrophy, 2:67-68
Enteroliths, 2:75 Epidermis, 1:512-513, 1:520 Epithelial rests of Malassez, 2:6
Enteropathogenic colibacillosis, 2:161-163 basement membrane zone, 1:513-514 Epithelial tumors
Enteropathy-associated T-cell lymphoma dermatohistopathology, 1:518-530 pulmonary, 2:495
(EATL), 3:230-232, 3:231f, 3:232.e1f disorders of differentiation, 1:547-554 skin, 1:703
Enterotoxemia, 2:115, 2:188-191, acne, 1:549 thymic, 3:152-153
2:189f-190f canine nasodigital hyperkeratosis, Epitheliogenesis imperfecta, 2:4, 2:4f
Enteroviral encephalomyelitis, 1:373f 1:549-550 Epithelioid macrophages, 1:527
Enterovirus/teschovirus ear margin dermatosis, 1:553 Epitheliomas, sebaceous, 1:717
polioencephalomyelitis of pigs, 1:372- equine coronary band dystrophy, Epitheliomatous sebaceous carcinomas,
373, 1:373f 1:553-554 1:717-718
Entheses, 1:130 exfoliative dermatoses, 1:553 Epitheliotropic T-cell tumors, 2:107-108
Entomophthoromycosis, 1:659-660, 2:201, hyperplastic dermatosis of West Epitheliotropism, 3:232
2:573-574 Highland White Terriers, 1:553 Epithelium
Envenomation, 1:568 ichthyosis, 1:554 exfoliation in coronavirus, 2:146
Environmental contaminants keratoses, 1:550-551 nasal, 2:466, 2:466f
liver and, 2:330-333 Labrador Retriever nasal parakeratosis, Epithrichial cysts, 1:705
thymic atrophy and, 3:144 1:550 Epitrichial sweat glands, 1:517-518
Enzootic ataxia, 1:328-329, 1:328f lichenoid-psoriasiform dermatosis, carcinomas, 1:719
Enzootic bovine leukosis, 3:235-236, 3:236f, 1:552-553 tumors, 1:718
3:236.e1f, 3:236.e2f Schnauzer comedo syndrome, 1:549 Epizootic bovine abortion (EBA), 3:148,
Enzootic hematuria, 2:461-462 sebaceous adenitis, 1:551-552, 1:552f 3:149f, 3:419-420
hemorrhagic urinary bladder mucosa, seborrhea, 1:548-549, 1:549f Epizootic catarrhal enteritis of ferrets (ECE),
2:461f tail gland hyperplasia, 1:549 2:150-151
Enzootic nasal tumor, 2:560, 2:560f vitamin A-responsive dermatosis, 1:552 Epizootic hemorrhagic disease virus (EHDV),
Enzootic pneumonia, 2:539 tumors, 1:706-714, 1:706f 2:39-40, 2:137, 2:137f, 3:431
Enzyme(s) Epidermoid cysts, 1:404 Epizootic lymphangitis, 3:97-98
defects of adrenal cortex, 3:339 Epidermolysis bullosa, 1:533-537, 1:534f, ε-cells, endocrine pancreas, 2:368
lysosomal, 1:284 2:15 Epulis, 2:20, 2:24, 2:24f
Eosinophilia, 3:111 cats, 1:536-537 Equid alphaherpesviruses (EHV), 2:568
Eosinophilic bronchopneumopathy, 2:501- cattle, 1:534-535 Equid besnoitiosis, 1:662
502, 2:502f, 2:501.e1f dogs, 1:536, 1:536f Equid gammaherpesviruses, 2:568-569
Eosinophilic conjunctivitis, 1:426 dystrophic, 1:534 Equid herpesvirus 1, 3:435-437, 3:436f,
Eosinophilic cystitis, 2:460 goats, 1:535 2:568.e2f
Eosinophilic dermatitis, 1:693-696 horses, 1:535-536 spleen and, 3:183f
with edema, 1:696 junctional, 1:534 thymic atrophy and, 3:145-146
Eosinophilic enteritis sheep, 1:535 Equid herpesvirus 2, 1:626-627, 2:514
cats, 2:96, 2:96f simplex, 1:534-535 Equid herpesvirus 3, 1:625-627
dogs, 2:92f Epidermolysis bullosa acquisita (EBA), 1:604 Equid herpesvirus 5, 1:626-627
horses, 2:96 Equine anterior uveal melanocytomas, 1:483
Index 529
Equine arteritis virus (EVA), 3:71-72, 3:72f, Erysipelothrix rhusiopathiae, 1:150, 2:20, Eurytrema, 2:365
3:427-428 2:433, 3:30-31 Eventration, 2:78
Equine aural plaques, 1:504 Erysipelothrix tonsillarum, 3:30-31 Eversion, of the bladder, 2:451
Equine bacterial pneumonia, 2:571-572 Erythema multiforme (EM), 1:607, 1:609- Excess free cytosolic calcium, 2:399
Equine bone fragility syndrome, 1:91, 1:91f 610, 1:610f Excessive moderator bands, 3:47
Equine canker, 1:642-643 Erythrocyte disorders, 3:112, 3:255-268. See Excess renal tissue, 2:392
Equine cannon keratosis, 1:550 also Anemia Excitotoxicity, 1:254
Equine coital exanthema, 3:507 hereditary, 3:126 Excrete metabolic wastes, 2:384
Equine coronary band dystrophy, 1:553-554 Erythrocytosis, 3:128 Exertional myopathies, 1:221-223
Equine coronavirus (EqCoV), 2:150 Erythroid hyperplasia, 2:73, 3:106f dogs, 1:223
Equine cutaneous onchocerciasis, 1:687-688 Erythrosine, 3:325 horses, 1:221-223, 1:222f
Equine degenerative myeloencephalopathy Eschar, 1:524 other species, 1:223
(EDM), 1:322-324 Escherichia coli, 2:51, 2:111, 2:115, 2:158- Exfoliative cutaneous lupus erythematosus
Equine ear papillomas, 1:707-708 167, 2:159f, 2:452, 2:589 (ECLE), 1:606, 1:606f
Equine encephalitides, 1:376-377, 1:377f abortion and, 3:417 Exfoliative dermatitis, 1:691-692
Equine encephalitis, 1:377f bovine, 2:112 Exfoliative dermatoses, 1:553
Equine eosinophilic nodular diseases, in Boxer dogs, 2:95 Exocrine pancreas, 2:353-368
1:694-695, 1:695f coliform arthritis due to, 1:151 atrophy, 2:362-363, 2:362f
Equine exercise-induced fatal pulmonary edema disease and, 2:163-166, 2:164f developmental anomalies, 2:355-356
hemorrhage (EAFPH), 2:491-492, endocarditits and, 3:30-31 hyperplastic and neoplastic lesions,
2:491.e1f enteroinvasive, 2:166 2:365-368, 2:365f-366f
Equine exercise-induced pulmonary enterotoxigenic, 2:112 insufficiency, 2:69, 2:363-364
hemorrhage (EIPH), 2:490-491, 2:491f, epididymitis due to, 3:491 necrosis, 2:357-360, 2:359f-360f
2:490.e1f gastric venous infarction due to, 2:51 pancreatitis, 2:360-362
Equine genital papillomas, 1:707-708 mastitis, 3:454-455, 3:454f parasitic diseases, 2:365
Equine grass sickness, 3:51 penis and prepuce injury, 3:507 regressive changes, 2:356-364
Equine herpesviral myeloencephalopathy, E-selectin, 1:515 Exocytosis, 1:519-520
1:383-384, 1:384f Eskimo Spitz dogs, platelet dysfunction in, Exogenous porcine growth hormone, 1:225
Equine hyperlipemia, 2:276-277 3:259 Exogenous steroids, 3:341
Equine infectious anemia virus (EIAV), Esophageal diverticula, 2:31 Exostoses, 1:33
3:114-116 Esophageal sarcocysts, 2:34 osteitis and, 1:97-98
Equine influenza, 2:567-568, 2:567.e3f Esophagitis, 2:31-32, 2:32f vitamin A toxicity and, 1:87
Equine intestinal clostridial diseases, 2:99 Esophagorespiratory fistulae, 2:31 Expansile nodules, symptomatic tumors of,
Equine laryngeal hemiplegia, 1:334-335 Esophagus, 2:30-35 2:110
Equine linear alopecia, 1:550, 1:550f anomalies, epithelial metaplasia, and ExPEC, 2:578
Equine lymphomas, 3:237-238, 3:238f, similar lesions, 2:31 Experimental disease, 1:3
3:238.e1f anomalies/epithelial metaplasia/similar External acoustic meatal stenosis, 1:502
Equine multinodular pulmonary fibrosis lesions, 2:31 External ear, 1:500-508
(EMPF), 2:568, 2:569f congenital duplication cysts, 2:31 dermatologic diseases of, 1:503-505
Equine onchocerciasis, 1:452 dysphagia, 2:33-34, 2:34f developmental disease, 1:501-502
Equine polysaccharide storage myopathy, congenital idiopathic megaesophagus hearing and, 1:501
1:205-207, 1:206f-207f (CIM), 2:33-34 histologic preparation and examination,
Equine postanesthetic degenerative cricopharyngeal dysphagia, 2:33 1:508
myopathy, 1:224 megaesophagus, 2:33 otitis externa, 1:497, 1:502-503, 1:502f,
Equine protozoal myeloencephalitis, pharyngeal dysphagia, 2:33 1:497.e2f
1:386-387, 1:387f esophageal diverticula, 2:31 parasitism, 1:505-507
Equine purpura hemorrhagica, 1:612 esophageal obstruction/stenosis/ pinnal tumor-like growths and neoplasia,
Equine recurrent ophthalmitis, 1:455-456 perforation, 2:32-33 1:504-505
Equine sarcoidosis, 1:700-701 esophagitis, 2:31-32 External hernias, 2:79-81, 2:245
Equine self-mutilation syndrome, 1:562 erosive/ulcerative esophagitis, 2:30 External hordeolum, 1:423
Equine serum hepatitis, 2:313-314, 2:314f hiatus hernia, 2:32 Extra-adrenal paragangliomas, 3:356
Equine stringhalt, 1:335 reflux esophagitis, 2:32 Extrahepatic biliary anomalies, 2:265-266,
Equine strongylosis, 2:216 thrush, 2:32 2:266.e1f
Equine suprascapular neuropathy, 1:335 esophagorespiratory fistulae, 2:31 Extramedullary hematopoiesis (EMH),
Equine systemic calcinosis, 1:223-224, lesions, 2:124, 2:124f 2:300-301, 2:441, 3:191
1:224f neoplasia, 2:43-44 Extramedullary plasmacytomas (EMP),
Equine thrush, 1:643 obstruction, stenosis, and perforation, 2:27-28, 2:109, 3:226-228, 3:226.e1f
Equine viral arteritis, 3:71.e2f 2:32-33, 2:33f Extranodal T-cell lymphoma, 3:232
Ergotism, 1:572-573, 1:573f papillomas, 2:43-44 Extraskeletal osteosarcomas, 1:115
Erosions parasitic diseases, 2:34-35, 2:35f Extrathyroidal lesions in hypothyroidism,
BVDV, 2:123-124, 2:124f Spirocerca lupi, 2:34-35 3:318-319
erosive and ulcerative stomatitides, 2:15-17 Estrela Mountain dogs, dilated Extrinsic compression, 2:74
erosive esophagitis, 2:31-32 cardiomyopathy in, 3:48 Exuberant fracture callus, 1:127
erosive polyarthritis, 1:157-158 Estrogen in physis, 1:25t Exuberant granulomas, 2:13
laryngeal, 2:481, 2:481.e2f Ethylene glycol, 2:425 Exudative epidermitis, 2:17
teeth, 2:9-11 intoxication, 2:425f of pigs, 1:630-632, 1:631f
Eructation, 2:36-37, 2:40 Eucoleus aerophilus, 2:585, 2:591 Eyelid(s)
Eryptosis, 3:114 Eucoleus boehmi, 2:585 abortion and, 3:401
Erysipelas Eumycotic mycetoma, 1:653-654, canine cutaneous histiocytoma, 3:244f
pigs, 1:149-150, 1:150f 1:654f developmental anomalies and acquired
sheep, 1:150 Eupatorium rugosum, 3:36 diseases, 1:423
Eyelid(s) (Continued) Feline cardiomyopathies, 3:46-48, 3:46.e2f Feline viral rhinotracheitis, 2:16, 2:588-589
neoplasms Feline ceruminous cystomatosis, 1:507 Feline X-linked muscular dystrophy,
Meibomian adenoma, 1:480-481, 1:481f Feline chronic gingivostomatitis, 2:16 1:194-195, 1:195f
squamous cell, 1:479-480, 1:479f-480f Feline chronic progressive polyarthritis, 1:158 Felty’s syndrome, 1:157
Eye(s), 1:408-488 Feline congenital myasthenia, 1:209 Female genital system, 3:358-464. See also
developmental anomalies, 1:409-427 Feline corneal sequestrum, 1:434, 1:434f Abortion; Gestation
anomalies of mesenchyme, 1:413-414 Feline coronavirus (FCoV) , 2:117, 2:150-151, endometrium, 3:382-387, 3:382f
anomalies of neuroectoderm, 1:419-421 2:587-588 mammae, 3:451-459
anomalies of surface ectoderm, Feline enteric coronavirus (FECV), 2:117, neoplastic conditions of tubular genitalia,
1:421-423 2:150-151, 2:587-588 3:447-450
defective differentiation, 1:413-423 Feline demodecosis, 1:680-681 normal sexual differentiation, 3:360-361
defective organogenesis and, 1:410-412, Feline diffuse iris melanomas, 1:483-484, ovaries, 3:366, 3:366f
1:410f 1:484f pathology, 3:370-375
defects primarily in anterior chamber Feline eosinophilic granuloma complex pathology
mesenchyme, 1:415-417 (EGC), 1:693-694, 1:693f-694f of cervix, vagina, and vulva, 3:441-442
early ocular organogenesis and, Feline eosinophilic keratitis, 1:438-439, of gravid, 3:393-398
1:409-410 1:439f of nongravid, 3:359-441
incomplete atrophy of posterior segment Feline epitrichial ductular adenomas, sexual development disorders, 3:360-370,
mesenchyme, 1:417-419 1:718-719, 1:719f 3:361f-362f
general considerations, 1:408-409 Feline hepatic steatosis, 2:277, 2:277f uterine (fallopian) tube pathology,
histologic section, 1:408-409, 1:409f Feline hereditary cerebellar cortical atrophy, 3:379-380
lesions with canine distemper virus, 2:576 1:319 uterus
lymphomas, 3:239f, 3:239.e1f Feline herpesvirus, 1:105 cysts arising from, 3:366-367
neoplasia, 1:478-488 Feline hippocampal necrosis, 1:307-308 mucometra, 3:374, 3:374f
melanocytic tumors, 1:482-485 Feline hyperesthesia, 1:199 pathology, 3:380-382, 3:380f
ocular neuroectoderm, 1:485-486, Feline idiopathic pulmonary fibrosis (IPF), vaginal anomalies, 3:369-370
1:485f 2:497 Femoral hernias, 2:80
ocular adnexa, 1:423-427 Feline immunodeficiency virus (FIV), Ferrets, 2:52
ocular fixation, 1:408-409 1:627-628, 3:240 adrenal tumors in, 3:347-348, 3:349f
Feline inductive odontogenic tumor, 2:24 epizootic catarrhal enteritis of, 2:150-151
F Feline infectious peritonitis virus (FIPV), fibrous osteodystrophy in, 1:78f
Facial clefts, 2:2-3, 2:3f 2:253-255, 2:254f, 3:90, 3:90f gastritis, 2:52
Facial eczema, 2:335 -associated uveitis, 1:453, 1:453f Fescue toxicosis, 1:573
Factor IX deficiency, 3:263 lymph nodes and, 3:206f Festoons, 1:520
Factor VII deficiency, 3:264 spleen and, 3:184f Fetlock joint, synovial pad proliferation of,
Factor VIII deficiency, 3:263-264 Feline interstitial cystitis, 2:460 1:163
Factor XII deficiency, 3:263-264 Feline ischemic encephalopathy, 1:297, Fetus
Fading follicular hyperplasia (FFH), 1:297f atelectasis, 2:486.e2f
3:222-223 Feline leishmaniasis, 1:663-664, 1:664f bovine viral diarrhea and, 2:122
Failure of omasal transport, 2:39 Feline leprosy, 1:640-641 death, 3:395
Falciform ligament, 2:245 Feline leukemia virus (FeLV), 1:105, endocrine function, 3:274-275, 3:275f
Fallopian tubes pathology, 3:379-380 1:627-628 infections, 2:122
False tendons, 3:22 anemia and, 3:127, 3:127f lobulations, kidney, 2:392-393
Familial AA amyloidosis, 2:278-279 lymphomas, 3:235, 3:239-240 lung development, 2:484
Familial Chinese Shar Pei fever, 1:158 thymic atrophy and, 3:145 maceration and emphysema, 3:396,
Familial hyperlipoproteinemia, 2:277-278 Feline lipogranulomatous conjunctivitis, 3:396f
Familial myoclonic epilepsy, 1:205 1:427, 1:427f mummification of, 3:395-396, 3:395f
Fanconi anemia, 1:57 Feline lower urinary tract disease (FLUTD), pneumonia, 3:404, 3:404f
Fanconi syndrome, 2:428, 2:428f 2:456, 2:460 Fiber balls, 2:75-76
Farcy, 1:641-642, 3:96 Feline lymphomas, 3:239-241 Fibrin exudation, in urinary space, 2:405-406
Fasciola gigantica, 2:322, 2:556-557 Feline mannosidosis, 1:288f Fibrin formation, 3:262-263
Fasciola hepatica, 2:255, 2:320, 2:321f, Feline multifocal uveal melanocytoma, 1:483 disorders, 3:265
2:556-557, 2:322.e1f, 2:321.e1f Feline Niemann-Pick disease type C, 1:325 laboratory evaluation, 3:262-263
Fascioloides magna, 2:322, 2:322.e1f Feline panleukopenia virus (FPLV), 1:283-284, Fibrinocellular crescent, 2:406f, 2:405.e1f
Fat, muscle steatosis and, 1:191, 1:191f 2:98-99, 2:153-156, 2:155f Fibrinogen, 3:256
Fatal gastric hemorrhage, 2:58 Feline paraneoplastic alopecia, 1:691, 1:692f concentration, 3:262-263
Fat embolism, 2:490 Feline parvoviral infection, 3:145 Fibrinoid
Fat-granule cells, 1:263 Feline plasma cell gingivitis-pharyngitis, 2:16 degeneration, 1:520
Fatty acid deficiency, 1:581 Feline post-traumatic sarcoma, 1:486, 1:487f necrosis, 1:520, 2:492.e1f
Fatty cysts, liver, 2:274-275, 2:274f Feline progressive histiocytosis (FPH), 1:730, Fibrinoid leukodystrophy, 1:341
Fatty liver, 2:275-276 3:252f-253f, 3:253-254, 3:253.e1f Fibrinolysis, 3:266-267
Feeding rations deficient, 2:40 Feline proliferative necrotizing otitis externa, endothelium-mediated, 3:266
Feedlot cattle 1:503-504 plasma-mediated, 3:266-267
acute interstitial lung disease, 2:513f, Feline pulmonary adenocarcinoma, 2:497.e1f Fibrinonecrotic bronchitis, 2:501
2:513.e1 Feline pulmonary Langerhans cell Fibrinonecrotic (diphtheritic) membranes,
bloat, 2:37 histiocytosis, 2:499, 3:246-247, 3:246.e1f 2:474-475
peracute fibrinous bronchopneumonia, Feline scleromyxedema, 1:697 Fibrinopurulent arthritis, 1:147-148
2:545f Feline spinal myelinopathy, 1:341 Fibrinopurulent exudate, 1:356f
pleuritis, 2:522f Feline spongiform encephalopathy (FSE), Fibrinosuppurative exudate with mastitis,
Felid herpesvirus 1, 1:425, 1:625-627, 1:627f, 1:349 3:453-454, 3:453f
2:588-589, 2:588.e2f Feline ulcerative stomatitis, 2:16 Fibrinous arthritis, 1:146-147
Feline buccal bone expansion, 1:99-100 Feline ventral abdominal cattle, 1:147f
Feline calicivirus (FCV), 2:15, 2:589 lymphangiosarcomas, 1:728 Fibrinous exudate, 1:6f
Index 531
Gastrointestinal disease, diagnosis of German Shepherd dogs (Continued) Giant Schnauzer dogs, cobalamin deficiency
(Continued) motor neuropathy, 1:335 in, 3:127
gastroenteritis, cattle, gastrointestinal mucous membrane pemphigoid, 2:15 Giardia, 2:113, 2:242-243
parasitism, 2:114 myxomatous valvular degeneration, 3:27 Gingivitis, 2:11-12
neonatal animals, undifferentiated diarrhea panhypopituitarism, 3:280, 3:280f foreign-body stomatitis and, 2:13,
of, 2:111 pannus keratitis, 1:438 2:13f
Gastrointestinal helminthosis, 2:204-227 peripheral vestibular disease, 1:494 Gitter cells, 1:263, 1:263f
Gastrointestinal malabsorption in humans, platelet dysfunction, 3:259-260 Gla-containing proteins, 1:19
1:69 primary parathyroid hyperplasia, 3:301 Gland acid–secretory mucosa, 2:44
Gastrointestinal mast cell tumors, 2:109 pyoderma, 1:635 Glanders, 2:573
Gastrointestinal microbiota, 2:65 pyotraumatic dermatitis, 1:560 Glandular structures, 2:452
Gastrointestinal mucosal defense, 2:63 seborrhea, 1:548 Glanzmann thrombasthenia, 3:259
Gastrointestinal mucosal mast cell tumors, selective deficiencies of immunoglobulins, Glasser’s disease, 1:151-152
2:109 3:139 Glaucoma, 1:459-465
Gastrointestinal neuroendocrine carcinomas, Sly syndrome, 1:58 histologic lesions of, 1:460-462, 1:460f
2:105-106 subvalvular aortic stenosis, 3:20 lesions causing, 1:462-465
goblet-cell carcinoids, 2:106 sudden unexpected death, 3:51 retinal changes in, 1:460, 1:461f
Gastrointestinal parasitism, 2:114 vascular ring anomalies, 2:33 Glial fibrillary acidic protein (GFAP), 1:10f,
Gastrointestinal tract, 2:62-63 vasculitis, 1:612, 3:70 1:261-262
bacterial diseases, 2:158-201 vitiligo, 1:555-556 Glia limitans, 1:261
carcinoid tumors, 2:106 German Shorthaired Pointer dogs Glial reactions, 1:366
mycotic diseases, 2:201-203 acne, 1:549 Gliomatosis cerebri, 1:400f
neoplasms metastatic, 2:101 canine X-linked muscular dystrophy, 1:192 Gliosis, focal and diffuse, 1:262-263,
Gastrointestinal ulceration, 2:109 epidermolysis bullosa, 1:536 1:263f
Gedoelstia spp., 1:426 malignant oral tumors, 2:21 Glipizide, 2:329
Geeldikkop, 2:338-339 sensory and autonomic neuropathy, 1:334 Glisson’s capsule, 2:260
Gelbvieh cattle subvalvular aortic stenosis, 3:20 Global assays of hemostasis, 3:263
congenital status spongiosus, 1:347 vitiligo, 1:555-556 Global glomerulosclerosis, 2:401.e6f
motor neuron disease, 1:332 Germ cell tumors Globe and orbit tumors, 1:488
necrotizing vasculopathy, 1:200, 1:200f ovary, 3:377-378 Globoid cell leukodystrophy, 1:339-342,
Geminous teeth, 2:6 suprasellar, 1:403-404, 3:287, 3:287f 1:339f
Gemistocytes, 1:261-262, 1:261f testes, 3:495-496, 3:495f Glomangiomas, 3:99
Generalized cerebral edema, 1:294 thymic, 3:158 Glomerular amyloidosis, 2:414, 2:416f,
Generalized Shwartzman-like reaction Gestation, 3:393-398. See also Female genital 2:415.e2f
(GSR), 3:65 system Glomerular basement membrane (GBM),
Generalized skeletal dysplasias, 1:37 abortion and stillbirth, 3:395, 3:398-440 2:377, 2:380f
Genetic disease/disorders diagnosing infectious causes of, anti-GBM glomerulonephritis, 2:408
of bone, 1:36-60, 1:37t 3:399-402 familial abnormalities of, 2:415-417
connective tissue, 1:542-546 in mares, 3:417-418 size-dependent barrier, 2:380
indirectly affecting the skeleton, protozoan infections causing, 3:420-424 thickening/remodeling, 2:406
1:57-60 adventitial placentation, 3:396-397 type IV collagen, 2:415-416
of muscles, 1:186-210 amniotic plaques, placental mineralization, Glomerular capillary walls, 2:406
osteochondrosis, 1:132 and avascular chorion, 3:397 Glomerular cellular crescent, 2:406f
rickets, 1:69-70 embryonic death, 3:395 Glomerular cystic atrophy, 2:407
vasculitis, 3:70 with persistence of membranes, 3:396 Glomerular damage, monocytes, 2:409
Genetics, diagnostic, 1:12 fatty liver in, 2:275 Glomerular disease, 2:377-378,
Genital tritrichomoniasis, 3:423-424 fetal death, 3:395 2:401-421
Gentamicin, 1:494, 2:424 fetal maceration and emphysema, 3:396 amyloidosis, 2:413-414
Geophilic dermatophytes, 1:649 general considerations, 3:393-394 in dog, 2:416f, 2:415.e2f
German Boxer dogs, cleft palate in, 2:3 hydramnios and hydrallantois, 3:397 eosinophilic in H&E sections,
German Pinscher dogs, vascular ring mummification of fetus, 3:395-396, 2:415
anomalies in, 2:33 3:395f histologically, 2:414-415
German Shepherd dogs mycotic abortion in cattle, 3:418-419 familial glomerulopathies, in dog breeds,
acquired protoporphyria, 2:271 postpartum uterus, 3:440-441 2:416f
bronchitis, 2:502 prolonged, 3:397-398 immune-complex, 2:413-415
canine panosteitis, 1:107f toxemia, 2:275 renal amyloidosis, in cat, 2:414f
chondrosarcoma, 1:118 viral infections during, 3:424-440 global glomerulosclerosis, 2:401.e6f
congenital idiopathic megaesophagus, Ghrelin, 2:368 glomerular blood flow, 2:401
2:33-34 Giant axonal neuropathy of German glomerulonephritis (GN), 2:401
corneal edema, 1:429 Shepherds, 1:330 classification, 2:401
corneal endothelial dystrophy, 1:433 Giant cell glomerulosclerosis, focal segmental,
degenerative radiculomyelopathy, 1:330 granuloma, peripheral, 2:21 2:401.e5f
diskospondylitis, 1:156, 1:156f hepatitis, 2:306, 2:306f, 2:438 membranoproliferative glomerulonephritis
fibrotic myopathy, 1:213-214 multinucleated syncytial, 3:297-298, (MPGN), 2:404f, 2:401.e4f
giant axonal neuropathy, 1:330 3:298f membranous glomerulonephropathy
hyposomatotropism, 1:589 -rich osteosarcomas, 1:114 (MGN), 2:402f, 2:401.e2f
malignant lymphoma, 1:123-124 sarcomas, 1:244 mesangioproliferative
masticatory myositis, 1:226 thyroid carcinoma, 3:331, 3:331f glomerulonephropathy, 2:403f,
maxillary or mandibular fibrosarcoma, tumor 2:401.e3f
1:121 of bone, 1:122 proliferative glomerulonephropathy, 2:403f,
motor neuron disease, 1:331 of tendon sheath, 1:161-162 2:401.e3f
Gross and histologic examinations Guttural pouch, 1:495-496, 2:480-481 Heart (Continued)
(Continued) disease, 1:498 endocardial, 3:27-33
classification of tumors, 1:107, 1:108b myocosis, 2:480-481, 2:480f heart failure and, 3:2.e1f
diagnostic imaging, 1:11-12 squamous cell carcinoma of, 1:500 morphologic patterns, 3:4-5
external ear, 1:508 Gynecomastia, 3:471 pathophysiologic patterns, 3:5-6
eye, 1:408-409, 1:409f Gyr cattle, Rhabditis bovis in, 1:507 examination, 3:12-14, 3:12f, 3:13t
feline panleukopenia, 2:155 failure, 2:493, 2:493f, 3:6-12, 2:493.e1f
genetics, 1:12 H congestive, 3:6, 3:10-12, 3:11f, 3:9.e1f
heart, 3:6, 3:12-14, 3:12f, 3:13t Habronema spp., 2:567, 3:508 heart disease and, 3:2.e1f
hematoxylin and eosin (H&E) stains, 1:9, splenic abscesses, 3:183-184 systemic responses in, 3:9-10
1:29 Haematobia irritans, 1:670 hemorrhages, 3:33
immunohistochemistry, 1:9, 1:10f Haemonchus, 2:54-55 neoplasms, 3:52-54, 3:52f
immunology, 1:11 Haemonchus contortus, 3:112-114 valves, 3:4
initial and ongoing competence of Haemophilus, 1:151-152 weight, 3:2
pathologists in, 1:14-15 Haemophilus parasuis, 2:543 Heartwater, 3:80-82, 3:81f-82f
liver, 2:277 Haflinger horses, axonal dystrophy in, 1:324 Heartworm disease, 3:83-85, 3:84f, 3:85.e1f
lungs, 2:489 Hailey-Hailey disease (HHD), 1:537 Heat-stable toxin, 2:160
male genital tract, 3:465-466 Hair Heinz bodies, 3:126f, 3:238.e1f
methodologies, 1:2 congenital and hereditary diseases of Helcococcus ovis, 2:562
microbiology, 1:10-11 congenital hypotrichosis, 1:538-541 Helianthrones, 1:578
molecular biology, 1:11 hypertrichosis, 1:539-541 Helichrysum blandowskianum, 2:331
morphologic diagnosis in, 1:5 follicles, 1:515-517 Helicobacter acinonychis, 2:52
osteosarcoma, 1:112-114, 1:113f tumors arising from, 1:714-717 Helicobacter heilmannii, 2:58
parasitology, 1:11 Hairy vetch, 1:574, 2:306, 3:43 Helicobacter pylori, 2:52
photography, 1:12 Halicephalobus gingivalis, 1:98, 1:390, 1:390f, gastritis and, 2:52, 2:55
problem-oriented, 1:7 2:19, 2:444f liver and, 2:318
quality assurance of pathology services Halogenated hydrocarbons, 2:332 Helicobacter spp., 2:55
and, 1:14 Halogenated salicylanilide toxicosis, 1:345 chronic, 2:52
sample selection and preservation, records, Halogeton glomeratus, 2:425-426 colonization, 2:52
1:8 Halothane, 2:329 Helminthic infections
of severely osteoporotic bones, 1:64 Hamartomas, 1:404, 1:520, 1:705, 3:98 central nervous system and,
skeleton, 1:28 collagenous, 1:723 1:389-391
special stains, 1:9 liver, 2:264, 2:264f gastrointestinal, 2:204-227
systematic, 1:4-6 ovarian, 3:366, 3:378-379 liver, 2:318-324
techniques and stains in postmortem pulmonary, 2:485 skin, 1:685-690
examination of skeleton, 1:28-29, Hammondia, 2:239 Hemal nodes, 3:162, 3:162f, 3:162.e1f
1:29f Hampshire sheep, abomasal dilation and Hemangioendothelioma (HE), 3:98
preparation artifacts in, 1:29, 1:29f emptying defect in, 2:51 Hemangiomas, 1:122, 1:726-727, 1:727f,
toxicology, 1:11 Hansen type II intervertebral disk 2:28, 2:447, 3:98-99
trimming of fixed autopsy and biopsy herniations, 1:144f, 1:145 conjunctival, 1:481-482, 1:482f
specimens, 1:8-9 Hansen type I intervertebral disk herniations, liver, 2:349-350
types of investigations, 1:2-3, 1:3f 1:144, 1:144f ovarian, 3:378
Ground substance, congenital abnormalities Hard callus, 1:35 scrotal, 3:472
of, 1:545-546 Harlequin ichthyosis, 1:530, 1:531f Hemangiosarcomas, 1:122, 1:244-245,
Ground (interstitial) substance, dermis, 1:514 Hassall’s corpuscles, 3:142 1:245f, 1:727, 3:99-101, 3:100f-101f
Growing axonal sprouts, 1:256 Havanese dogs, sebaceous adenitis in, 1:551 ear, 1:505
Growth arrest line, 1:60, 1:60f, 1:64 Haversian systems, 1:20, 1:21f metastasis, 1:736
Growth factors in bone matrix, 1:20 Head. See also Brain splenic, 3:192-194, 3:193f, 3:192.e1f
Growth hormone (GH), 1:25t, 3:276-277 defects, 1:37t Hematin, 2:271
adenomas, 3:285-286, 3:285f-286f traumatic injuries, 1:301-303 Hematocele, 3:473
castration-responsive dermatosis, 1:589 Hearing. See also Ear(s) Hematogenous osteomyelitis, 1:98
Growth plate, 1:22, 1:22f, 1:24 external ear and, 1:501 Hematomas
bulldog type chondrodysplasia, 1:38, 1:38f impairment, 1:491-494 aural, 1:504
copper deficiency and, 1:81 acquired deafness, 1:493 congenital, 3:22-23
damage, 1:30-31 congenital, 1:491-493 endocardium, 3:30
fibrous osteodystrophy and, 1:79-80 traumatic causes of deafness and, progressive ethmoid, 2:477
hormonal regulation of, 1:24, 1:25t 1:493-494 splenic, 3:166f
mucopolysaccharidoses, 1:58 internal ear and, 1:491 thymic, 3:147-148, 3:147f-148f,
thickness, 1:23-24 middle ear and, 1:496 3:146.e2f
Growth rate Heart Hematopoiesis, 2:264, 2:264f
growth retardation lattices, 1:104, 1:105f -base tumors dervied from ectopic thyroid, Hematopoietic neoplasia, 3:129-136,
osteochondrosis, 1:132 3:356 3:129t
Guernsey cattle, cyclopia in, 1:269-270 blood supply, 3:2 Hematopoietic stem cells (HSC), 3:103
Guinea pigs cardiac rhabdomyomas of, 1:241 Hematopoietic system, 3:102-268. See also
ptyalism, 2:29 cholesterol granuloma, 1:304f Lymphomas
scurvy, 1:83, 1:83f-84f congenital abnormalities, 3:14-24, 3:15t, bone marrow, 3:103-138, 3:103f
Gurltia paralysans, 1:390-391 3:66-67 histiocytic proliferative diseases,
Gut diseases, 3:2-54 3:243-255
external muscle, 2:62 cardiomyopathies, 3:44-51, 3:48.e2f, leukocyte disorders, 3:109-112
flora, 2:65 3:45.e1f, 3:46.e2f lymph nodes, 3:196-243
immune reactions, 2:67-68 conduction system, 3:51 lymphoid organs, 3:139-141
Hematopoietic system (Continued) Hepatic carcinoids, 2:349, 2:350f Hereditary nephritis, 2:417f, 2:415.e3f
sample procurement and processing, Hepatic coccidiosis, 2:324, 2:324f Hereditary nephropathy, 2:388-391
3:107-109, 3:108f Hepatic cysts, 2:264 Hereditary renal diseases, 2:391
spleen and hemolymph nodes, 3:158-196 Hepatic dendritic cells, 2:263 Hereditary striatonigral and cerebello-olivary
thymus, 3:141-158 Hepatic dysfunction, 2:290-295 degeneration, 1:319
Hematopoietic tumors, 1:403 Hepatic encephalopathy (HE), 1:262, 1:262f, Hereditary zinc deficiency, 1:532-533
Hematoxylin and eosin (H&E) stains, 1:9, 1:344, 1:344f, 2:291-292 Heredity. See Genetic disease/disorders
1:29 Hepatic endothelial cells, 2:262-263 Hereford cattle
Hemerocallin, 1:345 Hepatic fatty cirrhosis, 2:276, 2:276.e1f bovine familial convulsions and ataxia,
Hemidesmosomes, 1:513-514 Hepatic iron overload, 2:272 1:319
Hemimelia, 1:55-56 Hepatic lipodystrophy, 2:278 bovine hypomyelinogenesis, 1:338-339
Hemivertebrae, 1:57 Hepatic progenitor cells (HPCs), 2:262 Chediak-Higashi syndrome, 3:259
Hemochromatosis, 2:272 Hepatic regeneration, 2:286-287 congenital hypotrichosis, 1:538-539
Hemoconcentration, 3:343 Hepatic sinusoids, 2:260 hip dysplasia, 1:135-136
Hemocysts, 3:30 Hepatic stellate cells (HSC), 2:263 idiopathic spongy myelinopathies,
Hemodynamic effects of valvular Hepatic susceptibility, 2:325-326, 2:260 1:342-343
abnormalities, 3:4.e1f Hepatic veins, 2:260 motor neuron disease, 1:332, 1:332f
Hemoglobinuria, 2:436 injury, 2:296-297 osteopetrosis, 1:51
-associated ATI, 2:422-423 thrombosis, 2:298 Hernias
Hemolysis, intravascular, 3:114, 3:115f Hepatitis acquired diaphragmatic, 2:246-247,
Hemolytic anemia, 3:114-126 acute, 2:301 2:246f
Hemolytic-uremic syndrome (HUS), B antigen, 3:71 diaphragmatic, 2:80
3:65 chronic, 2:301-306, 2:305.e1f direct inguinal, 2:80
Hemomelasma ilei, 2:216-217, 2:217f cats, 2:305 external, 2:79-81, 2:245
Hemonchosis, 2:207-208, 2:207f-208f dogs, 2:302-305, 2:305f femoral, 2:80
Hemopericardium, 3:25, 3:25f horses, 2:305 hernial contents, 2:79-80
Hemoperitoneum, 2:247 lobular dissecting, 2:305, 2:305f, hiatal, 2:32
Hemophagocytic histiocytic sarcoma, 2:305.e1f indirect inguinal, 2:80
3:254-255, 3:254f-255f, 3:254.e1f equine serum, 2:313-314, 2:314f inguinal, 2:80, 3:498
Hemophilia A, 3:263-264 focal, 2:282, 2:282f internal, 2:79
Hemophilia B, 3:263 giant cell, 2:306, 2:306f mesenteric, 2:79
Hemorrhage, 2:57 infectious canine, 2:310-312, 2:310f-311f, omental, 2:79
adrenal gland, 3:339-340, 3:340f 2:311.e1f pelvic, 2:79
central nervous system, 1:300-301 necrotic, 2:316, 2:316.e1f perineal, 2:80
heart, 3:33, 3:78.e1f nonspecific reactive, 2:306 prepubic, 2:80
intrafollicular (ovary), 3:370 periportal interface, 2:301-302, 2:302f, scrotal, 3:498
liver, 2:294 2:304f sequelae of, 2:80
lymph node, 3:200f Hepatoblastomas, 2:347-348, 2:348f through natural foramen, 2:79
pulmonary, 2:490-492, 2:490.e1f Hepatocellular atrophy, 2:269, 2:269f, umbilical, 2:80
retinal, 1:473 2:269.e1f ventral hernia of abdominal wall, 2:80
septicemia of cattle, 2:546-547 Hepatocellular carcinoma, 2:346, 2:346.e1f Herniation, natural foramen, 2:79
subendocardial, 3:4 mixed cholangiocellular and, 2:349, Herpesviral infections, 1:625-627
testicular, 3:492, 3:492f 2:349.e1f adrenal cortex and, 3:340
thymic, 3:147-148, 3:146.e2f Hepatocellular cholestasis, 2:293 alphaherpesviruses
tracheal, 1:192, 2:483f Hepatocellular hypertrophy, 2:269-270, cattle, 2:537
Hemorrhagic adrenal necrosis, 3:65 2:269f horses, 2:568, 2:568.e2f
Hemorrhagic bowel syndrome, 2:114. See Hepatocellular steatosis, 2:273-278, Canid herpesvirus-1 (CaHV-1), 2:577,
also Jejunal hematoma 2:274f-276f, 2:274.e1f, 2:276.e1f 3:431-432, 3:432f, 3:434f
Hemorrhagic glomeruli turkey egg pattern, Hepatocutaneous syndrome, 1:586-587, cats, 1:425, 1:625-627, 1:627f, 2:588-589,
2:399 2:295, 2:329, 2:295.e1f 2:588.e2f
Hemorrhagic infarcts, 1:299f-300f Hepatocytes, 2:261-264 general features, 2:537
Hemorrhagic inflammation, 1:353 Hepatocytotropic T-cell lymphoma (HC- male goats, 3:507
Hemorrhagic shock, 2:84 TCL), 3:232 myocardial necrosis and, 3:34
Hemosiderin, 1:434, 2:271, 3:165, 3:165f Hepatogenous photosensitization, 1:579-580, pigs
Hemosiderosis, chronic hemolytic anemia, 2:294, 2:294f causing abortion in, 3:432-433
2:429 Hepatoid glands, 1:517 pregnant uterus, 3:433
Hemostasis disorders, 3:255-268 Hepatopancreatic ampullary carcinoma pups and pregnant bitches, 3:431-432,
dysregulation of hemostasis, 3:267-268 (HC-TCL), 2:367 3:432f
fibrin formation, 3:265 Hepatorenal syndrome, 2:294, 2:430 Herpetic keratitis of cats, 1:438
fibrinolysis, 3:266-267 Hepatosis dietetica, 2:284, 2:285f Hertwig’s epithelial root sheath (HERS),
platelet plug formation, 3:255-257 Hepatosplenic T-cell lymphoma (HS-TCL), 2:4-5
regulation of coagulation, 3:265-266 3:232 Heterobilharzia americana, 2:323, 3:93-94,
thrombin formation, 3:260-261, 3:263-265 Hepatozoon americanum, 1:98, 1:240, 2:414, 3:94f
Hemothorax, 2:521, 2:521.e3f 3:110-111 Heterophilic otitis media, 1:493, 1:493.e2f
Hemotropic mycoplasmas, 3:124-125 Hepatozoon canis, 3:110 Heterotopic polyodontia, 2:6
Hendra virus, 2:569 Hepatozoonosis, 1:240 Hexachlorophene poisoning, 1:344-345,
Henle loop, 2:377 Hereditary deafness, 1:492-493, 1:492f 1:345f
Hepatic acinus of Rappaport, 2:261 cryptorchidism, 3:476-478, 3:476f Hiatal hernia, 2:32
Hepatic arterial buffer effect, 2:260 Hereditary equine regional dermal asthenia Hidradenitis, 1:520
Hepatic arteriovenous malformations, 2:266, (HERDA), 1:544 “High-altitude disease” of cattle, 3:66
2:266f Hereditary footpad hyperkeratosis, High-endothelial venules (HEV), 3:196
Hepatic artery, 2:260 1:532 Highland cattle, cropped or notched pinnae
injury, 2:296-300 Hereditary hypopigmentation, 1:555-557 in, 1:502
Index 537
Inflammation/inflammatory response Inherited myopathy of Great Dane dogs, Intervertebral disk diseases, 1:128-129
(Continued) 1:197-198 degenerative, 1:143, 1:144f
typhlocolitis in dogs, 2:97-98 Inherited photoreceptor dysplasias, 1:469 Hansen type I intervertebral disk
typhlocolitis in horses, 2:99-100 Inherited storage diseases, 1:286-292, 1:287f herniations, 1:144, 1:144f
ciliate protozoa, 2:99 Inherited thrombocytopenia, 3:258 Hansen type II intervertebral disk
equine intestinal clostridial diseases, Injections herniations, 1:144f, 1:145
2:99 interstitial lung disease reactions to, Intestinal adenocarcinomas, 2:102
Potomac horse fever, 2:99 2:512 Intestinal carcinomas, 2:104, 2:104f
subacute/chronic diarrhea in horses, site reactions, 1:560 microscopic appearance, 2:103
2:99 Injury. See Trauma; specific injuries Intestinal/colonic biopsies, interpretation of,
typhlocolitis in ruminants, 2:100 Inorganic (mineral) component of bone 2:62
typhlocolitis in swine, 2:100 matrix, 1:20 Intestinal diverticula, 2:74
dysentery, 2:100 Insects Intestinal emphysema, 2:87f
postweaning colibacillosis, 2:100 caterpillar larvae, 1:671 Intestinal encephalopathy, 2:88
lesions of joint structures, 1:155-159 fire ants, 1:671 Intestinal eosinophils, 2:64
liver and biliary tract, 2:300-309, fleas, 1:672-673 Intestinal fluke infection, 2:225-227
2:326 flies, 1:666-671 Intestinal histoplasmosis, 2:202-203,
lupus erythematosus (LE), 1:604-607 horn fly, 1:670 2:203f
lymph nodes, 3:202-212 hypersensitivity, 1:597-599, 1:670-671 Intestinal ischemia
male genital system lice, 1:671-672 arterial thromboembolism, 2:84
penis and prepuce, 3:506-508 mites, 1:673-684 colon, 2:81
prostate and bulbourethral gland, mosquito, 1:599, 1:670-671, 1:671f infarction, 2:81-86
3:501-502, 3:502f Insulin, 2:368 reduced perfusion, 2:84-86
spermatic cord, 3:498-499 Insulinomas, 2:374 acute acorn poisoning in horse, 2:85
testis and epididymis, 3:485-491 Intact nephron hypothesis, 2:377-378 nonsteroidal anti-inflammatory drugs
vesicular glands, 3:499-500, 3:499f Integumentary system. See Skin (NSAIDs), 2:85
mammae, 3:451-452 Intercellular adhesion molecules (ICAMs), shock gut, 2:85
mucosa, 2:47 3:198 transient/noninfarctive slow flow, 2:85
muscle necrosis and, 1:182, 1:182f Interface dermatitis, 1:525, 1:526f reperfusion injury, 2:81
myocarditis, 3:41-44, 3:42f, 3:42t Interferons, 2:548-549 sequelae of, 2:81-82
nervous system and, 1:351t-352t Interfollicular smooth muscles, 1:515 small intestine, 2:81
oral cavity, 2:13-19 Interglobular dentin, 2:5 venous infarction, 2:82-84
salivary glands, 2:29 Interleukins, 2:263, 2:548-549 cecal inversion, 2:84
spleen, 3:182-189, 3:182.e1f Internal ear, 1:488-495 cecocolic intussusception in horse, 2:84
teeth, 2:9-12 hearing, 1:491 displacements of, 2:83
thymus, 3:148-150 impairment, 1:491-494 duodenal sigmoid flexure volvulus, 2:83
uterine (fallopian) tubes, 3:380 Horner and Pourfour du Petit syndromes, intussusception, 2:83
uterus, 3:387-393 1:494-495 mesenteric volvulus, 2:83
vaginal and vulval, 3:443 neoplasia, 1:494 segmental ischemic necrosis of small
vasculitis, 3:67-88, 3:68b peripheral vestibular disease, 1:494 colon, 2:84
Inflammatory airway diseases, 2:506 Internal hernias, 2:79 volvulus, large colon, 2:83
Inflammatory aural polyps, 1:498-499, Internal hordeolum, 1:423 Intestinal lipofuscinosis, 2:86-87, 2:86f
1:498.e2f Interphalangeal joints, 1:142 Intestinal lymphangiectasis, 3:95
Inflammatory bowel disease (IBD), 1:66-67, Interstitial cells Intestinal lymphomas, 3:239-241, 3:240f,
2:91, 2:93f of Cajal, 2:62 3:240.e1f
idiopathic, 2:91-96 tumors of testes, 3:493, 3:493f Intestinal mucosa
Inflammatory ceruminous otitis externa, Interstitial edema, 1:294 mast cells, 2:64
1:548 Interstitial emphysema, 2:486 microscopic lesion, 2:125-126
Influenza Interstitial fibrosis, 2:510 Intestinal mucus, 2:60
cats, 2:587-588 cats, 2:515, 2:515f Intestinal obstruction, 2:74-78
dogs, 2:577 dogs, 2:514-515, 2:515f extrinsic obstruction, 2:76-77
horses, 2:567-568, 2:567.e3f Interstitial lesions, miscellaneous, 2:441-442 neoplasms, 2:76-77
pigs, 2:526-527, 2:526f, 2:526.e1f, acute ascending pyelonephritis, 2:441.e1f functional obstruction, 2:77-78
2:527.e1f bone, 2:442 adynamic (paralytic) ileus, 2:77
Infractions, 1:34, 1:34f extramedullary hematopoiesis, 2:441 feline dysautonomia, 2:77
Infundibular cysts, 1:704 renal telangiectasia, 2:442 grass sickness in horses, 2:77
Infundibular keratinizing acanthoma, 1:714, Interstitial lung disease, 2:509, 2:510f, intestinal smooth muscle, intrinsic
1:715f 2:511b disease of, 2:77-78
Infundibular necrosis, 2:10, 2:10f dogs, 2:514-515, 2:515f megacolon in Clydesdale foals, 2:77
horses, 2:10, 2:10f eosinophilic, 2:513 pseudo-obstruction, 2:77
Infundibular stalk, 3:277 feedlot cattle, 2:513f, 2:513.e1 proximal to obstruction, 2:75
Infundibulum, 1:516 foals, 2:514 stenosis/obturation, 2:75-76
Ingesta, 2:247 granulomatous, 2:513 cecal rupture, 2:76
Inguinal hernias, 2:80, 3:498 noninfectious, 2:512-520 cecum/colon in horses, 2:76
Inhalation Interstitial macrophages, 2:471 enteroliths, 2:75
oxygen, 2:518 Interstitial myocarditis, 3:42 fiber balls, 2:75-76
smoke Interstitial nephritis, 2:431-432 foreign bodies, 2:75
lung injury, 2:518 acute, 2:431 impaction of colon, 2:76
trachea and, 2:483, 2:483f chronic, 2:431 small intestinal obstruction, 2:76
toxic gases, 2:518 Interstitial orchitis, 3:486 Intestinal parasite hypersensitivity,
Inherited dyshormonogenic goiter, 3:322-323 Interstitial pneumonia, 2:509 1:599-600
Inherited erythrocyte enzyme deficiencies, Interstitium, 3:3 Intestinal phycomycosis, 2:201
3:126 Intertrigo, 1:559 Intestinal sclerosis, 2:77-78
Index 541
Intestinal smooth muscle, intrinsic disease of, Intestines (Continued) Intravascular lymphoma, 1:734, 3:99
2:77-78 congenital colonic aganglionosis, 2:74 Intrinsic cardiac responses, 3:6-9, 3:7f
Intestinal spirochetosis, 2:100 intestinal diverticula, 2:74 Intrinsic disorders of platelet function,
Intestinal stromal tumors, 2:110-111 persistent Meckel’s diverticulum, 2:74 3:259-260
gastrointestinal, 2:110 segmental anomalies, 2:73 Intrinsic hepatotoxins, 2:327
leiomyoma, 2:110 short colon, 2:74 Intrinsic lesion, 2:74
leiomyosarcoma, 2:110 small intestinal mucosa, hypoplasia of, Intrinsic obstruction, 2:32
Intestinal T-cell lymphomas, 2:107-108 2:74 Intrinsic pathway, 3:261
Intestinal tract, miscellaneous conditions, displacements, 2:78-81, 2:83 Intussusception, 2:82-83
2:86-89 cecal/colonic dilation, 2:78 Invasive tumors of bones, 1:125
chinaberry tree, 2:89 colonic volvulus, 2:79 Involucrum, 1:96, 1:96f, 1:98
idiopathic muscular hypertrophy, 2:87 eventration, 2:78 Involution
intestinal emphysema, 2:87 external hernia, 2:79-81 B-dependent tonsillar lymphoid follicles,
intestinal encephalopathy, 2:88 abdominal wall, ventral hernia of, 2:20
intestinal lipofuscinosis, 2:86-87 2:80 thymic, 3:144-147, 3:146f
jejunal hematoma, 2:88 diaphragmatic hernias, 2:80 Iodine, 1:570
muscular hypertrophy of, 2:87 direct inguinal hernia, 2:80 deficiency and goiter, 3:320-322, 3:320f
oleander toxicosis, 2:89 femoral hernias, 2:80 excess, 3:325
rectal prolapse, 2:88 indirect inguinal hernias, 2:80 ion and thyroid function, 3:273, 3:311
small intestinal bacterial overgrowth inguinal hernia, 2:80 uptake blockage, 3:325
(SIBO), 2:86 perineal hernias, 2:80 Iodism, 1:570
small intestine, pseudodiverticulosis of, prepubic hernias, 2:80 Iodothyronine, 3:271
2:87 sequelae of hernias, 2:80 Ionophore toxicosis, 1:219
Intestinal trichostrongylosis, 2:212-213 umbilical hernia, 2:80 Iridociliary epithelial tumor, 1:485, 1:485f
Intestine internal hernia, 2:79 Iridovirus, 2:430
large, 2:97-100 torsion, 2:78 Iriki virus, 1:280
colitis cystica profunda, 2:97 tympany, 2:78 Iris
colitis in cats, 2:98-99 electrolyte and water transport, 2:65-66 atrophy of, 1:447
feline panleukopenia virus (FPLV), enteroendocrine cells, 2:60 hypopigmentation, 1:415
2:98-99 gastrointestinal mucosal barrier, 2:62-65 hypoplasia, 1:413-415, 1:415f
necrotic colitis, 2:99 gastrointestinal mucosal defense, elements melanomas, feline diffuse, 1:483-484,
typhlocolitis in dogs, 2:97-98 of, 2:63 1:484f
typhlocolitis in horses, 2:99-100 globule leukocytes, 2:63 normal, 1:445, 1:445f
ciliate protozoa, 2:99 IgA-producing lymphocytes, 2:64 Irish Dexter cattle, cropped or notched
equine intestinal clostridial diseases, IgG-producing plasma cells, 2:64 pinnae in, 1:502
2:99 immune elements, 2:62-65 Irish Setter dogs
Potomac horse fever, 2:99 immunoinflammatory events, 2:66 canine atopic dermatitis, 1:591
subacute/chronic diarrhea in horses, interpretation and colonic biopsies, 2:62 color dilution alopecia, 1:539-540
2:99 intestinal intraepithelial T lymphocytes, congenital idiopathic megaesophagus,
typhlocolitis in ruminants, 2:100 2:63 2:33-34
typhlocolitis in swine, 2:100 intestinal mucosal mast cells, 2:64 gastric volvulus, 2:49
dysentery, 2:100 intussusception, 2:83f globoid cell leukodystrophy, 1:339
postweaning colibacillosis, 2:100 lamina propria, 2:61-62 hypothyroidism, 1:587
small, 2:81, 2:82f, 2:92 muscular hypertrophy, 2:87 seborrhea, 1:548
amyloid deposition, 2:91 normal form/function, 2:60-62 selective deficiencies of immunoglobulins,
cardinal finding, 2:92 oligomucous cells, 2:60 3:139
eosinophilic enteritis, 2:96 Paneth cells, 2:60 vascular ring anomalies, 2:33
chronic, 2:96 segmental anomalies of, 2:73 Irish Terrier dogs
gastric changes, 2:94 stem cells, 2:60 canine X-linked muscular dystrophy,
granulomatous enteritis, 2:97 submucosa, 2:62 1:192
transmural granulomatous enteritis, Intima, vascular system, 3:54 ichthyosis, 1:532
2:97 Intimal bodies, 3:61, 3:61f Irish Wolfhound dogs
idiopathic inflammatory bowel disease, Intimal sclerosis of testicular veins, 3:498 dilated cardiomyopathy, 3:48
2:91-96 Intoxication hypothyroidism, 1:587
idiopathic mucosal colitis, 2:92-93 hepatic steatosis by, 2:276 iris cysts, 1:446
lymphangiectasia, 2:90-91, 2:90f steroidal sapogenins, 2:338-340 Iron
lymphocytic-plasmacytic, 2:94 vitamin D, 3:301-302, 3:301f deficiency anemia, 3:112-114, 3:114f,
mucosa, 2:124 Intracelluar edema, 1:522 3:127
hypoplasia, 2:74 Intracranial pressure, 1:293-295 in hemoglobin synthesis, 3:107
vascular supply, 2:61 Intracranial thrombophlebitis, 1:300 hepatotoxicity, 2:272, 2:333
obstruction, 2:76 Intracytoplasmic inclusion bodies, 2:448f Irradiation, cataract due to, 1:443-444
dogs, 2:75f Intradural abscess, 1:354f Ischemic damage, 1:211, 1:211f
pseudodiverticulosis of, 2:87 Intraepidermal vesicular and pustular brain, 1:297-300, 1:297f
small intestinal bacterial overgrowth dermatitis, 1:527, 1:528f heart failure and, 3:9
(SIBO), 2:86, 2:364 Intrafollicular hemorrhage of ovaries, 3:370 Ischemic tubular necrosis, 2:423f
Intestines Intranuclear inclusions, 2:270 Ischemic ulcers, 2:82
B/T lymphoblasts, 2:64 Intraosseous epidermoid cysts, 1:126-127 Islands of Calleja, 1:262
cecum and colon, 2:61 Intrapancreatic hepatocytes, 2:356 Islet amyloid polypeptide (IAPP)-derived
congenital anomalies of, 2:73-74 Intratubular orchitis, 3:486, 3:486f amyloidosis, 2:414
atresia ani, 2:74 Intratubular red blood cell cast, 2:409.e1f Islet cells, 2:355, 2:370f
atresia coli, 2:74 Intravascular hemolysis, 3:114, 3:115f hyperplasia and nesidioblastosis, 2:373
Labrador Retriever dogs (Continued) Large intestine, inflammation of, 2:97-100 Lentiviral encephalomyelitis of sheep and
centronuclear myopathy, 1:197, 1:197f colitis cystica profunda, 2:97 goats, 1:378-380
chondrodysplasia, 1:45 colitis in cats, 2:98-99 Lentiviruses, 2:558-560, 2:559f, 2:558.e1f
chronic hepatitis, 2:304 feline panleukopenia virus (FPLV), Leonberger dogs
dysplasia of right atrioventricular valve, 2:98-99 leukoencephalomyelopathy, 1:340-341
3:21-22 necrotic colitis, 2:99 motor neuropathy, 1:335
exercise-induced collapse, 1:198 typhlocolitis in dogs, 2:97-98 Leporipoxvirus, 1:616
hip dysplasia, 1:135 typhlocolitis in horses, 2:99-100 Lepromatous leprosy, 1:641
Hunter syndrome, 1:58 ciliate protozoa, 2:99 Leprosy, feline, 1:640-641
hypothyroidism, 3:315 equine intestinal clostridial diseases, Leptomeningitis, 1:354-358, 1:355f-357f
ichthyosis, 1:532 2:99 Leptospira borgpetersenii, 2:435-436
laryngeal paralysis, 2:481 Potomac horse fever, 2:99 Leptospira fainei, 2:438
lymphomas, 3:238 subacute/chronic diarrhea in horses, 2:99 Leptospira interrogans, 2:431, 2:433-434
malignant hyperthermia, 1:210 typhlocolitis in ruminants, 2:100 Leptospiral serovars, 2:434t
myxomatous valvular degeneration, 3:27 typhlocolitis in swine, 2:100 Leptospira spp., 2:435t
nasal parakeratosis, 1:550 dysentery, 2:100 abortion and stillbirth in horses and,
pyotraumatic dermatitis, 1:560 postweaning colibacillosis, 2:100 3:411
seborrhea, 1:548 Large White X Essex pigs, 1:545 abortion in cattle and, 3:409-410
spongy myelinopathy, 1:343 Larval paramphistomes, 2:43 abortion in sheep and, 3:411
true retinal dysplasia, 1:420 Larval strongyles, 2:319, 2:319f abortion in swine and, 3:410-411
vitiligo, 1:555-556 Larynx, 2:467, 2:481-482, 2:481f hemolytic anemia and, 3:126
X-linked myotubular myopathy, 1:197 equine laryngeal hemiplegia, 1:334-335 liver and, 2:317-318, 2:317.e1f
Labyrinthitis, 1:493, 1:493.e2f laryngitis, 2:481 Leptospires, 2:435, 2:437-438
Laceration, 1:302 paralysis, 2:481, 2:481f Leptospirosis, 2:433-439
Lacrimal system, 1:423-424 rhabdomyomas, 1:177f, 1:241, 1:242f abortion, 2:435
La Crosse virus, 1:280, 1:383 L-asparaginase, 3:298 cattle, 2:435-437
Lactate dehydrogenase (LDH) Late-onset progressive spinocerebellar dogs, 2:437-438
diaphragmatic dystrophy in cattle, degeneration, 1:319 in domestic animals, 2:434t
1:199 Lateral domain, liver, 2:262 horses, 2:438-439
nemaline myopathy of cats, 1:198 Lathyrus odoratus, 1:91 maintenance and incidental hosts,
Lactation, “kangaroo gait” and, 1:336 Lawsonia intracelluaris, 2:177-180, 2:178f, 2:435t
Lactational osteoporosis, 1:65-66 3:202, 3:202f renal failure, 2:435
cattle, 1:66, 1:66f Lead poisoning, 1:86, 1:87f, 1:316-317 sheep, goats, and deer, 2:437
Lactotroph adenomas, 3:286-287 Lectin staining, 2:445 swine, 2:438
Lafora bodies, 1:255, 1:255f Left atrioventricular valvular insufficiency or Lesions. See also Non-neoplastic lesions
Lafora disease (LD), 1:292 stenosis, 3:22 adrenal, 3:341-343
Lagenidiosis, 1:657-659 Left atrium, heart, 3:2 brain
Lamellar bodies, 1:512-513 failure, 3:6 ischemic, 1:297-300, 1:297f
Lamellar bone, 1:20-21 Left-sided heart failure, 3:10-11 bronchopneumonia, 2:506f
Lamina cribosa, 1:476 Left ventricle, heart, 3:2 canine distemper virus, 2:576
Lamina densa, 1:513-514 Legg-Calvé-Perthes disease, 1:31, 1:96, 1:96f degenerative joint diseases, 1:138,
Lamina fibrous zone, 1:513-514 dogs, 1:97, 1:97f 1:138f
Lamina lucida, 1:513-514 Leiomyomas, 1:726, 2:110, 2:463-464, 3:378, dental, 2:576
Lamina propria, 2:51, 2:61 3:447-448, 3:447f-448f diffuse alveolar damage, 2:509
Laminitis, 1:702-703 gastrointestinal, 2:110 endocardial, 3:27-30
Landrace pigs, 1:42 liver, 2:350 endocrine gland, 3:271-272
Landseer-European Continental Type (ECT) Leiomyometaplasts, 2:87 esophageal, 2:124, 2:124f
dogs, platelet dysfunction in, 3:259 Leiomyosarcomas, 1:726, 2:110, 2:110f exocrine pancreas, 2:365-368
Langerhans cells female genital system, 3:447-448, 3:448f glaucoma-causing, 1:462-465
canine cutaneous histiocytosis, 1:729, gastrointestinal, 2:110, 2:110f granulomatous, 1:233-234
3:245-246, 3:246f liver, 2:350 hypothyroidism, 3:318-319
feline pulmonary Langerhans cell urinary system, 2:463-464 incidental, 1:7
histiocytosis, 3:246-247, 3:247f, Leishmania infantum, 1:240, 2:19 laryngeal, 2:481-482, 2:481.e2f
3:246.e1f Leishmania spp., 1:98, 1:240, 1:503, liver and bile ducts, 2:344-352
histiocytosis, 3:243 1:663-664, 2:412 microcirculatory, 1:301
immune function, 1:515 feline, 1:663-664, 1:664f middle ear, 1:498-499
skin, 1:513 penis and prepuce lesions, 3:508 muscle, 1:171
Lantana camara, 3:36 spleen, 3:174-175, 3:175f-176f, 3:175.e1f oral cavity, 2:20-28
toxicity, 2:293, 2:338 Lens, 1:441-444 osteomalacia, 1:73
Lapland dogs, glycogen storage disease type anomalies, 1:422-423 osteoporosis, gross, 1:63-64
II in, 1:204 aphakia, 1:422 ovarian, 3:370-371
Large-bowel diarrhea, 2:70-71 cataract, 1:442-444, 1:442f pericardium, 3:24-25, 3:24f
Large cell carcinoma, 2:497 congenital cataract, 1:422 photographs of, 1:8
Large-cell/lymphoblastic lymphoma, 2:108 congenitally ectopic, 1:422 photosensitization dermatitis, 1:578
Large dark fibers in muscular dystrophy, ectopia lentis, 1:441-442 postpartum uterus, 3:440-441
1:193 -induced uveitis, 1:453-454, 1:457-459 pulmonary idiopathic hypertension, 2:492
Large granular lymphocytic leukemia, lenticonus and lentiglobus, 1:422 pyelonephritis, 2:383
3:235 microphakia, 1:422 retinitis, 1:474-475
Large granular lymphocytic lymphoma Lenticonus, 1:422 rickets, microscopic, 1:72, 1:72f
(LGL), 3:231, 3:231f Lentiglobus, 1:422 rinderpest, 2:129, 2:129f
Large granular lymphoma, 2:108 Lentigo simplex, 1:554, 1:721 sepsis, 1:358-362, 1:358f, 2:512f
Male genital system (Continued) Mammary gland carcinomas, 1:736 Mature (peripheral) B-cell neoplasms,
sampling of male genital tract, 3:465-466 Mammomonogamus ierei, 2:557 3:219-228
scrotum, 3:471-473 Mammomonogamus laryngeus, 2:557 Mature (peripheral) T-cell neoplasms,
sexual development disorders, 3:468-471, Mammomonogamus nasicola, 2:557, 2:567 3:228-229
3:476-481, 3:476f, 3:499-501, 3:505 Mandibular osteomyelitis, 1:103f Maxillary or mandibular fibrosarcoma, 1:121,
spermatic cord, 3:497-499 cattle, 1:102-103 1:121f-122f
spermatogenesis, 3:466-467 Mandibular osteopathy, 2:9 M cells, 2:63-64
testis and epididymis, 3:474-497 Manganese chloride, 2:329 Mean platelet volume (MPV), 3:258
circulatory disturbances, 3:491-492 Manganese deficiency, 1:80 Mebendazole, 2:329
disorders of sexual development, cattle, 1:80, 1:81f Mechanical forces and injury effects on
3:476-481, 3:476f Mange bones, 1:30-36
hypoplasia, 3:478-479, 3:478f chorioptic, 1:676-677, 1:677f Mechanical gastritis, 2:52
neoplasms, 3:492-497 demodectic, 1:678-682, 1:680f Mecistocirrus, 2:54-55
testicular immune function, 3:467-468 notoedric, 1:675, 1:675f Meconium aspiration syndrome, 2:516,
vaginal tunics, 3:473-474, 3:473f-474f otodectic, 1:677-678 2:516.e1f
Malignant angioendotheliomatosis, 3:99 psorergatic, 1:678 Media, vascular system, 3:54
Malignant catarrhal fever (MCF), 2:131-136, psoroptic, 1:675-676 Medial hypertrophy of pulmonary arteries,
2:133f-136f, 2:459-460 sarcoptic, 1:673-675, 1:674f 3:67, 3:67f
Malignant edema and gas gangrene, 1:232 Mannheimia haemolytica, 2:557, 3:69 Medullary necrosis, gross lesions of,
Malignant hyperthermia, 1:209-210 liver and, 2:314-315 2:399-400
dogs, 1:210 respiratory system and, 2:543-544, 2:545f, Medullary rays, 2:378
horses, 1:210 2:562-563, 2:540.e2f Medullary solute washout, 2:381
pigs, 1:209-210 Mantle cell lymphoma (MCL), 3:226, Medulloblastoma, 1:402, 1:402f
Malignant lymphomas, 1:123-124, 1:245, 3:227f Medulloepitheliomas, 1:485-486, 1:486f
1:245f, 2:107-109 Manx cats, corneal endothelial dystrophy in, Megacolon, in Clydesdale foals, 2:77
cats, 3:241.e1f 1:433 Megaesophagus, 2:33-34, 2:34f
cattle, 1:124 Maple syrup urine disease, 1:344, 1:345f congenital, 2:34
large-cell/lymphoblastic lymphoma, Mare reproductive loss syndrome, 3:417 Megakaryocytes, 3:106-107
2:108 Marginal zone lymphoma (MZL), 3:224, hypoplasia, 3:258
large granular lymphoma, 2:108 3:225f, 3:226.e1f pulmonary embolism and, 2:490
pigs, 3:242f, 3:241.e2f Marked acute tubular necrosis, 2:428.e1f Megalencephaly, 1:268
small-cell lymphocytic villus lymphoma, Markers of remodeling, 1:27 Megalocornea, 1:421
2:107-108 Maroteaux-Lamy syndrome, 1:58 Megalocytosis, 2:270, 2:337f
Malignant/malevolent sarcoids, 1:708 Marshallagia, 2:54-55 Megavoltage X-radiation and cataract,
Malignant melanomas, 1:721-722, 2:26-27, Massive fat necrosis in cattle, 2:249 1:444
2:26f, 2:240f Massive liver necrosis, 2:284-285, Megestrol acetate, 2:329
cats, 2:26-27 2:284f Meibomian adenoma, 1:480-481, 1:481f
iris, 1:483-484, 1:484f Masson trichrome Melanin, 1:513
dogs, 2:21, 2:26, 2:26f method, 1:29 disorders of pigmentation, 1:554-558
Malignant mixed thyroid tumors, 3:331, stain, 2:383 lymph node, 3:200
3:331f Mastadenovirus, 2:145 Melanocortin receptor (MR2), 3:270-271
Malignant neoplasms, 2:100-101 Mast cells, 1:514-515 Melanocytes, 1:513
Malignant pheochromocytoma, 3:349-351 epidermal, 1:519 dermal, 1:514
Malignant pilomatricomas, 1:717 liver, 2:264 tumors, 1:720-722, 1:720f-721f
Malignant transformation, 2:22 tumors, 1:730-733, 1:731f, 2:27, 2:109 Melanocyte-stimulating hormone (MSH),
Malignant trichoepitheliomas, 1:715 conjunctival, 1:482 3:276-277
Malignant tumors of joints, 1:159-160 gastrointestinal, 2:109 Melanocytic tumors of eye, 1:482-485
histiocytic sarcoma, 1:159-160 mastocytosis, 3:137 Melanocytoma-acanthoma, 1:721
synovial cell sarcoma, 1:159 metastasis to lymph nodes, 3:212-213, Melanocytomas, 1:481, 1:721
Malleus, 1:495 3:213f Melanocytopenic hypomelanosis, 1:555-556
Malnutrition. See Nutritional deficiency/ metastasis to spleen, 3:194 Melanomas, 1:720-722, 1:720f-721f
disease Masticatory myositis of dogs, 1:226-227, malignant, 1:721-722, 2:26-27, 2:240f
Maltese dogs 1:226f-227f cats, 2:26-27
cochleosaccular degeneration, 1:492 Mastitis iris, 1:483-484, 1:484f
myelinolytic leukodystrophy, 1:341 bovine, 3:452-457, 3:452f dogs, 2:21, 2:26, 2:26f
Mammae, 3:451-459 camelids, 3:458-459 lymph node, 3:213.e1f
benign neoplasms, 3:460 coliform, 3:454-455, 3:454f-455f Melanopenic hypomelanosis, 1:556-557
bovine mastitis, 3:452-457, 3:452f dogs and cats, 3:458, 3:458f Melanosis, congenital and acquired, 2:270,
carcinomas, 3:451t, 3:460-463, 3:461f- fibrinosuppurative exudate with, 3:453- 2:270.e1f
462f, 3:463t 454, 3:453f Melanotic tumors, cytologic evaluation of,
cats, 3:463-464, 3:464f horses, 3:457 2:26
coliform mastitis, 3:454-455, 3:454f mycoplasma, 3:456, 3:456f Melia azedarach, 2:89
developmental biology, 3:451, 3:451t nocardia, 3:457, 3:457f Melioidosis, 1:637, 2:563, 3:188-189, 3:188f
inflammatory disease, 3:451-452 staphylococcal, 3:452-454 Melophagus ovinus, 1:670
innate and acquired resistance of, streptococcal, 3:453-455, 3:454f Membrane permeability transition (MPT)
3:451-452 summer, 3:455-456 pore, 2:281
masses including neoplasia, 3:459-464, swine, 3:457 Membrane receptor (RANK), 3:294-295
3:459f tuberculosis, 3:456-457 Membranoproliferative glomerulonephritis
mycoplasma mastitis, 3:456, 3:456f Mastocytosis, 3:137 (MPGN), 2:404f, 2:411f, 2:411.e1f,
sarcomas, 3:463, 3:463f Materia alba, 2:9 2:401.e4f, 3:123-124
streptococcal mastitis, 3:455 Maternal leptospiremia, 2:435 proteinuria and azotemia, 2:412
summer mastitis, 3:455-456 Matrical cysts, 1:704 Membranous glomerulonephropathy (MGN),
Mammomonogamus auris, 1:498 Matrix vesicles, 1:20 2:402f, 2:401.e2f
Index 547
Miniature Schnauzer dogs (Continued) Mucociliary clearance, 2:471-472 Mural endocarditis, 3:32
demyelinating neuropathy, 1:341-342 Mucocutaneous leishmaniasis, 3:174 Mural folliculitis, 1:528
factor VII deficiency, 3:264 Mucocutaneous pyoderma, 1:630 Murray Grey cattle, inherited progressive
hypothyroidism, 1:587 Mucocyte bodies, 1:255 spinal myelopathy of, 1:325
pancreatic necrosis, 2:358 Mucoepidermoid carcinomas, 2:30 Muscle crush syndrome, 1:212
pigmented plaques, 1:710-711 Mucolipidoses, 1:290 Muscle(s), 1:165-246. See also Tendons
Schnauzer comedo syndrome, 1:549 Mucometra, 3:374, 3:374f, 3:382-383, basic reactions of, 1:173-186
sick sinus syndrome, 3:51 3:383f, 3:386 atrophy, 1:173-178
XY disorder of sexual development, 3:471, Mucoperiosteal exostoses, 1:499, 1:499f fibrosis, 1:184-185
3:471f Mucopolysaccharidoses (MPS), 1:58, 1:58f, hypertrophy, 1:178-180
Minimal change disease, 2:418, 2:420f, 1:289-290 injury and necrosis, 1:180-182
2:418.e2f hearing and, 1:491-492 other myofiber alterations,
Minimata disease, 1:321 Mucosa. See also Buccal cavity 1:185-186
Miscellaneous glomerular lesions, 2:418-421 -associated lymphoid tissue (MALT), 2:20 postmortem changes, 1:186
Misshapen teeth, 2:6 -associated lymphoid tissue (MALT)oma, regeneration, 1:182-183
Mites, 1:673-684 3:225f circulatory disturbances of, 1:210-213
Demodex, 1:678-682 buccal cavity and, 2:12-19 compartment syndrome, 1:211
trombiculiasis, 1:682-683 disease, 2:114, 2:123 downer syndrome, 1:212
Mitochondria, 1:251-252 hypertrophy, 2:48 muscle crush syndrome, 1:212
Mitochondrial cytochrome P450 enzymes, infarction, 2:385-386 postanesthetic myopathy in horses,
3:341 microscopic appearance, 2:67 1:213
Mitochondrial myopathy nasal cavity, 2:466 vascular occlusive syndrome, 1:212
dogs, 1:205 polyps, 2:104f congenital and inherited diseases,
horses, 1:207 ulcers, 2:82 1:186-210
Mitochondrial outer membrane Mucous cells, 2:469 malignant hyperthermia, 1:209-210
permeabilization (MOMP), 2:280 Mucous glands, 2:378 metabolic myopathies, 1:204-209
Mitotic index (MI), 1:721 Mucous membrane pemphigoid, 1:603, muscular defects, 1:189-192
Mittendorf’s dot, 1:417-418 1:603f, 2:15 muscular dystrophy, 1:192-197
Mixed-breed dogs, 2:415-416 Mucous metaplasia and hyperplasia, 2:47 myasthenia gravis, 1:209
factor VII deficiency, 3:264 Mucous neck cells, 2:45 myopathies, 1:197-200
severe factor X deficiency, 3:264 Mucus, 2:471 myotonic and spastic syndromes,
Mixed germ cell-sex cord stromal tumor, Mucus-producing carcinomas, 2:101-102 1:200-204
3:496 Muellerius capillaris, 2:565, 2:565t, 2:566f, primary central nervous system
Mixed liver hamartomas, 2:264 2:565.e2f conditions, 1:187-189
Mixed neuronal-glial tumors, 1:401 Mulberry heart disease, 1:217, 3:39-41, degenerative myopathies, 1:221-224
Mixed toxic insults, liver, 2:327 3:39f-41f, 3:39.e1f equine systemic calcinosis, 1:223-224
Modeling, 1:24-25, 1:26f Multicentric lymphoma, 3:241, 3:241f dermal, 1:515
Molecular biology, 1:11 Multidrug-resistance-associated protein-2 histochemical fiber types, 1:169-170,
Molluscipoxvirus, 1:616, 1:621-622, (MRP-2), 2:293 1:169f-170f
1:622f Multifocal intramural myocardial infarction, immune-mediated conditions, 1:225-230
Molybdenosis, 1:84 3:36 masticatory myositis of dogs,
Molybdenum, 1:81-82 Multifocal necrotizing panniculitis, 2:360 1:226-227
Monensin, 1:219, 3:34-35 Multifocal osseous metaplasia, 2:517, microscopic structure, 1:165-167,
Monkeypox virus, 1:616 2:517.e1f 1:166f
Monocytes, dermal, 1:514 Multifocal polyphasic necrosis, 1:218 myogenesis, 1:167-169
Monoiodotyrosine (MIT), 3:311 Multifocal renal cortical hemorrhages, myopathies
Monomyelocytic leukemia, 2:352f 2:432f associated with endocrine disorders,
Monorchia, 3:479 Multifocal symmetrical myelinolytic 1:224-225
Moraxella bovis, 1:425 encephalopathy, 1:341 associated with serum electrolyte
infectious bovine keratoconjunctivitis and, Multilobular tumor of bone, 1:117-118, abnormalities, 1:225
1:440 1:117f-118f myositis resulting from infection,
Morgagnian globules, 1:442 Multinucleated giant cells, 1:527, 2:27 1:230-234
Morgan horse, axonal dystrophy in, 1:324 Multinucleated keratinocytes, 1:523 clostridial, 1:230-233
Morphea, 1:698 Multinucleated macrophages, 2:540.e2f malignant edema and gas gangrene,
Morphologic diagnosis, 1:5 Multinucleated syncytial giant cells, 1:232
Mortierella wolfii, 2:554 3:297-298, 3:298f suppurative myositis, 1:230
Mortierellosis, 2:554 Multinucleation, liver, 2:270 neoplastic diseases of, 1:240-246
Mosaicism, 3:363 Multiple acquired cortical cysts, 2:396f muscle pseudotumors, 1:246,
Mosquito-bites Multiple cartilaginous exostosis, 1:54 1:246f
dermatitis, 1:670-671, 1:671f Multiple endocrine neoplasia (MEN), nonmuscle primary tumors of muscle,
flaviviruses, 1:374-376 3:356-357 1:244-245
hypersensitivity, 1:599 Multiple epiphyseal dysplasia, 1:44, 1:45f rhabdomyoma, 1:241, 1:242f
Motility and salmonellosis, 2:168 Multiple hepatic peribiliary cysts, 2:264 rhabdomyosarcoma, 1:241-243,
Motor neuron disease, 1:255, 1:255f, Multiple myeloma (MM), 3:137, 3:138f, 1:243f-244f
1:330-332, 1:331f-332f 3:228, 3:228f secondary tumors of skeletal muscle,
“shaker calf”, 1:332, 1:332f Multiple persistent vitelline duct cysts, 2:74 1:244-246, 1:245f-246f
Motor units, muscular, 1:165 Multisystemic, eosinophilic, epitheliotropic nutritional myopathy, 1:214-218
Mouth. See Buccal cavity; Oral cavity disease in the horse, 1:695-696 cattle, 1:215-216
Mucinosis, 1:522-523 Multisystemic epitheliotropic syndrome, 2:96 etiology and pathogenesis, 1:214-215
Mucocele Multisystem neuronal degeneration of horses, 1:218
gallbladder, 2:307, 2:345, 2:345f Cocker Spaniel dogs, 1:320 other species, 1:218
paranasal, 2:477, 2:477.e4f Mummification of fetus, 3:395-396, 3:395f pigs, 1:217
salivary, 2:29 Munro’s microabscess, 1:523 sheep and goats, 1:216-217
Index 549
Pars distalis, 3:276, 3:277f Perendale sheep, 1:324 Peripheral nervous system tumors, 1:404-406
adenoma, 3:287-288, 3:288f Perforating dermatitis, 1:699, 1:699f Peripheral neuroblastic tumors, 1:405-406
Pars intermedia, 3:276 Perforation, 2:48 Peripheral T-cell lymphomas, 3:229, 3:229f
adenomas, 3:282-285, 3:283f-284f corneal, 1:437, 1:437f Peripheral vestibular disease, 1:494
Pars nervosa, 3:277 esophageal, 2:32-33 Peripheral vestibular function, 1:490
Parson Russell Terrier dogs, 1:325 rectal, 2:247 Periportal interface hepatitis, 2:301-302,
Pars tuberalis, 3:276 Perianal glands, 1:517 2:302f, 2:304f
Particle deposition in lungs, 2:471 adenomas, 1:718, 1:718f Periportal liver necrosis, 2:283
Parturient paresis, 3:299 carcinomas, 1:718 Perirenal edema, 2:427f
Parvoviral enteritis, 2:153-158 epitheliomas, 1:718 Peritoneal milky spots, 2:244
cats, 2:153, 2:155f Periapical abscess, 2:11 Peritoneopericardial diaphragmatic hernia,
cattle, 2:44, 2:157-158, 3:429-430 Periarteriolar lymphoid sheaths (PALS), 2:245, 3:22
dogs, 2:156-157, 2:156f-157f 3:159-160 Peritoneum and retroperitoneum, 2:244-257
Parvoviral infections, 1:628 Periarteriolar macrophage sheath (PAMS), abnormal contents in, 2:247-249
myocardial necrosis and, 3:34 3:160-161 anomalies, 2:245
myocarditis and, 3:42, 3:43f Periarteritis nodosa, 3:71 ascites, 2:248-249
in pregnant uterus, 3:429-430 Periarticular fibroma, 1:161 cysts, 2:256
thymic atrophy and, 3:145 Periarticular histiocytic sarcoma, 3:252f, general considerations, 2:244-245
Passive congestion 3:250.e1f neoplasia, 2:256-257, 2:256f
of liver, 2:297-298, 2:298f, 2:298.e1f Peribronchiolar metaplasia, 2:495, parasitic diseases, 2:255
of spleen, 3:169 2:495.e2f peritonitis, 2:249-255
Pastern leukocytoclastic vasculitis, 1:612 Pericardial sac, 3:2-3 reactions to injury, 2:245-246
Pasteurellacae, 2:543, 2:562 Pericarditis, 3:25-27 Peritonitis, 2:249-255
Pasteurella multocida, 1:230, 2:543-544, constrictive, 3:26, 3:27f cats, 2:253-255, 2:254f, 3:90, 3:90f
2:562 fibrinous, 3:25-26, 3:26f -associated uveitis, 1:453, 1:453f
Patellar luxations, 1:137, 1:137f purulent, 3:26 lymph nodes and, 3:206f
dogs, 1:137, 1:137f traumatic, 2:39 spleen and, 3:184f
horses, 1:137 Pericardium, 3:5 cattle, 2:251-252, 2:251f
Patent ductus arteriosus (PDA), 3:17-18, congenital absence of, 3:22 consequences of, 2:250-251
3:18f-19f disease, 3:24-27 dogs, 2:252-253
Pathologic fracture, 1:33-36 noninflammatory lesions, 3:24-25, horses, 2:251
Pathologists, competence of, 1:14-15 3:24f pigs, 2:252, 2:252f
Patnaik system, 1:731 hemo-, 3:25, 3:25f sheep and goats, 2:252
Pattern recognition, 1:3-4, 1:3f hydro-, 3:24-25, 3:24f Peritubular capillaries, 2:398
molecules, 2:63 serous atrophy of fat of, 3:25, 3:25f Perivascular cuffing, 1:263, 1:264f, 1:366
Pautrier’s microabscess, 1:523, 1:523f Perichondrial ring of LaCroix, 1:23 Perivascular dermatitis, 1:525, 1:525f
Pax genes, 1:21-22 Periciliary liquid layer, 2:471-472 Perivascular pyogranulomatous nephritis,
PCR-based diagnosis, 2:435 Perifolliculitis, 1:528 2:432f
PCR for antigen receptor rearrangements demodectic mange and, 1:680 Perivascular Virchow-Robin space, 1:263
(PARR) assay, 3:215, 3:216f Perilla ketone, 2:519 Perivascular wall tumor (PWTs), 1:723,
Pearsonema mucronata, 2:443 Perimetritis, 3:390 1:724f
Pediculosis, 1:671 Perineal hernias, 2:80 Perivasculitis, cerebrospinal, 1:298-299,
Peer review, 1:14 Perinephric abscess, 2:439 1:298f
Pekingese dogs Perinephric pseudocyst, 2:396.e2f Periventricular leukomalacia of neonates,
degenerative diseases of cartilaginous Perineurioma, 1:405 1:274
joints, 1:143-144 Periodic acid-Schiff (PAS) positive, amylase- Peromelia, 1:56
hyperestrogenism, 1:589 resistant inclusions, 1:204 Perosomus elumbus, 1:57, 1:277-278
Pelger-Huët anomaly (PHA), 3:110 Periodic acid-Schiff stain, 2:383 Persian cats
Peliosis hepatis/telangiectasis, 2:299-300, Periodic paralyses, 1:202 Chediak-Higashi syndrome, 3:259
2:299f-300f, 2:299.e1f Periodontal bone expansion, 1:101f epidermolysis bullosa, 1:536
Pelodera dermatitis, 1:689, 1:689f Periodontal disease, 2:11-12, 2:12f feline ceruminous cystomatosis, 1:507
Pelvic flexure, infarction of, 2:85f Periodontal ligament, 2:5-6 feline corneal sequestrum, 1:434, 1:434f
Pelvic hernia, 2:79 Periodontal ligament origin Persistence of the right aortic arch, 3:23-24,
Pelvis deformities, 1:56-57 fibromatous epulides of, 2:24-25 3:23f
Pembroke Welsh Corgi dogs. See Corgi dogs fibromatous epulis of, 2:24 Persistent atrial standstill, 3:51
Pemphigus complex, 1:518, 1:600-603 Periodontal osteomyelitis, 1:101f Persistent hyaloid artery, 1:417
Pemphigus erythematosus (PE), 1:602 Periodontium, 2:6 Persistent hyperplastic primary vitreous,
Pemphigus foliaceus, 1:601, 1:601f infectious and inflammatory diseases of, 1:417-418, 1:418f
Pemphigus vegetans, 1:602 2:9-12 Persistently infected (PI) calf, 2:122
Pemphigus vulgaris (PV), 1:602, 1:602f, Perioophoritis, 3:371 Persistent Meckel’s diverticulum, 2:74
2:14 Periorchitis, 3:473-474, 3:474f Persistent posterior perilenticular vascular
Pendrin, 3:311-312 Periosteal damage, 1:33 tunic, 1:417
Penis and prepuce, 3:505-510, 3:506f Periosteal fibrosarcomas, 1:121 Persistent pupillary membrane, 1:415,
inflammation, 3:506-508 Periosteum, 1:24, 1:24f 1:416f
neoplasms, 3:508-510 Periostitis, 1:97 Persistent vitelline artery, 2:245
Pentachlorophenol (PCP), 1:572 Peripheral axonopathies, 1:334-336 Persistent vitelline duct, 2:245
Pentastomiasis, 2:585 Peripheral chromatolysis, 1:253 Peruvian Paso horses, osteopetrosis in, 1:52
Pepsin, 2:45 Peripheral circulatory failure, 3:10 Peste des petits ruminants virus (PPRV),
Peptic ulcers, 2:55 Peripheral giant cell granuloma, 2:21 2:115, 2:130-131, 2:131f, 2:557
chronic, 2:56 Peripheral nerve sheath tumors, 1:404-405, Pestiviruses, 1:281-283, 2:122-128
Peptides, immunoreactive, 3:285, 3:285f 1:406f Petechiae, 2:397
Peundculated lipoma, 2:256, 2:257f Pick bodies, 1:255 Plant toxicities (Continued)
Peyer’s patches, 2:63, 2:124-126 Picornaviridae, 2:117, 3:43 myocardial necrosis and, 3:34-41, 3:35f
PFK. See Phosphofructokinase (PFK) Piebaldism, 1:555 parathyroid suppression associated with,
deficiency Piecemeal liver necrosis, 2:285 3:301-302, 3:301f
Phacoclastic uveitis, 1:457-459, 1:458f-459f Piedra, 1:660-661 Romulea, 1:322
Phacolytic uveitis, 1:457 Pigeon fever, 1:230 sheep, 1:90-91
Phaeohyphomycosis, 1:654-655, 1:655f Pigeonpox virus, 1:616 Plaque, 2:9
Phalaris poisoning, 1:292-293, 1:293f Pigmentary incontinence, 1:523 Plaques, 1:524
myocardial necrosis and, 3:36 Pigmentation amniotic, 3:397
Pharyngeal (branchial) cysts, 2:29 buccal cavity, 2:12 canine pigmented, 1:710-711, 1:711f
Pharyngeal dysphagia, 2:33 disorders, 1:554-558 Plasma cells
Pharynx, 2:480-481 acquired hyperpigmentation, gingivitis-pharyngitis, 2:16
cysts, 2:29 1:554 hemostasis disorders, 3:255-268
dysphagia, 2:33 acquired hypopigmentation, 1:557 hyperplasia, 3:201
lymphoid hyperplasia, 2:480.e3f acromelanism, 1:555 myeloma
neuroendocrine carcinoma of, 2:27 canine acanthosis nigricans, 1:555 cats, 1:123
Phenobarbital, 2:329 copper deficiency, 1:558, 1:558f-559f dogs, 1:123, 1:123f
Phenothiazine photosensitization, 1:579 focal macular melanosis, 1:554 horses, 1:123
Phenotype, gonad, 3:360 hyper-, 1:554-555 in nodular and diffuse dermatitis, 1:527
Phenotypic sexual development, 3:360 hypo-, 1:555-558 pododermatitis, 1:613-614
Phenytoin, 2:329 leukotrichia, 1:557-558 tumor, 1:403
Pheochromocytoma, 3:89, 3:89f, 3:349-351, drug-induced thyroid, 3:325 Plasmacytic/lymphocytic synovitis, 1:159
3:350f-352f liver, 2:270-272, 2:271f Plasmacytomas, 2:27-28, 3:226-228, 3:228f,
Phlebectasia, 3:89 tooth, 2:7 3:226.e1f
Phlebitis, 3:90, 3:90f Pigment granuloma, 2:274-275, 2:275f laryngeal, 2:482
Phlebothrombosis, 3:89-91 Pigments storage, 1:254 Plasma-mediated fibrinolysis, 3:266-267
Phomopsin, 2:334-335, 2:335f Pilar cysts, 1:704 Plasma membrane, BMZ, 1:513-514
Phosphate-buffered 10% formalin, 1:8 Pilomatricomas, 1:716-717, 1:716f Plasmacytomas, 1:735, 1:735f
Phosphatonins, 1:63 Pilus adhesins, 2:168 Platelet-activating factor (PAF), 3:256
Phosphofructokinase (PFK) deficiency, Pimelea spp., 2:519-520 Platelet-derived growth factor (PDGF),
1:186-187, 1:290, 3:126 Pineal tumors, 1:403 3:257, 3:257f
English Springer Spaniels and American Pinnae, 1:501 Platelet Function Analyzer (PFA), 3:257-258
Cocker Spaniels, 1:204-205 cropped or notched, 1:502 Platelet integrin, αIIbβIII (or GPIIb/IIIa),
Phospholipidosis, 2:278 dermatologic diseases, 1:503-504 3:256
alveolar, 2:517, 2:517.e1f tumor-like growths and neoplasia, Platelets
Phosphorus 1:504-505 adhesion, 3:256
calcium homeostasis and, 1:61-63 Pinnal necrosis in pigs, 1:503, 1:503.e1f aggregation, 3:256-257
deficiency, 1:61, 2:8 Pinworms, 1:688 test, 3:257-258
odontodystrophy and, 2:8 Pit caries, 2:10 disorders, 3:257-260
osteoporosis and, 1:66 Pithomyces chartarum, 2:335 acquired, 3:260
rickets and osteomalacia and, Pituicytoma, 3:291, 3:291f intrinsic, 3:259-260
1:68-69 Pituitary gland, 3:276-291 thrombocytopenia, 3:258
liver toxicity, 2:332-333 blood supply to, 3:278 von Willebrand disease, 3:258-259
Phosphotungstic acid hematoxylin (PTAH), chromophobe carcinoma, 3:288 function evaluation, 3:257-258
1:241 cysts, 3:279-281, 3:280f hyperreactivity, 3:260
Photoaggravated dermatoses, 1:580 development, structure, and function, plug formation, 3:255-257
Photoallergy, 1:575 3:276-278, 3:276f Platynosomum fastosum, 2:322
Photography, 1:12 diseases, 3:278-281, 3:279f Pleomorphic adenomas, 2:30
Photomicroscopy, 1:12 neoplasia, 3:281-289, 3:281f Pleomorphic rhabdomyosarcoma, 1:241-243,
Photosensitization, 1:575, 2:294, 2:294f tumors 1:244f
dermatitis, 1:577-580, 1:578f granular cell, 3:289 Pleura, 2:520-523
hepatogenous, 1:579-580 metastatic to, 3:288-289, 3:289f neoplasms, 2:523
phenothiazine, 1:579 PKD1 gene defect, 2:395-396 mesothelioma, 2:523, 2:523.e2f
primary, 1:578-579 Placenta noninflammatory pleural effusions, 2:521
resulting from defective pigment synthesis, adventitial, 3:396-397 pleural effusions, 2:520
1:579 mineralization, 3:397 noninflammatory, 2:521
Phthisis bulbi, 1:448 subinvolution of placental sites, 3:441, pleuritis, 2:521-523, 2:522f, 2:521.e3f,
Phycomycosis, intestinal, 2:201 3:441f 2:521.e1f
Phylloerythrin, 1:579-580 Placentitis, 3:415, 3:415f, 3:418f pneumothorax, 2:487, 2:487f, 2:521,
Physaloptera spp., 2:54, 2:211 mycotic, 3:419, 3:419f 2:521.e3f
Physeal dysplasia in cats, 1:46, 1:46f nocardioform, 3:417 Pleuritis, 2:521-523, 2:522f, 2:521.e3f
Physicochemical diseases of skin, 1:558-575 Plant toxicities, 1:90-91, 1:219-220 suppurative, 2:522, 2:521.e1f
chemical injury, 1:566-575 avocado, 3:38 Pleuropneumonia, 2:571-572
physical injury, 1:559-566 coyotillo, 1:326 Plexiform arteriopathy, 2:492, 2:492f
Physiologic steatosis, 2:275 cyanide poisoning, 1:305-306 Pneumatosis cystoides intestinalis, 2:87
Physis, 1:22, 1:22f cycad, 1:322, 1:323f Pneumoconiosis, 2:518
bacterial osteomyelitis, 1:98-99, 1:99f fluoracetate, 3:38 Pneumocystis carinii, 2:536f, 3:140
hormonal regulation of, 1:24, 1:25t gousiekte, 3:38 respiratory system and, 2:535-536,
osteoporosis, 1:64, 1:65f hepatogenous photosensitization and, 2:536f
rickets, 1:70-71, 1:71f 1:580 Pneumonia
Physocephalus spp., 2:54 horses, 1:91 aspiration, 2:508-509, 2:508f-509f,
Phytobezoars, 2:38, 2:50, 2:75-76 liver and, 2:329-344 2:508.e1f
Phytophoto-contact dermatitis, 1:578-579 mesquite, 1:326 meconium, 2:516, 2:516.e1f
Index 557
Pneumonia (Continued) Polycystic kidney disease (PKD), 2:395-396, Porcine reproductive and respiratory
atypical, 2:509 2:395f syndrome (PRRS), 2:523-526, 2:525f,
bacterial, 2:542-546, 2:545f, 2:562-563, congenital, 2:396 3:424
2:562f mutation of, 2:394 Porcine reproductive and respiratory syndrome
equine, 2:571-572 Polycystic liver disease, 2:265 virus (PRRSV), 1:383
bronchointerstitial, 2:511-512, Polycystic ovarian disease, 3:374-375, Porcine respiratory coronavirus (PRCoV),
2:514.e2f 3:375f 2:147, 2:529
caseonecrotic broncho-, 2:553f Polydactyly, 1:55, 1:55f Porcine salmonellosis, 2:170-172, 2:170f-172f
dogs, 2:577 Polymelia, 1:55, 1:55f Porcine stress syndrome (PSS), 1:209-210,
embolic, 2:520, 2:520.e2f Polymerase chain reaction (PCR), 1:11 3:39
eosinophilic interstitial, 2:513.e1 Polymicrogyria, 1:268 Porcine ulcerative dermatitis syndrome,
granulomatous interstitial, 2:513 Polymyositis 1:698
hypersensitivity, 2:512-513 cats, 1:228-229 Porencephaly, 1:272-274, 1:272f, 1:285f
interstitial, 2:509 dogs, 1:227-228, 1:228f orbiviruses and, 1:281
lipid, 2:516-518, 2:516.e1f Polyodontia, 2:6 Porphyromonas gingivalis, 2:11
ovine progressive, 2:558-560, 2:559f, Polypeptide hormones, 3:270-271, 3:270f Porphyromonas spp., 2:9, 2:11
2:558.e1f Polyploidy, liver, 2:270 Portal hypertension, 2:297
proliferative and necrotizing, 2:529, Polypoid intestinal adenocarcinomas, 2:102 Portal tract, liver, 2:261, 2:261f
2:529.e1f Polyps Portal veins
Pneumonyssoides caninum, 2:585 endometrial, 3:385, 3:386f aneurysms, 2:266
Pneumoperitoneum, 2:247 inflammatory aural, 1:498-499 hypoplasia, 2:267-268
Pneumothorax, 2:487, 2:487f, 2:521, nasal, 2:477-478, 2:477f, 2:579 injury, 2:296-297
2:521.e3f Pomeranian dogs thrombosis, 2:297f
Poisoning alopecia X, 1:589-590 Portosystemic shunting, 2:298-299, 3:127
arsenic, 1:327-328, 1:570 myxomatous valvular degeneration, Portosystemic vascular anomalies, 2:267,
carbon monoxide, 1:306 3:27 2:267f
copper, 2:343 Pompe’s disease, 1:208, 3:50 Portuguese Water dogs
corynetoxin, 1:309 Poodle dogs dilated cardiomyopathy, 3:48
coyotillo, 1:326 amelogenesis imperfecta, 2:7 follicular dysplasia, 1:540-541
cyanide, 1:305-306 color dilution alopecia, 1:539-540 Portulacca oleracea, 2:425-426
cycad, 1:322, 1:323f dilated cardiomyopathy, 3:48 Postanesthetic myopathy in horses, 1:213
fluoracetate, 1:306 hyperadrenocorticism, 1:588 Posterior staphyloma, 1:413
gangrenous ergotism and fescue toxicosis, hypothyroidism, 1:587 Posterior tunica vasculosa lentis, 1:418
1:572-573, 1:573f myxomatous valvular degeneration, Posterior uveitis, 1:446
hexachlorophene, 1:344-345, 1:345f 3:27 Postinfectious encephalomyelitis, 1:395-396
lead, 1:86, 1:87f, 1:316-317 osteogenesis imperfecta in, 1:50 Postmortem examination. See Gross and
mercury, 1:570 rabies vaccine-induced vasculitis and histologic examinations
mimosine, 1:572 alopecia, 1:612 Postmortem rupture of viscus, 2:247
myocardial necrosis and, 3:35, 3:37-38 sebaceous adenitis, 1:551 Postnecrotic scarring, 2:284, 2:289,
nitrate/nitrite, 1:306 Poorly differentiated chondrosarcoma, 2:289f
organochlorine/organobromine, 1:119-120, 1:120f Postoperative conjunctival inclusion cysts,
1:571-572 Poorly differentiated osteosarcoma, 1:113, 1:478
organomercurial, 1:320-321, 1:321f 1:113f Postpartum uterus, lesions of, 3:440-441
organophosphate, 1:326 Poorly differentiated sarcomas, 1:244 Postparturient vascular lesions, 3:370
Phalaris, 1:292-293, 1:293f Porcine adenovirus, 2:144-145, 2:144f Postrenal azotemia, 2:384-385
quassinoid, 1:574-575 Porcine circovirus 2 (PCV-2), 2:116, 2:412- Postvaccinal canine distemper encephalitis,
salt, 1:314-315 413, 2:527-529, 3:210-212, 3:210f-211f, 1:384
selenium, 1:570-571, 1:571f 3:440, 3:440f Postweaning colibacillosis, 2:100, 2:165,
solanum, 1:321-322 encephalopathies, 1:382-383 2:165f
thallium, 1:568-569, 1:569f Porcine deltacoronavirus (PDCoV), 2:147-148 Postweaning diarrhea, 2:115
trachyandra, 1:292 Porcine dermatitis and nephropathy Postweaning multisystemic wasting syndrome
trichothecene toxicoses, 1:573-574 syndrome (PDNS), 2:412f, 3:210-212, (PMWS), 2:527-529, 2:528f, 3:210-212,
vetch, 1:574 3:210f 3:210f-212f, 3:440, 3:440f
vitamin D, 3:61 Porcine dermatoses, 1:698-699 Potassium depletion, chronic, 2:430
yellow-wood tree, 2:428 Porcine ear necrosis syndrome (PENS), Potomac horse fever, 2:99, 2:200-201
Polioencephalomalacia, 1:297, 1:297f, 1:503, 1:645, 1:503.e1f Poultry mite, 1:683
1:310f-311f, 2:43 Porcine encephalitis associated with PRRSV Pourfour du Petit syndrome, 1:494-495
ruminants, 1:309-312, 1:310f-311f infection, 1:383 Poxviral infections, 1:616-625
Poliomalacia, 1:307-308 Porcine epidemic diarrhea virus (PEDV), sheep and goats, 2:557
Poll evil, 1:155-156 2:113, 2:147 trachea and, 2:483
Polypay sheep, osteopetrosis in, 1:52, Porcine erysipelas, 1:149 PP cells, endocrine pancreas, 2:368
1:52f Porcine hemagglutinating encephalomyelitis Precipitation of pentobarbital salts, 1:8f
Polyalveolar lobe, 2:485 virus (HEV), 1:372 Precursor lymphoblastic leukemia/
Polyarteritis nodosa, 3:71 Porcine hypomyelinogenesis, 1:338 lymphoma, 3:219, 3:220f
Polyarthritis, 1:148 Porcine intestinal spirochetosis, 2:182 Pregnancy. See Abortion; Gestation
erosive, 1:157-158 Porcine juvenile pustular psoriasiform Pregnancy toxemia in sheep, 2:419-421
feline chronic progressive, 1:158 dermatitis, 1:698, 1:698f Pre-iridal fibrovascular membrane, 1:447,
idiopathic, 1:158 Porcine lymphomas, 3:241-243 1:448f
immune-mediated, 1:157-159 Porcine parvovirus (PPV), 3:429 Prekallikrein deficiency, 3:263
non-erosive, 1:158-159 Porcine proliferative enteropathy, 2:179, Preparation artifacts in histologic sections,
-polymyositis syndrome, 1:158 2:179f 1:29, 1:29f
Prepubic hernias, 2:80 Proliferative optic neuropathy, 1:476 Pseudotuberculosis, 3:209-210, 3:209f
Preputial diverticulitis, 3:507-508, 3:507f Proliferative pododermatitis, 1:642-643 Pseudotumors, muscle, 1:246, 1:246f
Prerenal azotemia, 2:384 Proliferative zone, growth plate, 1:22-23 Psorergatic mange, 1:678
Presa Canario dogs, dilated cardiomyopathy Prolonged gestation, 3:397-398 Psoriasiform dermatitis of goats, 1:698
in, 3:48 Prolonged renal ischemia, 2:422-423 Psoroptes spp., 1:505-506
Presbycusis, 1:493 Pro-opiomelanocortin (POMC), 3:285, Psoroptic mange, 1:675-676
Preservation, sample, 1:8 3:285f Psychogenic alopecia, 1:561
Primary abomasal impaction in cattle, 2:50 Prosencephalic hypoplasia, 1:266-267, Psychogenic injury, 1:561-562, 1:561f
Primary ciliary dyskinesia, 2:504 1:266f Pteridium spp., 2:173-180
Primary cleft palate, 2:3 Prostaglandins, 2:46 Ptyalism, 2:28-29
Primary endocardial fibroelastosis, 3:22 Prostate gland, 3:500-504, 3:500f Puerperal tetany, 3:299
Primary epithelial neoplasms of liver, disorders of sexual development, 3:500- Pug dogs
2:345-346 501, 3:500f canine atopic dermatitis, 1:591
Primary gastric dilation, 2:48 hyperplasia and metaplasia, 3:502-503, canine necrotizing meningoencephalitis,
Primary glaucoma, 1:462-463, 1:463f 3:503f 1:392-393
Primary hairs, 1:515-516 inflammation, 3:501-502, 3:501f hereditary stenosis of common bundle,
Primary hyperaldosteronism, 1:225 neoplasms, 3:503-504, 3:504f 3:51
Primary hyperfunction of endocrine gland, Prostatitis, 3:501, 3:502f motor neuron disease, 1:331
3:272 Protein-calorie deficiency, 1:581 pigmented plaques, 1:710-711, 1:711f
Primary hyperparathyroidism, 1:74, Protein core, epidermal, 1:513 Pulmonary adenocarcinoma, 2:447
3:304-305 Protein C pathway, 3:265-266 Pulmonary arterial hypertension (PAH),
Primary hypofunction of endocrine gland, Protein-energy malnutrition, 2:69 2:492-494, 2:492f, 3:66-67, 2:492.e1f
3:272-273 Protein hydrolysis, 2:45 Pulmonary artery, 2:467-468, 2:468f
Primary idiopathic hyperlipidemia, Protein-losing gastroenteropathy, 2:72 transposition with aorta, 3:22.e1f
2:277-278 Protein-losing nephropathy (PLN), 2:418 Pulmonary aspergillosis, 2:573, 2:573f
Primary irritant contact dermatitis, 1:566- Protein-losing syndromes, 2:89-97 Pulmonary blastomas, 2:498
568, 1:567f Protein maldigestion, 2:70 Pulmonary carcinomas/adenocarcinomas,
Primary ossification center, 1:22 Proteinuria, 2:401 1:736, 2:495-500, 2:497f, 2:495.e2f,
Primary parathyroid hyperplasia, 3:301 Proteoglycans, 1:19-20, 1:514 2:497.e1f
Primary photosensitization, 1:578-579 deficiency, 1:545-546 classification, 2:496t
Primary portal vein hypoplasia (PVH), Protistant infections, 2:227-244 Pulmonary edema, 2:487-489, 2:488b,
2:267-268 Protoplasmic astrocytes, 1:260-261 2:489.e1f
Primary spongiosa, 1:23, 1:23f Protostrongylus rufescens, 2:565-566, 2:565t Pulmonary emphysema, 2:486-487, 2:487f
Primary synovial chondromatosis, 1:162, Prototheca, 1:451, 1:665, 1:666f Pulmonary hamartoma, 2:485
1:162f enterocolitis, 2:203-204 Pulmonary hemorrhage, 2:490-492, 2:490.e1f
Primary thyroid hypoplasia, 3:314 Prototheca wickerhamii, 2:476 Pulmonary hyalinosis, 2:517
Primary tympany of forestomachs, 2:36, Prototheca zopfii, 2:433, 2:476 Pulmonary hypertension, 2:492-494, 3:60
2:37f Protozoal infections canine pulmonary veno-occlusive disease
Primary vascular disease, 2:398 abortion and, 3:399b, 3:420-424, 3:420f (PVOD), 2:493, 2:493f, 2:493.e1f
Primidone, 2:329 arthritis, 1:155 causes, 2:492b
Primordial germ cells (PGC), 3:469 diseases of skin, 1:661-665 pulmonary arterial hypertension (PAH),
Principal bronchus, 2:467 endophthalmitis, 1:451 2:492-494, 2:492f, 3:66-67
Prion diseases, 1:347-350 liver and, 2:324 Pulmonary hypoplasia, 2:484, 2:484.e3f
Prion proteins, 2:20 Protrusion of nictitans gland, 1:424 Pulmonary immune responses, 2:472
Probiotics, 2:65 Proud flesh, 1:560-561 Pulmonary infarcts, 2:490.e1f
Procoagulant activities, 3:55 Proximal axonopathy, 1:257, 1:257f Pulmonary intravascular macrophages
Proficiency testing of pathologists, 1:14 Proximal esophagus, segmental aplasia of, (PIMs), 2:471, 2:471.e1f
Profilaggrin, 1:513 2:31 Pulmonary Langerhans cell histiocytosis,
Progesterone, 3:383 Psammoma bodies, 1:304 2:499, 3:246-247, 3:247f, 3:246.e1f
Prognathism, 2:3 Psammomatous meningioma, 1:397, 1:397f Pulmonary macrophages, 2:470
Progressive ataxia, 1:341f Pseudallescheria boydii, 2:476 Pulmonary mineralization, 2:494-495,
of Charolais cattle, 1:341, 1:341f Pseudamphistomum truncatum, 2:324 2:494f
Progressive atrophic rhinitis (PAR), Pseudoachondroplastic dysplasia, 1:44 Pulmonary neoplasia, 2:495-500, 2:495b
2:533 Pseudoaneurysms, 2:398 Pulmonary surfactant, 2:470
Progressive axonopathy of Boxer dogs, Pseudoanodontia, 2:6 Pulmonary thromboembolism, 2:489, 2:489b,
1:329-330 Pseudoarthrosis, 1:36 2:489.e1f
Progressive ethmoid hematomas (PEH), Pseudo-blackleg, 1:233 Pulmonary vasculitis, 2:494, 2:494.e2f
2:477 Pseudocowpox virus, 1:616, 1:618 Pulmonary veins, 2:467-468, 2:468f
Progressive motor neuron disease, 1:255, Pseudocysts, pancreatic, 2:361 Pulmonary venous hypertension, 2:492-493
1:255f, 1:330-332, 1:331f-332f Pseudoepitheliomatous hyperplasia, 3:151 Pulmonic stenosis, 3:19, 3:19f
Progressive neuronopathy of Cairn Terrier, Pseudoglandular stage of lung growth, 2:484 Pulmonic valves, 3:2-3
1:332-333 Pseudohepatorenal syndromes, 2:430 Pulpitis, 2:11
Progressive renal mineralization, 2:441 Pseudomembranous stomatitis, 2:18 Pure red cell aplasia, 3:127-128, 3:128f
Proinflammatory cytokines, 2:72 Pseudomembranous rhinitis, 2:474-475 Pure silica stones, 2:455
Prolactin, 3:276-277 Pseudomonas aeruginosa, 3:30-31 Purified protein derivatives (PPD), 2:548
Prolapse, female genital organ, 3:381 Pseudomonas spp., 2:459 Purkinje fibers, 3:2
Proliferative and necrotizing pneumonia, Pseudomycetoma, 1:653 Purpura hemorrhagica, 1:229, 1:229f
2:529, 2:529.e1f Pseudo-obstruction, 2:77 Purulent (suppurative) arthritis, 1:147-148,
Proliferative arthritis, 1:147-148 Pseudo-oligodontia, 2:6 1:148f
Proliferative glomerulonephropathy, 2:403f, Pseudoplacentational endometrial Purulent bronchitis, 2:501
2:401.e3f hyperplasia, 3:383, 3:384f Purulent pericarditis, 3:26
Proliferative hemorrhagic enteropathy, Pseudopolyodontia, 2:6 Purulent splenitis, 3:183-184
2:179-180, 2:180f Pseudorabies, 1:370-372, 1:371f, 2:530 Purulent streptococcal meningitis, 1:357f
Index 559
Rhabdomyomas, 1:241, 1:242f, 1:726, 3:52, Rocky Mountain spotted fever, 1:449, Saccular stage of lung growth, 2:484
3:52f 1:474-475, 3:82-83 Saint Bernard dogs
ear, 1:505 Rod cells, 1:262-263 dilated cardiomyopathy, 3:48
laryngeal, 2:482, 2:482f, 2:482.e1f Rodenticides, 3:301-302, 3:301f gastric volvulus, 2:49
Rhabdomyosarcomas, 1:241-243, 1:243f- hemothorax, 2:521.e3f pyotraumatic dermatitis, 1:560
244f, 1:726, 2:464 intoxication, 3:264 subvalvular aortic stenosis, 3:20
Rheumatoid arthritis, 1:157, 1:157f Roeckl’s granuloma of cattle, 1:234 Salinomycin, 3:34-35
Rheum rhaponticum, 2:425-426 Romney sheep Salivary calculi (sialoliths), 2:29
Rhinitis, 2:474-477 axonal dystrophy, 1:324 Salivary glands, 2:28-30
allergic, 2:476, 2:476.e1f osteogenesis imperfecta, 1:49, 1:49f acute reactions to injury, 2:28
atrophic, 2:533 Romulea poisoning, 1:322 dilations of duct, 2:29
nonprogressive (NPAR), 2:533 Rosenthal fibers, 1:262 foreign bodies, 2:29
pigs, 1:102 Rotavirus, 2:112, 2:115-117, 2:151-153, necrotizing sialometaplasia, 2:30
progressive, 2:533 2:152f neoplasms, 2:30
bovine rhinitis virus, 2:542 Rottweiler dogs ptyalism, 2:29
causes, 2:475b axonal dystrophy, 1:324 salivary mucocele/sialocele, 2:29
chronic, 2:475 canine X-linked muscular dystrophy in, sialoadenitis, 2:29
idiopathic lymphoplasmacytic, 2:476 1:192, 1:193f Salmonella Arizonae, 2:115
inclusion body, 2:529-530, 2:530f diabetes mellitus, 2:373 Salmonella choleraesuis, 2:170
mycotic, 2:579, 2:580f ichthyosis, 1:532 Salmonella enterica, 2:99
Rhinosporidium seeberi, 2:476, 2:579-580, juvenile-onset distal myopathy, 1:198 Salmonella Typhimurium, 2:100, 2:171,
2:581f leukoencephalomyelopathy, 1:340-341, 2:173f, 2:175f
Rhipicephalus sanguineus, 1:240, 1:506 1:340f Salmonella typhisuis, 2:172
Rhizoctonia leguminicola, 2:29 motor neuropathy, 1:335 Salmonellosis, 2:117, 2:167-176
Rhodesian Ridgeback dogs nephritis, 2:417 abortion and, 3:401, 3:412-413
congenital myotonia in, 1:201 neuroepithelial degeneration, 1:492 asymptomatic carriage of, 2:167-168
degenerative radiculomyelopathy, 1:330 severe combined immunodeficiency bacterial osteomyelitis and, 1:99, 1:99f,
dermoid cysts, 1:547, 1:704-705 (SCID), 3:140-141 1:101f
myotonic dystrophy-like disorder, spongy enceophalomyelopathies, 1:346 canivores, 2:176
1:202-203 static spinal stenosis in, 1:136, 1:136f cattle, 2:174-175, 2:174f
Rhodococcus equi, 2:113-114, 2:197-198, vitiligo, 1:555-556 gastric venous infarction due to, 2:51
2:198f, 2:514, 3:418 Rouge-des-prés calves, central and peripheral horses, 1:99f, 2:172-174, 2:173f
lymph nodes and, 3:206f, 3:204.e1f axonopathy of, 1:332 infectious arthritis and, 1:148
respiratory system and, 2:569-571, Roughage, 2:36 liver and, 2:314-315
2:571f Row of tombstones, 2:14-15 pathogenesis of salmonellosis, 2:168
splenic abscesses, 3:183-184 Rubriblasts, 3:104 pigs, 2:170-172, 2:170f-172f
Rhodotorula glutinis, 3:491 Rumen salmonellosis, 2:99, 2:112
Rhodotorula spp., 1:661 fluid, 2:455 sheep, 2:175-176
Rib and sternum congenital abnormalities, flukes, 2:43, 2:43f, 2:226 suppurative rhinitis and, 2:476
1:56 mycotic inflammatory lesions of, 2:39-40 in tonsils of swine, 2:20
Ribbon trichoblastoma, 1:716, 1:716f papillae, adhesion of, 2:36f Salmon poisoning disease, 2:117, 2:226,
Riboflavin deficiency, 1:582 Rumenitis, 2:39-40, 2:41f-42f 3:148-149, 3:150f, 3:149.e1f
Ribonucleic acid (RNA) extraction, and acidosis caused by carbohydrate Salpingitis, 3:380
1:30 overload, 2:40-43 Salt poisoning, 1:314-315
Rickets, 1:61, 1:66, 1:68-74, 3:82-83, 3:274, mycotic, 2:42 Saluki dogs
3:296 Rumenitis-liver abscess complex, color dilution alopecia, 1:539-540
calcium deficiency in, 1:61, 1:66, 1:69 2:41-42 motor neuron disease, 1:331
hereditary, 1:69 Ruminal acidosis, 2:40 Samoyed dogs
vitamin D-resistant, 1:70 diagnosis of, 2:41 alopecia X, 1:589-590
hypophosphatemic, 1:70, 1:70f Ruminal carcinomas, 2:44 canine hypomeylinogenesis, 1:337
microscopic lesions of, 1:72, 1:72f Ruminal drinkers, 2:38 canine uveodermatologic syndrome,
phosphorus deficiency in, 1:68-69 Ruminal mucosa, 2:36, 2:36f 1:557
rickettsial vasculitides, 3:80-83 microscopic examination of, 2:41 canine X-linked muscular dystrophy in,
sheep, 1:70, 1:70f Ruminal papillae, 2:36 1:192
vitamin D deficiency in, 1:68 Ruminant forestomachs, 2:44 chondrodysplasia in, 1:45
vitamin D-dependent type I, 1:69-70 Ruptures early onset diabetes mellitus, 2:373
Rift Valley fever virus (RVFV), 1:281, abomasal, 2:50-51 sebaceous adenitis, 1:551
2:312-313, 3:439-440, 2:312.e1f arterial, 3:62-63, 3:62f spongy myelinopathy, 1:343
Right atrioventricular valve dysplasia, biliary tract, 2:309 true retinal dysplasia, 1:420
3:21-22 gastric, 2:48 Samoyed hereditary glomerulopathy,
Right atrium, heart, 3:2 liver, 2:268 2:415-416
failure, 3:6 muscle, 1:213-214 Samoyed hereditary nephropathy,
Right-sided heart failulre, 3:11 spleen, 3:165-166, 3:166f, 3:166.e1f 2:415-416
Right ventricle, heart, 3:2 vaginal and vulval, 3:442 Sample selection and preservation, 1:8
double-chambered, 3:22 vein, 3:89 for study of muscle, 1:171-172,
Rigor mortis, 1:186 1:172f-173f
Rinderpest, 2:128-130, 2:129f-130f, S San Angelo virus, 1:280
3:182-183, 3:183f, 3:182.e1f Sabulous cystitis, in horse, 2:451f Sancassania berlesei, 1:683-684
Ringbinden, 1:185, 1:185f Sabulous (matrix-crystalline) urethral plugs, San Miguel sea lion virus (SMSV), 2:121
Ringbone, 1:142 in male cats, 2:456 Sarcina-like bacteria, 2:50
Ringworm, 1:649-653 Saccharated iron, 3:34-35 Sarcobatus vermiculatus, 2:425-426
Shorter-acting sulfonamides, crystalline Sinus node, 3:2 Skin immune system (SIS), 1:515
nephropathy, 2:424 Sinusoidal domain, liver, 2:262 Skull bones, 1:21
Shorthorn cattle Sinusoidal endothelial cells, 2:260 congenital abnormalities, 1:56, 1:56f
bovine hypomyelinogenesis, 1:338-339 Sinusoidal leukocytosis, 2:300-301 craniomandibular osteopathy, 1:91-92,
lethal trait A46, 3:141 Sinusoidal lining cells necrosis, 2:285 1:92f
Shoulder joint, degenerative joint disease of, Size-dependent barrier, 2:380 fractures, 1:302-303
1:143 Skeletal dysplasias, 1:37t sutures, 1:128
Shunted blood flow to heart, 3:6 localized, 1:54-57, 1:54f Skye Terrier dogs, chronic hepatitis in, 2:304
malformation causing, 3:16-18, 3:16f osteochondromatosis, 1:54 Slaframine, 2:29
Shunts, hepatic, 2:267, 2:267f, 2:267.e1f Skeletal muscles, dermal, 1:515 SLC2A9 gene, 2:457
acquired portosystemic, 2:290, 2:298-299, Skeleton. See also Bone(s) SLC3A1 genes, 2:458
2:299f genetic and congenital diseases of, 1:36-60, SLC7A9 genes, 2:458
Shwartzman reaction, 2:398-399 1:37t Slipped epiphysis, 1:31
Sialoadenitis, 2:29 genetic diseases indirectly affecting, Sly syndrome, 1:58
Sialocele 1:57-60 Small-bowel diarrhea, 2:70-71
nasopharyngeal, 2:477.e4f manganese deficiency and, 1:80 Small-cell carcinoma
salivary, 2:29 postmortem examination of, 1:28-30, 1:29f neuroendocrine, 2:497-498
Siamese cats Skin, 1:509-736 thyroid, 3:330-331
congenital hypotrichosis, 1:539 actinic diseases of, 1:575-580 Small-cell lymphocytic villus lymphoma,
congenital idiopathic megaesophagus, 2:34 algal diseases of, 1:665 2:107-108
Maroteaux-Lamy syndrome, 1:58 bacterial diseases of, 1:629-646 Small intestinal bacterial overgrowth (SIBO),
photosensitization, 1:579 basement membrane zone (BMZ), 2:86, 2:364
vitiligo, 1:556 1:513-514 Small intestine, 2:81, 2:82f
Siberian Husky dogs canine cutaneous histiocytoma, 3:243-245, cardinal finding, 2:92
alopecia X, 1:589-590 3:244f-245f, 3:244.e1f, 3:243.e1f idiopathic inflammatory bowel disease,
canine uveodermatologic syndrome, 1:557 canine juvenile cellutitis, 1:690-691, 1:691f 2:92
degenerative radiculomyelopathy, 1:330 canine reactive histiocytosis, 3:247-250, lymphangiectasia, 2:90f
motor neuropathy, 1:335 3:248f, 3:247.e1f mucosa, 2:124
oral eosinophilic granuloma, 2:16 congenital and hereditary diseases of, hypoplasia, 2:74
vitiligo, 1:555-556 1:530-547 vascular supply, 2:61
zinc-responsive dermatoses, 1:585-586 dermal muscles, 1:515 obstruction, 2:76
Sick sinus syndrome, 3:51 dermatohistopathology, 1:518-530 dogs, 2:75f
Siderocalcinosis, 3:61 gross terminology, 1:524 pseudodiverticulosis of, 2:87
Siderosis, 1:297, 1:298f histologic terms, 1:518-524 Small ruminant lentiviruses, 2:558-560,
Siderotic pigmentation, 1:255 pattern analysis, 1:524-530 2:559f, 2:558.e1f
Siderotic plaques, splenic, 3:163, 3:164f, dermis, 1:514-515 Smoke inhalation
3:163.e2f endocrine diseases of, 1:587-590 lung injury, 2:518
Signet ring cells, 2:101-102 epidermal differentiation disorders, trachea and, 2:483, 2:483f
Signet-ring malignant melanomas, 1:722 1:547-554 Smooth Fox Terrier dogs
Silica calculi, 2:455 epidermis, 1:512-513 canine congenital myasthenia, 1:209
Silicate pneumoconiosis, 2:518 fungal diseases of, 1:646-661 multisystem axonal degeneration, 1:325
Silicates, 2:518 general considerations, 1:511-518 Smooth muscle cells, lungs, 2:469
Silky Terrier dogs hair follicles, 1:515-517 Smooth-surface caries, 2:10
rabies vaccine-induced vasculitis and helminth diseases of, 1:685-690 Snakebite envenomation, 1:568
alopecia, 1:612 immune-mediated dermatoses, 1:590-615 Snowshoe hare virus, 1:383
spongy myelinopathy, 1:343-344 autoimmune dermatoses, 1:600-607 Snorter dwarfism, 1:39, 1:39f
Silo gas, 2:518 drug eruptions, 1:607-608 Sodium absorption, 2:65-66
Silver fox hypersensitivity, 1:590-600 Sodium fluoroacetate, 3:37-38
spongiform myelinopathy, 1:343f, 1:344 immunologic function, 1:515 Sodium iodide symporter (NIS), 3:311
status spongiosus, 1:342f lesions with canine distemper virus, Soemmering ring cataract, 1:444, 1:444f
Simmental cattle 2:576 Soft callus, 1:34-35
epidermolysis bullosa simplex, 1:535 lymphomas, 3:237, 3:237f, 3:239f, Soft tissue sarcomas, 1:245
inherited progressive spinal myelopathy, 3:239.e1f Solanaceae, 2:331
1:325 neoplastic and reactive diseases, 1:703-736 Solanum glaucophyllum, 3:301-302,
osteopetrosis, 1:51 nutritional diseases of, 1:580-587 3:301f-302f
Simondsia spp., 2:54 paraneoplastic syndromes, 1:691-693 Solanum poisoning, 1:321-322
Simple follicles, 1:515-516 perianal glands, 1:517 Solar dermatitis, 1:576, 1:576f
Simple renal cysts, 2:394-395 physiochemical diseases of, 1:558-575 Solar elastosis, 1:577, 1:577f
Simple secretory epitrichial adenomas, 1:718 chemical injury, 1:566-575 Solar keratoses, 1:577
Sinus erythrocytosis, 3:199-200, 3:200f, physical injury, 1:559-566 Solar radiation
3:200.e1f pigmentation disorders, 1:554-558 burns and, 1:566
Sinuses protozoal diseases of, 1:661-665 direct effect of, 1:575-577
diseases, 2:477, 2:477f sebaceous glands, 1:517 Solid basal cell carcinoma, 1:714
neoplasms, 2:478-480, 2:478f subcutis, 1:518 Solid-cystic epitrichial adenomas, 1:718-719
nonflammatory thrombosis of cranial dural, sweat glands, 1:517-518 Solid-cystic epitrichial carcinomas, 1:719
1:300 tags, 1:722-723 Solitary biliary cysts, 2:264
non-neoplastic proliferative disorders, tumor-like lesions, 1:705 Solitary mucosal lymphoid nodules, 2:64
2:477-478 viral diseases of, 1:615-628 Somatostatin, 2:368
Sinus hairs, 1:517 Skin-associated lymphoid tissue (SALT), Somatostatinoma, 2:375
Sinusitis, chronic suppurative, 2:477-478, 1:515 Somatotroph adenomas, 3:285-286,
2:477.e1f Skin-homing memory T-cells, 1:515 3:285f-286f
Stomach and abomasum (Continued) Streptococcus equi (Continued) Suifilaria suis, 1:690
gastric dilation and displacement, suppurative myositis and, 1:230 Suipoxvirus, 1:616, 1:625, 1:625f
2:48-50 Streptococcus equi Sulfides, absorption of, 2:40
gastric mucosal barrier, 2:46 Streptococcus porcinus, 3:208-209, 3:208f Sulfonamides, 3:324
gastritis, 2:52-55 Streptococcus spp. in sheep, 1:151, 2:562 Sulfur compounds and PEM, 1:312
gastroduodenal ulceration, 2:55-60 Streptococcus suis, 1:150-151 Summer mastitis, 3:455-456
heart failure and, 3:11-12 tonsils, 2:20 Sunlight-induced cataract, 1:443-444
neoplastic/proliferative lesions, 2:100-111, Streptococcus zooepidemicus, 2:578 Superficial bacterial pyoderma, 1:629-634,
2:101t Streptomyces, 3:417 1:630f
tumors of lower gastrointestinal tract, Streptomycin, 2:424 Superficial necrolytic dermatitis, 1:586-587,
2:100-101 Stress-related lesions, horses, 1:36 1:587f
normal form/function, 2:44-46 Striated myofibrils, 1:167 Superficial plexus, dermal, 1:514
mucous neck cells, 2:45 Stromal tumors, intestinal, 2:110-111 Superficial stomatitis, 2:13-14
pyloric stenosis, 2:48 gastrointestinal, 2:110 Suppurative arthritis, 1:148f
response of gastric mucosa to injury, leiomyoma, 2:110 Suppurative hypophysitis, 3:289, 3:290f
2:46-48 leiomyosarcoma, 2:110 Suppurative lymphadenitis, 3:203-204,
rupture, 2:50-51 Strongyloides felis, 2:212 3:204f
volvulus, 2:49-50, 2:50f Strongyloides papillosus, 1:690, 2:212, Suppurative meningitis, 1:355f
Stomatitis 3:507 Suppurative myocarditis, 3:42
catarrhal, 2:14 Strongyloides ransomi, 2:212 Suppurative myositis, 1:230, 1:230f
chronic gingivostomatitis, 2:15-16 Strongyloides spp., 2:211-227, 2:211f Suppurative osteomyelitis, 1:100-101
chronic ulcerative, 2:16 Strongyloides stercoralis, 2:212 cattle, 1:102f
deep stomatitides, 2:17-19 Strongyloides tumefaciens, 2:212 Suppurative pleuritis, 2:522, 2:521.e1f
feline ulcerative, 2:16 Strongyloides westeri, 2:212 Suppurative rhinitis, 2:476
foreign-body, 2:13, 2:13f Strongylus edentatus, 2:216, 2:255 Suppurative streptococcal encephalitis,
lymphocytic/plasmacytic, 2:16 Strongylus equinus, 2:216, 2:255 1:360f
necrotic, 2:17, 2:17f Strongylus vulgaris, 2:84, 2:216-217, 3:85-87, Suppurative thymitis, 3:148, 3:149f
superficial, 2:13-14 3:86f, 3:87.e1f Suppurative uveitis, 1:449
vesicular, 2:14-15, 2:117-158, 2:120f Struvite calculi, 2:455-456 Suprabasilar acantholysis, 2:14-15
Storage diseases, 1:284-293 Strychnine poisoning, 1:317 Supragingival plaque, 2:9
ceroid-lipofuscinoses, 1:290-292 Stypandra toxicosis, 1:345 Suprasellar germ cell tumor, 1:403-404,
glycogenoses, 1:290 Subcapsular nephrogenic zone, 2:382.e1f 3:287, 3:287f
glycoproteinosis, 1:288-289 Subchondral (juxtacortical) bone, 1:129 Surface ectoderm, anomalies of, 1:421-423
induced, 1:292-293 cysts, 1:126, 1:134, 1:134f Surgical pathology, 1:2
inherited, 1:286-292, 1:287f Subcorneal pustular dermatosis, 1:696 Surveillance, 1:1-2
Lafora disease, 1:292 Subcutaneous fungal infections, 1:653-661 Sutures, 1:21-22, 1:128
lysosomal, 1:284-293, 1:285f-286f, 2:429 Subcutaneous mast cell tumors, 1:245 Swainsonine, 1:292, 2:29
liver, 2:278, 2:278f, 2:278.e1f Subcutaneous “panniculitis-like” T-cell Swayback, 1:328-329, 1:328f
skeleton, 1:57-59 lymphoma, 3:234, 3:234f Sweat glands, 1:517-518
spinal cord, 1:285f-286f Subcutis, 1:518 hamartomas, 1:705
mucolipidoses, 1:290 Subdural abscess, 1:353-354, 1:354f tumors, 1:718-720
mucopolysaccharidoses (MPS), 1:58, 1:58f, Subdural hemorrhage of spinal cord, 1:303f Swedish Golden Retrievers, 1:334
1:289-290 Subendocardial fibrosis, 3:30 Swedish Lapland dogs, motor neuron disease
hearing and, 1:491-492 Subendocardial hemorrhage, 3:4 in, 1:331
neuronal, 1:285, 1:473 Subendocardial mineralization, 3:4, 3:30, Swelled head, 1:232
Stored-product mite, 1:683-684 3:30f Swelling
Strains, muscle, 1:213-214 Subendothelial connective tissues, 3:55 brain, 1:293-295, 1:295f
Strangles, 2:572, 3:208-209, 3:208f, 3:208.e2f Subepidermal vesicular and pustular of foot processes, 2:406
Strangulation obstruction, 2:74-75 dermatitis, 1:527-528, 1:528f vulval, 3:442-443
Stratum basale, 1:512 Subepiglottic cysts, 2:481 Swine dysentery, 2:100, 2:181-182,
Stratum corneum (SC), 1:511-512 Subintima, 1:130-131 2:182f
seborrhea, 1:548-549 Subinvolution of placental sites, 3:441, Swine influenza, 2:526-527, 2:526f,
Stratum granulosum, 1:512 3:441f 2:526.e1f, 2:527.e1f
Stratum spinosum, 1:512 Subluxations, vertebral, 1:303 Swinepox virus, 1:616, 1:625, 1:625f
Straw-itch mite, 1:683 Submucosa, 2:62 Swine rotaviral infection, 2:152, 2:152f
Streptococcal adenitis, 3:208-209, 3:208f Subnormal wear, 2:8 Swine vesicular disease (SVD), 2:121
dogs, 3:209 Substituted phenols, 3:325 Sylvatic dermatophytes, 1:649
pigs, 3:208-209 Subungual squamous cell carcinomas, Symmetrical lupoid onychitis (SLO),
Streptococcal arthritis, 1:150-151, 1:151f 1:713 1:702
Streptococcal mastitis, 3:453-455, 3:454f Subvalvular aortic stenosis, 3:20-21 Sympathetic nervous system neoplasms,
Streptococcal polyarthritis, 1:148 Sudan grass, 1:91 3:352-353
Streptococcus canis, 1:636 Suffolk sheep Symphyses, 1:128
Streptococcus dysgalactiae, 1:151 abomasal dilation and emptying defect, Syncerus caffer, 2:117-118
Streptococcus equi, 2:412 2:51 Synchondroses, 1:128
associated purpura hemorrhagica, 1:229, axonal dystrophies, 1:324 Syndactyly, 1:54
1:229f epidermolysis bullosa, 1:535 Syndesmoses, 1:128
cats, 2:589 Suid herpesvirus 1 (SuHV-1), 2:530, Synophthalmos, 1:411f
endocarditits and, 3:30-31 3:432-433 Synovial bursae, 1:155-156
splenic abscesses, 3:183-184 pseudorabies and, 1:370, 1:371f Synovial cell sarcoma, 1:159
strangles, 2:572, 3:208-209, 3:208f, Suid herpesvirus 2 (SuHV-2), 2:529-530, Synovial chondromatosis, 1:162, 1:162f
3:208.e2f 3:433 Synovial cysts, 1:162-163
Thromboembolism (TE), 3:63-66, 3:63f, Thyroid gland (Continued) Toxicities, plant (Continued)
3:265 action, 3:313-314 gousiekte, 3:38
pulmonary, 2:489, 2:489b, 2:489.e1f release blockage, 3:325 hepatogenous photosensitization and,
Thrombophlebitis, 3:89-91 secretion, 3:312-313, 3:313f 1:580
caudal vena cava, 3:90.e1f -stimulating hormone (TSH), 3:276-277 horses, 1:91
intracranial, 1:300 thyroxine, 3:272 liver and, 2:329-344
parasitic, 3:91-94 hyperplasia, 3:320-323, 3:320f myocardial necrosis and, 3:34-41, 3:35f
Thrombosis hypofunction, 3:315-319, 3:315f parathyroid suppression associated with,
aortic, 1:6f location, 3:293f 3:301-302, 3:301f
aortic-iliac, 3:64, 3:64.e1f neoplasms, 3:326-336 sheep, 1:90-91
arterial, 3:63-66, 3:63f, 3:63.e1f Thyroidization, 2:440f Toxic lung injury, 2:518-520
balance between antithrombosis and, Thyrotroph adenomas, 3:286 Toxic metabolite-dependent idiosyncrasies,
3:53.e1f Thyrotropin-releasing hormone (TRH), 2:327
caudal vena cava, 2:298, 2:299f 3:312-313 Toxic myocardial degeneration, 3:34-35
cerebrospinal arterioles, 1:299, Thyroxine, 3:311 Toxic myopathies, 1:218-220
1:299f -binding globulin, 3:312 ionophore toxicosis, 1:219
portal vein, 2:297f Thysanosoma actinoides, 2:319-320, Toxicology, 1:11
pulmonary, 2:489.e1f 2:319.e1f Toxicopathology, 1:3
splenic, 3:171f Tibetan Mastiffs, hypertrophic neuropathy in, anoxia and nervous system, 1:305-307
testicular arteries, 3:491 1:341-342 thyroid gland, 3:323-326
Thrombotic microangiopathy, 2:421f, Tibetan Terrier dogs Toxicosis. See Poisoning
2:419.e1f canine atopic dermatitis, 1:591 Toxic retinopathies, 1:471-472
Thromboxane A2 (TxA2), 3:256 diabetes mellitus, 2:373 Toxic shock syndrome (TSS), 1:636-637
Thrush, 2:14, 2:32 Ticks, 1:152, 1:684 Toxocara canis, 2:219, 2:220f, 2:442
Thymitis, 3:148, 3:149f Babesia transmission by, 1:611, 3:117-120, Toxocara vitulorum, 2:220
Thymomas, 1:691-692, 3:153-157, 3:153f- 3:117f Toxoplasma gondii, 1:451, 1:664,
154f, 3:153.e1f -borne fever, 3:178 2:236-238
Thymus, 3:141-158 external ear, 1:506-507 abortion and, 3:420-424, 3:420f-421f
atrophy, 1:6f, 3:123, 3:144-147, flaviviral encephalitides, 1:373-376 adrenal cortex and, 3:340
3:145f Hepatozoon transmission by, 3:110 central nervous system and, 1:389
carcinomas, 3:156-157, 3:157f Tiger-stripe pattern, 2:125 myositis, 1:237
cortical lymphocytes, 3:143 Tissue-activatable fibrinolysis inhibitor respiratory system and, 2:590, 2:590f,
cysts, 3:151, 3:152f, 3:151.e1f (TAFI), 3:266 2:590.e3f
developmental diseases, 3:144 Tissue factor pathway, 3:260-261 Toy Manchester Terrier dogs, dilated
fibrosis, 3:147f inhibitor (TFPI), 3:261, 3:266 cardiomyopathy in, 3:48
germ cell tumors, 3:158 Tissue samples. See Gross and histologic Trabecular adenomas, 3:326-327
hematomas, 3:147-148, 3:147f-148f, examinations Trabecular meshwork, 1:461-462, 1:462f
3:146.e2f T lymphoblasts, 2:64 Trabecular trichoblastomas, 1:716
hemorrhage, 3:147-148, 3:146.e2f Tobramycin, 2:424 Trachea, 2:467-469, 2:482-483
hyperplasia, 3:150-151, 3:150f Toluidine blue stains, 1:29 bronchus, 2:467
hyperplastic and neoplastic diseases, Tongue abnormalities, 2:4, 2:4f collapse, 2:483f, 1:192.e1
3:150-158 Tonsillar crypts, 2:20 smoke inhalation and, 2:483, 2:483f
inflammatory diseases, 3:148-150 Tonsillar diseases, 2:19-20 transitional metaplasia, 2:501, 2:501.e1f
involution and atrophy, 1:6f, 3:123, Tonsillitis, 2:13-19, 2:13f Tracheal puddle, 2:571-572
3:144-147, 3:145f-146f pigs, 2:13f Trachyandra poisoning, 1:292
lymphomas, 3:157-158, 3:157f-158f, 3:237, Tonsillophilus, 2:20 Traction alopecia, 1:560
3:240f, 3:157.e1f Tonsils, 2:20 Traction diverticulum, 2:31
medullary lymphocytes, 3:143 Torsion, 2:78 Transepidermal elimination, 1:524
necrosis, 3:145-146, 3:146f, 3:145.e1f bladder, 2:451 Transglutaminases, 1:513
neoplasms, 3:151-158, 3:152t liver lobe, 2:268 Transitional cell carcinoma, 1:736
remnants, 3:147f, 3:153f lung lobe, 2:485-486, 2:485f nasal, 2:478-479, 2:479f
structure and function of normal, testis, 3:491-492 Transitional metaplasia of trachea, 2:501,
3:141-144, 3:142f, 3:142.e1f Total myeloschisis, 1:279 2:501.e1f
thymomas, 1:691-692, 3:153-157, Toxascaris canis, 2:219 Transmissible gastroenteritis virus (TGEV),
3:153f-154f, 3:153.e1f Toxascaris leonina, 2:219-220 2:113, 2:147, 2:148f
with anaplasia, 3:157 Toxemia, pregnancy, 2:275 Transmissible genital papilloma, 3:508-509,
Thyroglossal duct Toxic bone diseases, 1:84-91 3:509f
cysts, 2:29, 3:310, 3:314 fluorosis, 1:84-86 pig, 3:449
neoplasms, 3:332, 3:332f lead toxicity, 1:86, 1:87f Transmissible mink encephalopathy (TME),
Thyroid gland, 3:310-336 molybdenosis, 1:84 1:349
biosynthesis of thyroid hormones, plant toxicities, 1:90-91 Transmissible spongiform encephalopathies
3:311-312 vitamin A toxicity, 1:67, 1:86-89 (TSEs), 1:347
C cells, 3:296-297 vitamin D toxicity, 1:89-90 Transmural granulomatous enteritis, 2:97
tumors, 3:332-336, 3:333f, 3:335f Toxic epidermal necrolysis (TEN), 1:607- Transphyseal blood vessels, 1:27-28, 1:28f
development, structure, and function, 615, 1:610f Transposition complexes, 3:22
3:310-314, 3:310f Toxic hepatic disease, 2:325-344 Trans-synaptic degeneration, 1:254
diseases, 3:314-326, 3:314f agents, 2:328 Transverse ridge arthrosis, 1:142
effects of drugs and chemicals on, Toxic insult, acute, 2:425 Trapped neutrophil syndrome, 3:110
3:323-326 Toxicities, plant, 1:90-91, 1:219-220 Trauma
function evaluation, 3:319 avocado, 3:38 abdominal, 2:246-247, 2:246f
hormones, 1:25t fluoroacetate, 3:38 acute conjunctival, 1:424
Trauma (Continued) Triiodothyronine, 3:272, 3:311 Tubular epithelial injury, acute, 2:428.e3f,
articular cartilage response to, 1:131-132 Trimethoprim-sulfonamides, 2:329 2:421.e2f
blood loss anemia and, 3:112-114 Trimming of fixed autopsy and biopsy Tubular genitalia development, 3:360-361,
central nervous system, 1:301-303 specimens, 1:8-9 3:361f
chronic conjunctival, 1:424 Tritrichomonas foetus, 2:98, 2:243, 3:423-424 Tubular injury, acute, 2:427f-428f,
corneal, 1:429-432, 1:430f, 1:431t, Troglostrongylus acutum, 1:391 2:433f
1:432f Troglostrongylus brevior, 2:591 Tubular necrosis, acute, 2:398-399
deposits secondary to, 1:434, 1:434f Troglostrongylus subcrenatus, 2:591 caused by ethylene glycol intoxication,
deafness caused by, 1:493-494 Trombiculiasis, 1:682-683 2:426f, 2:425.e2f
head, 1:301-303 Trueperella pyogenes, 2:19 Tubular protein casts, 2:407
hemolytic anemia due to, 3:125-126 Trueperella (Arcanobacterium) pyogenes, Tubules, 2:383
infectious arthritis and, 1:149 1:102, 1:230, 3:507 Tubule segment, structure, 2:381
ischemic damage to muscle fibers, 1:211, abortion in cattle and sheep and, 3:412 Tubuloglomerular feedback, 2:379
1:211f endocarditis and, 3:30-31, 3:31f Tubulointerstitial diseases, 2:431-443
liver, 2:285-290, 2:287f, 2:326 infectious arthritis and, 1:148 chronic interstitial nephritis, 2:431
hepatic artery, 2:296 oral cavity lesions, 2:19 Encephalitozoon cuniculi, 2:431
portal vein, 2:296-297 splenic abscesses, 3:183-184 histologic features, 2:431
lung, 2:500-520, 2:500f, 2:500.e1f True retinal dysplasia, 1:420 Leptospira interrogans, 2:431
toxic, 2:518-520 Trypanosoma brucei brucei, 3:124, 3:473-474 nonsuppurative interstitial nephritis,
ventilator-induced, 2:511 Trypanosoma cruzi, 3:44, 3:121, 3:124 2:431-432
mammae, 3:451 Trypanosoma equinum, 3:124 Tubulointerstitial nephritis, chronic,
muscle, 1:180-182, 1:180f, 1:213-214 Trypanosoma equiperdum, 3:121, 3:445-447, 2:433.e1f
myocardial necrosis secondary to neural, 3:508 Tubulointerstitium, from proteinuric dog,
3:39 Trypanosoma evansi, 3:124 2:407f
neurons response to, 1:252-256, 1:252f Trypanosoma simiae, 3:124 Tubulorrhectic ATI, 2:422-423
osteochondrosis, 1:132 Trypanosomatidae, 3:174 Tularemia, 3:184-186, 3:185f
peritoneal, 2:245-246 Trypanosoma vivax, 3:121f, 3:491 Tumoral calcinosis, 1:127, 1:127f
response of gastric mucosa to, 2:46-48 Trypanosomiasis, 3:121-124, 3:121f Tumor-like proliferative lesions, 2:101t
retinal, 1:473 Trypanosom suis, 3:124 Tumor necrosis factor-α, 2:548-549
skin, 1:559-561 T-2 toxin, 1:573 Tumors, 2:447-448. See also Lymphomas;
mechanical, frictional, and traumatic, Tuberculoid granuloma, 2:549 Metastases, tumor; Non-neoplastic
1:559-566 Tuberculoid leprosy, 1:641 lesions
psychogenic, 1:561-562, 1:561f Tuberculoproteins, 2:548 adrenal medullary, 3:349-352
spinal cord, 1:128 Tuberculosis, 1:639. See also Mycobacterial benign cortical fibromas, 2:447
tendon, 1:247 infections bone, 1:107-127
tracheal, 2:483 bovine, 2:547-551, 2:549f cartilage-forming, 1:116-121
Traumatic lens rupture, 1:444 caseous, 3:389 fibrous, 1:121-122, 1:121f
Traumatic neuroma, 1:724-725 dogs and cats, 2:550 forming, 1:109-116, 1:109f
Traumatic pericarditis, 2:39 horses, 2:550 giant cell, 1:122
Traumatic reticuloperitonitis of forestomachs, liver and, 2:315f secondary, 1:124-125
2:38-39 lymph nodes and, 3:204f-205f, 3:203.e1f vascular, 1:122
Traumatic synovitis, 1:141 mastitis, 3:456-457 brain, 1:296f
Trematodes, 1:391, 2:320-324 pigs, 2:550 carcinoma, 2:447
Trema tomentosa, 2:331 Tubular backleak, 2:423 cholangiocellular, 2:348-349, 2:348f
Tremor, congenital, 1:338 Tubular basement membranes, 2:422-423 dental tissue, 2:22-25
Tremorgenic mycotoxicoses, 1:318, Tubular cells, degeneration and swelling of, endocrine gland, 3:271-272
1:322 2:421-422 epithelial
Trianthema portulacastrum, 2:425-426 Tubular diseases, 2:421-431 pulmonary, 2:495
Tribulosis, 2:338-340 acute tubular injury (ATI), 2:421-428 skin, 1:703
Trichiasis, 1:421 ischemic tubular necrosis, 2:423f thymic, 3:152-153
Trichinella spiralis, 2:19 with karyomegaly, 2:428f granular cell, 1:245, 2:27
myocarditis and, 3:44 epithelial injury, 2:428.e3f heart, 3:52-53
Trichinellosis, 1:237-238 myoglobin-induced acute tubular injury, laryngeal, 2:482
Trichobezoars, 2:38, 2:50, 2:76f 2:423f pulmonary, 2:498
Trichobezoars, 2:50 nephrotoxic, 2:423 hemangioma, 2:447
Trichoblastomas, 1:716, 1:716f amaranthus, 2:427 hepatocellular, 2:345-348, 2:346f
Trichoepitheliomas, 1:714-715, 1:715f aminoglycosides, 2:424 hypersecretion of hormones by,
Trichofolliculomas, 1:705 amphotericin B, 2:424-425 3:274
Tricholemmoma, 1:715-716 chelation of calcium, 2:426 interstitial cell, 2:447
Trichomegaly, 1:421 cyanuric acid, 2:426-427 intestinal stromal tumors, 2:110-111
Trichophytobezoars, 2:50 degeneration and swelling, 2:421-422 gastrointestinal, 2:110
Trichophyton, 1:652, 1:652f ethylene glycol, 2:425 leiomyoma, 2:110
Trichostrongylus axei, 2:54-55, 2:208-209 grapes and raisins, 2:428 leiomyosarcoma, 2:110
Trichostrongylus colubriformis, 1:66, 2:212 marked acute tubular necrosis, 2:428.e1f -like lesions
Trichostrongylus rugatus, 2:212 melamine acid, 2:426-427 of bones, 1:125-127
Trichostrongylus spp., 3:112-114 mycotoxins, 2:427 of joints, 1:159-163
Trichostrongylus vitrinus, 2:212 nephrotoxic in domestic animals, 2:424b liver mesodermal, 2:349-351, 2:350f
Trichothecene toxicoses, 1:573-574 oxalate poisoning, 2:425-426 lymphoma, 2:447
Trichuriasis, 2:115-116 plant toxicoses, 2:427-428 male genital system
Trichuris spp., 2:220-221, 2:221f primary renal glucosuria, 2:429 germ cell, 3:495-496, 3:495f
Trichuris vulpis, 2:98 specific tubular dysfunctions, 2:428-429 interstitial testicular, 3:493, 3:493f
Trifolium hybridum, 2:341-342, 2:341f sulfonamides, 2:424 Sertoli cell, 3:494-495, 3:494f
Trifolium subterraneum, 2:458 tetracyclines, 2:424 sex cord-gonadal stromal, 3:492-495
Index 569
Uriniferous pseudocyst, 2:451 Vaginal eventration, 2:78 Vena caval syndrome, 3:85
Urolithiasis, 2:454f Vaginal stenosis, 3:369, 3:370f Venom, 1:568
Urolith initiation Vaginal tunics, 3:473-474, 3:473f-474f Venous drainage, 2:18
crystallization-inhibition theory, 2:453 Vaginitis, necrotic, 3:445, 3:445f-446f Venous infarction, 2:82f
matrix-nucleation theory, 2:453 Vagus indigestion, 2:39 Ventilator-induced lung injury, 2:511
Uroperitoneum, 2:247 Valgus deformity, 1:31 Ventral hernia of abdominal wall,
Uroplakins, 2:462.e1 Valvular cysts, 3:30 2:80
Urothelial cell carcinomas, 2:447f, 2:462-463, Valvular endocarditis, 3:30-31, 3:31.e1f Ventricles, heart, 3:2
2:462f, 2:447.e1f Vanishing bone disease, 1:54 restricted filling, 3:6
metastasize, 2:462-463 Varicocele, 3:497-498, 3:498f wall thickness, 3:5
Urothelial papilloma, 2:447 Varicose tumor of the scrotum, 3:99 Ventricular pre-excitation, 3:51
Urothelium, 2:448 Variola virus, 1:616 Ventricular septal defect (VSD), 3:17,
Urticaria, 1:594 Varus deformity, 1:31 3:17f-18f
Uterine (fallopian) tubes pathology, Vascular anomalies Veratrum californicum, 1:90, 1:269-270,
3:379-380 heart, 3:23-24, 3:23f 2:3
Uterus liver, 2:266-268 cleft palate and, 2:3
abscess, 3:390 Vascular endothelial growth factor (VEGF) Verminous arteritis, 3:83-88
accumulation of secretory or inflammatory receptors, 2:421 Verminous endoarteritis, 2:84
exudates, 3:386-387 Vascular-epithelial structure, 2:379-380 Verminous granulomas, 3:498
carcinoma, 3:449-450, 3:450f Vascular hamartomas of ovary, 3:366, Vernonia rubricaulis, 2:331
cysts arising from, 3:366-367 3:378-379 Verotoxin-producing E. coli (VTEC),
inflammatory diseases of, 3:387-393 Vascular malformation, 3:99 2:162
mucometra, 3:374, 3:374f Vascular neoplasia, 3:98-101 Verrucous sarcoids, 1:708, 1:709f
neoplasia, 3:449-450, 3:450f Vascular nevus, 1:727 Vertebrae
pathology, 3:380-382, 3:380f, 3:393-398 Vascular occlusive syndrome, 1:212, congenital abnormalities, 1:57
postpartum, 3:440-441 1:212f diskospondylitis, 1:156, 1:156f
rupture, 3:381, 3:381f Vascular ring anomalies, 2:33 osteomyelitis, 1:101-102, 1:102f
UVA/UVB radiation. See Solar radiation Vascular smooth muscle cells, 3:55-56 subluxations, 1:303
Uvea, 1:445-465 Vascular system Very low-density lipoproteins (VLDLs),
degenerations, 1:445-446 arteries, 3:56-88 2:273, 2:276-277
glaucoma, 1:459-465 congenital abnormalities, 3:14-24 Vesicle, 1:524
melanocytoma, 1:482-483, 1:483f dermal, 1:514-515 Vesicoureteral reflux, 2:439
uveitis, 1:446-459 diseases, 3:54-101 Vesicular adenitis, 3:499-500, 3:499f
bacterial endophthalmitis, 1:449 hemodynamic effects of valvular Vesicular cutaneous lupus erythematosus,
significance of, 1:447-448, 1:447f-448f abnormalities, 3:4.e1f 1:607
Uveitis, 1:446-459 leakage, 1:298f Vesicular exanthema (VE), of swine,
bacterial endophthalmitis, 1:449 liver, 2:266-268, 2:296-300 2:120-121
bovine malignant catarrhal fever-associated, lungs, 2:467-468, 2:468f Vesicular exanthema of swine virus (VESV),
1:453 neoplasms, 3:98-101 2:121
canine adenovirus I, 1:452-453 retina, 1:466 Vesicular stomatitis (VS), 2:14-15, 2:117-
equine recurrent ophthalmitis, 1:455-456 spleen, 3:161, 3:161f 158, 2:120f
feline infectious peritonitis-associated, tumors Vestibular membrane, 1:489
1:453, 1:453f bone, 1:122 Vestibular window, 1:489
histologic classification, 1:448-449 dogs, 1:122 Vestibulocochlear nerve, 1:489-491
idiopathic immune-mediated, 1:453-455, oral cavity, 2:28 Vetch toxicosis, 1:574
1:454f skin, 1:726-728 Vicia villosa, 3:36
idiopathic lymphocytic, in dogs, 1:456 veins, 3:88-94 Villaneuva’s bone stain, 1:29
idiopathic lymphonodular, of cats, 1:456 Vasculitis, 1:525-526, 1:526f, 1:607, 3:67-88, Villus, 1:524
lens-induced, 1:453-454, 1:457-459 3:68b, 3:68.e1f Villus atrophy, 2:67-68, 2:96
mycotic endophthalmitis, 1:449-451 cerebrospinal, 1:298-299, 1:298f-299f Villus fusion, 2:146
protozoal endophthalmitis, 1:451 chronic fibrosing, 3:71, 3:71f Vimentin, 1:261
significance of, 1:447-448, 1:447f-448f cutaneous, 1:611-612, 1:611f Viral agents, 2:57
uveodermatologic syndrome, 1:453-454, lymphocytic, 1:526, 1:611 Viral antigen, 2:22
1:456-457, 1:457f male genital system, 3:498 Viral arthritis, 1:154
viral endophthalmitis, 1:452 necrotizing, 1:200, 1:200f, 3:69, 3:69f Viral endophthalmitis, 1:452
Uveodermatologic syndrome, 1:453-454, neutrophilic, 1:526, 1:611 Viral inclusion bodies, 1:255
1:456-457, 1:457f nodular eosinophilic, 1:612 Viral infections
pastern leukocytoclastic, 1:612 abortion and stillbirth due to, 3:398,
V photoactivated, 1:580 3:399b
Vaccinal fibrosarcomas, 1:725 pulmonary, 2:494, 2:494.e2f alimentary tract, 2:117-158
Vaccine administration and injection-site rabies vaccine-induced, 1:612-613, 1:613f bone, 1:104-105
reactions, 1:560 Vasoactive intestinal polypeptide, 2:368 central nervous system and, 1:365-385
Vaccine-induced polyarthritis, 1:158 Vasogenic edema, 1:294, 1:295f developmental defects of central nervous
Vaccinia virus, 1:616, 1:620 Vasopressin. See Antidiuretic hormone system and, 1:280-284
Vacuolar degeneration, 1:185, 1:185f, 1:254, (ADH) liver, 2:309-325
1:254f, 1:522 Veins, 3:54, 3:88-94 lobular necrosis and, 2:282
Vacuolation, 2:272-273, 2:272f drainage, 2:18 lymphomagenesis and, 3:235
Vagal indigestion, diagnosis of, 2:39 hepatic, 2:260 myocarditis and, 3:42, 3:43f
Vagal lesions, 2:39 infarction, 2:82f parvo-, 1:628
Vagina inflammation. See Phlebitis pregnant uterus, 3:424-440
anomalies, 3:369-370, 3:370f invasion by neoplasms, 3:89, 3:89f respiratory system, 2:523-531
inflammatory diseases, 3:443 obstruction of cerebrospinal, 1:300 cats, 2:587-589
pathology of, 3:442-447, 3:442f pulmonary, 2:467-468, 2:468f cattle, 2:537-542
Index 571
Yorkshire Terrier dogs (Continued) Zenker’s degeneration, 1:181-182 Zona fasciculata, 3:336
primary portal vein hypoplasia, Zenker’s fixative, 1:408, 1:449, 3:474-475 Zona glomerulosa, 3:336
2:267-268 Zinc hyperplasia, 3:343, 3:344f
rabies vaccine-induced vasculitis and chemical abomasitis and, 2:52 Zona reticularis, 3:336-337
alopecia, 1:612, 1:613f deficiency, 1:583-585, 1:584f Zone of degeneration, growth plate, 1:23
spongy encephalomyelopathies, 1:346-347 dogs, 1:585-586, 1:585f Zonisamide, 2:329
Yucatan minipigs, 1:604 hereditary, 1:532-533 Zoophilic dermatophytes, 1:649
toxicity and pancreas, 2:356, 2:357f Zoospores, 1:632, 2:203
Z Z-line streaming, 1:190, 1:193-194, Zoo ungulates, 1:214-215
Zalophus californianus, 2:121 1:194f Zygomycetes, 1:659, 2:42, 2:324, 2:324f,
Z bands, 1:167 Zollinger-Ellison syndrome, 2:55-56, 2:573
in muscular dystrophy, 1:193-194, 1:194f 2:375 Zygomycosis, 1:659-660
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