6.

3 Endocrine Pathology 2 SUBJECT

Dra. Bailon | February 11, 2014 2nd 2013-2014

OUTLINE
I. Parathyroid Glands V. Endocrine Tumors
II. Pathology of Parathyroid Glands VI. Adrenal Glands
III. Endocrine Pancreas VII. Adrenal Endocrine Syndromes
IV. Diabetes Mellitus VIII. Tumors of the Adrenal Cortex
IX. Tumors of the Adrenal Medulla
References:
Robbins and Cotran: Pathologic Basis of Disease. Lecturer’s PPT.
I. PARATHYROID GLANDS
A. Review of Anatomy
 Located adjacent to the thyroid gland hence during total
thyroidectomy these glands maybe iatrogenically removed and
cause hypoparathyroidism.
Figure 3. Parathyroid Adenoma. It has compact acini compressing the normal
 Composed mainly of chief cells – polygonal with central round nuclei
parathyroid parenchyma. The adenoma has very minimal or absent fat cells
and secretory granules. compared to a normal parathyroid parenchyma. It is normally almost always
 Secrete the Parathyroid Hormone (PTH, parathormone) solitary, as a well circumscribed, reddish-brown nodule with a delicate capsule.
o Secretion is not under pituitary control. It is usually composed of uniform, polygonal chief cells with centrally placed
o Responsive to the plasma concentration of ionized calcium. nuclei.
o Decrease in calcium concentration will stimulate PTH
production. II. PATHOLOGY OF PARATHYROID GLANDS
A. Hyperparathyroidism
1. Primary Hyperparathyroidism – a disease of adults and is more
common in women than men (4:1), most cases occur during 50’s.
 Causes with corresponding frequency:
o Parathyroid Adenoma - 85 to 95%, most common cause.
o Parathyroid Hyperplasia - 5 to 10%
o Parathyroid Carcinoma - 1%
o Parathyroid hormone-like hormone production (PTHrP) by
tumors elsewhere.
o Multiple Endocrine Neoplasia (MEN) type I and type IIa.
 Clinical Manifestations: symptomatic primary
hyperparathyroidism patients are associated with “painful bones,
Figure 1. Parathyroid Glands Gross
renal stones, abdominal groans and psychic moans.”
o Osteitis Fibrosa Cystica
 Also known as Von Reclinghausen’s disease of the bone.
 Cystic changes in the bone due to osteoclastic resorption;
bone appears osteoporotic.
 Bone appears with widely spaced, delicate trabeculae,
thin cortex, increased fibrous tissue with foci of
haemorrhage and cyst formation.
 ‘Brown tumors’ – aggregates of osteoclasts, reactive
giants cells and hemorrhagic debris forming masses which
may be mistaken for neoplasms.
o Nephrocalcinosis and renal calculi – kidney stones.
Figure 2. Parathyroid Gland Microscopy. Normal parathyroid gland o Hypercalcemia
parenchyma consists of parathyroid acini, interspersed are adipose cells or o Predisposed to peptic ulcer
adipose tissue, and oncocytic* cells.  Abnormalites most directly related to hyperparathyroidism are
*Oncocytic – having increased mitochondria, as in oxyphil cells. nephrolithiasis and bone disease, while those attributable to
hypercalcemia include fatigue, weakness and constipation.
 Laboratory Abnormalities:
o Increased PTH
o Hypercalcemia
o Hypercalciuria - increase in calcium in the urine.
o Hypophosphatemia - because with increase in calcium, there
is decrease in phosphate.
o Decreased Tubular reabsorption of phosphorus
o Increased Alkaline Phosphatase

Page 1 of 14

Gopez – Hidalgo (Hidalgo – 09178678622)

 PATHOLOGY 6.3
2. Secondary Hyperparathyroidism
 Causes:
o Any condition causing chronic hypocalcemia.
o Renal failure is by far the most common cause of secondary
hyperparathyroidism.
o Other causes are low intake of calcium, steatorhhea, and vit.
D deficiency.
o These conditions lead to compensatory overactivity of the
parathyroid glands.
 Clinical Manifestations:
o Diffuse osteoclastic bone disease (renal osteodystrophy)
o Metastatic calcification
o Vascular calcification may cause ischemia to skin and other
organs (Calciphylaxis)
o Histologically the parathyroids are hyperplastic
 Laboratory Abnormalities:
o Increased PTH
o Hypocalcemia (may be slightly reduced)
o Hyperphosphatemia
o Increased alkaline phosphatase
3. Tertiary Hyperparathyroidism
 Persistent parathyroid hyperfunction in spite of correction of
hypocalcemia and preexisting secondary hyperparathyroidism.
 The only therapy may be parathyroidectomy.
B. Hypoparathyroidism
 Decrease in PTH , far less common than the hyper state.
 Most common cause is accidental removal of the parathyroid gland
during thyroidectomy.
 If the parathyroid gland is removed it will cause severe
hypocalcemia with neuromuscular excitability and tetany (Chvostek Figure 5.Insulin action on a target cell. Insulin acts on target cells and insulin is
and Trousseau sign). able to enter the cells through insulin receptors using the MAP kinase Signaling
 There may also be len calcification, cataracts, prolonged QT interval Pathway and PI-3K/AKT Signaling Pathway causing cell growth, proliferation,
and gene expression, synthesis of lipids, proteins, and glycogen. If diabetes
and dental abnormalities (dental hypoplasia, failed tooth eruption,
mellitus is present the lipid, protein, and carbohydrate metabolisms are
defective enamel and root formation, abraded carious teeth). affected.
C. Pseudohypothyroidism
 Autosomal recessive IV. DIABETES MELLITUS
 Renal end-organ unresponsiveness to PTH  A group of metabolic disorders with hyperglycemia or increased
 The PTH resistance is the most obvious clinical manifestation, glucose levels in the blood as a common feature.
presenting as hypocalcemia, hyperphosphatemia, and elevated  It is important because it is a leading cause of end-stage renal
circulating PTH. disease, adult onset blindness, and non-traumatic lower extremity
amputations.
III. ENDOCRINE PANCREAS
 Pre-diabetic Stage:
 The pancreas is divided into the exocrine pancreas which consists of
o 5-10% of pre-diabetics will advance to Diabetes Mellitus (DM)
the pancreatic acini and the endocrine pancreas is comprised of the
per year
Islet cells of Langerhans.
o Increase risk for Cardiovascular disease in pre-diabetics due to
 In the islet cells is consists of: due to increased plasminogen activator inhibitor-1 (PAI-1), low
o Alpha cells which secrete glucagon HDL, etc.
o Beta cells which secrete insulin
 Normal blood glucose level = 70 - 120 mg/dL
o Delta cells which secrete somatostatin
 Criteria for the Diagnosis of Diabetes according to the American
Diabetes Association:
o Glycosylated Hemoglobin (A1C) > 6.5%
 The A1C test measures the patient’s average blood glucose
for the past 2 to 3 months. The patient doesn’t have to fast
or drink anything.
o Fasting Plasma Glucose (FPG) > 126mg/dL (7.0 mmol/L)
 When FPG test is done the patient needs to fast for at least
8 hours; no caloric intake for 8 hours. This test is usually
done in the morning, before breakfast.
Figure 4. Immunoperoxidase stain. Alpha cells with glucagon (Left) and beta o 2 hour blood glucose > 200 mg/dL (11.1 mmol/L) during an Oral
cells with insulin (Right). Most of the cells in the Islets are the beta cells Glucose Tolerance Test
followed by the alpha cells, and the delta cells are the least common.  OGTT is a two-hour test that checks the patient’s blood
glucose levels before and 2 hours after the patient is given a
Page 2 of 14
 PATHOLOGY 6.3
glucose load which is equivalent to 75 g of anhydrous Thyroid hormone
glucose dissolved in water. α-interferon
o Random Plasma Glucose level > 200 mg/dL (11.1 mmol/L) Protease inhibitors
 Random plasma glucose test is a blood check at any time of β-adrenergic agonists
the day when the patient has severe diabetes symptoms Thiazides
such as hyperpolyphagia, polydipsia, and polyuria (Diabetic Nicotinic acid
Triad) or diabetic crisis. Phenytoin
o For all three tests, risk is continuous, extending below the lower Vacor
limit of a range and becoming disproportionately greater at 9. Genetic syndromes associated with diabetes
higher ends of the range. Down syndrome
o In the absence of unequivocal hyperglycemia, result should be Kleinfelter syndrome
confirmed by repeat testing. Turner syndrome
 Laboratory Results indicating Pre-diabetes (increased risk for Prader-Willi Syndrome
diabetes) are: 10. Gestational diabetes mellitus
o Fasting Plasma Glucose is 100 - 125 mg/dL => impaired fasting
blood glucose Table 2. Classification of Diabetes used by the American Diabetes Association.
o 2 hour Plasma Glucose in 75 g OGTT is 140 - 199 mg/dL => 1. Type 1 diabetes
impaired glucose tolerance - β-cell destruction
o Glycosylated Hemoglobin is 5.7 - 6.4% => increased risk of 2. Type 2 diabetes
cardiovascular disease - progressive insulin secretory defect
Table 1. Classification of Diabetes Mellitus from Robbins and Cotran, 8th ed 3. Other specific types of diabetes
1. Type 1 diabetes (β-cell destruction, leads to absolute - Genetic defects in β-cell function, insulin action
insulin deficiency) - Diseases of the exocrine pancreas
Immune-mediated - Drug- or chemical-induced
Idiopathic 4. Gestational diabetes mellitus (GDM)
2. Type 2 diabetes (insulin resistance with relative insulin * Dr. Bailon will be using this diabetes classification in the exam.
deficiency)
3. Genetic defects of β-cell function
Maturity-onset diabetes of the young (MODY), caused by
mutations in:
Hepatocyte nuclear factor 4α[HNF-4α] (MODY1)
Glucokinase (MODY2)
Hepatocyte nuclear factor 1α[HNF-1α] (MODY3)
Insulin promoter factor [IPF-1] (MODY4)
Hepatocyte nuclear factor 1β[HNF-1β] (MODY5)
Neurogenic differentiation factor 1 [Neuro D1] (MODY6)
Neonatal Diabetes (activating mutations in KCNJ11 and
ABCC8, encoding Kir 6.2 and SUR1, respectively)
Mitochondrial DNA mutations
Defects in proinsulin conversion
Insulin gene mutations
4. Genetic defects in insulin processing or insulin action
Type A insulin resistance
Lipoatrophic diabetes, including mutations in PPARG Figure 6. Insulin synthesis and secretion. Glucose entry to the cell is mediated
5. Exocrine pancreatic defects by GLUT-2 (an insulin-independent glucose transporter in beta cells). Once
Chronic pancreatitis inside the cell it undergoes oxidative metabolism in the beta cells to yield ATP.
Pancreatectomy/trauma ATP will then inhibit the potassium channel receptor (a complex of sulfonylurea
(SUR1) receptor and potassium channel protein (KIR 6.2) on the surface of the
Neoplasia
beta cells. Inhibition of this receptor will lead to membrane depolarization,
Cystic fibrosis calcium influx and release of stored insulin from the beta cells into the blood
Hemachromatosis stream. The action of the sulfonylureas which are your oral hypoglycemic
Fibrocalculous pancreatopathy agents is to bind the sulfonylureareceptor protein.
6. Endocrinopathies
Acromegaly
Cushing syndrome
Hyperthyroidism
Pheochromocytoma
Glucagonoma
7. Infections
Cytomegalovirus
Coxsackie virus B
Congenital Rubella
8. Drugs
Glucocorticoids

Page 3 of 14

Figure 7. Metabolic actions of insulin in adipose tissue, striated muscle, and
liver. Glucose homeostasis is regulated by 3 main mechanisms: glucose
production in the liver, glucose uptake and use in peripheral skeletal muscle
tissue, and hormone regulation of insulin and glucagon. Insulin’s principal
function is to transport glucose into cells of tissues (esp. skeletal and adipose)
providing energy.
Table 3. Type 1 vs. Type 2 Diabetes Mellitus.
Type 1 DM
(previously known as
the juvenile diabetes)
Clinical Onset: usually childhood
and adolescence
Normal weight or weight
loss preceding diagnosis
Progressive decrease in
insulin levels
Circulating islet
autoantibodies (anti-
insulin, anti-GAD, anti-
ICA512)
Diabetic Ketoacidosis is
common in the absence
of insulin therapy.
Genetics 30-70% concordance in
twins
Major linkage to MHC
class I and II genes;
also linked to
polymorphisms in CTLA4
and PTPN22, and insulin
gene VNTRs
Pathogenesis Autoimmune destruction
of β-cells mediated by T-
cells and humoral
mediators (TNF, IL-1,
NO)
PATHOLOGY 6.3
Multiple obesity-
associated factors
(circulating
nonesterified fatty
acids, inflammatory
mediators,
adipocytokines) linked
to pathogenesis of
insulin resistance.
Absolute Insulin Relative Insulin
deficiency deficiency
Islet Cells Early Insulitis No Insulitis
Pathology Marked atrophy and Amyloid deposition
fibrosis and focal atrophy
Beta cell depletion Mild beta cell
depletion
Clinical Insulin absolutely Diet, exercise, oral
Management required hyperglycemic agents
or insulin
Type 2 DM
(previously known as
the adult onset DM)
Onset: usually adult;
but there is increasing
incidence in childhood
and adolescence
Vast majority are
obese (80%)
Increased blood insulin
(early); normal or
moderate decrease in
insulin (late)
No anti-islet cell
antibodies
Non-ketotic
hyperosmolar coma is
more common;
Ketoacidosis is rare
50-90% concordance in
twins
No HLA linkage. Figure 8. Sequence of metabolic derangements underlying the clinical
manifestations of diabetes. An absolute insulin deficiency leads to a catabolic
state, culminating in ketoacidosis and severe volume depletion. These cause
Linkage to candidate sufficient central nervous system compromise to lead to coma and eventual
diabetogenic and death if left untreated.
obesity-related genes
(TCF7L2, PPARG, FTO, A. Pathogenisis of Type 1 DM
etc.)
 Severe lack of insulin due to immunologically mediated
Insulin resistance in
destruction of beta cells by T lymphocytes reacting with beta cell
skeletal muscle,
antigens. Genetic susceptibility and environmental factors play a
adipose tissue and
role.
liver, failure of
compensation by β-
//*Please see appendix for Figure 9: Genetic Susceptibility and
cells.
Environmental Factors in playing a role in the pathogenesis of type 1
Diabetes Mellitus*//
Page 4 of 14
 PATHOLOGY 6.3
 Mechanisms of β cell destruction:
o The fundamental immune abnormality in type 1 diabetes is a
failure of self-tolerance in T-cells.
o T lymphocytes react against β cell antigens and cause cell
damage.
1. CD4+ Tcells  activate macrophages  tissue injury
2. CD8+ cytotoxic T lymphocytes:
A. directly kill β cells
B. secrete cytokines that activate macrophages
o Cytokines damage β cells and induce β cell apoptosis by:
1. IFN–γ produced by T cell
2. TNF, IL–1 produced by macrophages activated during
immune reaction.
o Auto-Ab’s against islet cells and insulin are detected in blood of Figure 11. Insulin resistance in Diabetes mellitus. There is either insulin
70-80% of patients. resistance at insulin receptors, defective 2ndary signalling after inslun has
B. Pathogenisis of Type 2 DM (Non-insulin dependent activated the receptor or decreased insulin secretion.
Diabetes Mellitus)
 Causes:
A. Genetic factors
 autosomal dominant inheritance linked to chromosomes 7
& 20. Defect in chromosome 7 due to mutation in the gene
encoding glucokinase (part of glucose-sensing mechanism
regulating insulin secretion in β cells.
 recent: polymorphism in genes associated with beta cell
function and insulin secretiongenetic risk for developing
type 2 D.M.
B. Obesity and Overeating
 Two metabolic defects in Type 2 D.M.:
A. decreased ability of peripheral tissues to respond to insulin
(insulin resistance).
B. β-cell dysfunction  inadequate insulin secretion in the face of
insulin resistance and hyperglycemia.

Figure 12. Development of type 2 Diabetes. Insulin resistance associated

with obesity is induced by adipokines, free fatty acids, and chronic
inflammation in adipose tissue. Pancreatic Beta-cells compensate for insulin
resistance by hypersecretion of insulin. However, at some point, the
compensation is followed by Beta-cell failure, and diabetes ensues.

 Metabolic syndrome:
Table 4. Clinical Signs, Laboratory Abnormalities, Comorbid Illnesses in Type 2
Diabetes Mellitus
Clinical Signs Laboratory Comorbid Illnesses
Abnormalities
Figure 10. Beta-cell dysfunction in type 2 Diabetes Mellitus
Central (upper body) Elevated fasting Hypertension (usually
obesity and/or postprandial mild)
 Insulin Resistance (IR):
Acanthosis nigricans glucose Atherosclerosis
o IR associated with obesity is induced by adipokines, FFA, and
(hypertrophic, Insulin resistance Hyperandrogenism
chronic inflammation in adipose tissue  beta cells compensate
hyperpigmented skin with with polycystic ovary
for insulin resistance by hypersecretion of insulin  beta cell
changes) hyperinsulinemia syndrome
compensation  beta cell failure  D.M.
CVS risk factors: Dyslipidemia
o Central obesity (abdominal fat) is more likely linked with insulin
 mild hypertension Abnormal
resistance than peripheral fat deposits (gluteal/subcutaneous).
 dyslipidemia ( thrombolysis
HDL,  circulating Hyperuricemia
TG, small dense Endothelial and
LDL particles) vascular smooth
closely related to muscle dysfunction
insulin resistance
in target tissues
 compensatory
hyperinsulinemia
Page 5 of 14

Figure 13. Metabolic Derangement in Type 2 Diabetes Mellitus
Figure 14. Metabolic derangement in type 2 Diabetes Mellitus
C. Morhphology of Diabetes and its Late Complications
 In most patients, morphologic changes of Diabetes are likely found
in arteries (macrovascular disease), basement membranes of small
vessels (microangiopathy), kidneys (diabetic nephropathy), retina
(retinopathy) and nerves (neuropathy).
A. Pancreas
 Lesions in the pancreas are inconstant and rarely of diagnostic
value.
 Distinctive changes are more commonly associated with type 1
than type 2 diabetes.
 One of the following alterations may be present:
1. Reduction in the number and size of islets.
 This is most often seen in type 1 diabetes, particularly
with rapidly advancing disease.
 Most of the islets are small and inconspicuous.
2. Leukocytic infiltrates in the islets.
 Insulinitis
 Primarily composed of T lymphocytes.
 Lymphocytic infiltrates may be present in type 1 diabetics
at the time of clinical presentation.
 The distribution of insulinitis may be strikingly uneven.
 Eosinophilic infiltrates may also be found, particularly in
diabetic infants who fail to survive the immediate
postnatal period.
PATHOLOGY 6.3
3. In type 2 diabetes there may be a subtle reduction in islet
cell mass
4. Amyloid deposition within islets in type 2 diabetes
 Begins in and around capillaries and between cells.
 At advanced stages, the islets may be virtually obliterated.
 Fibrosis may also be observed.
 Similar lesions may be found in elderly nondiabetics,
apparently as part of normal aging.
5. An increase in the number and size of islets
 Characteristic of nondiabetic newborns of diabetic
mothers.
 Fetal islets undergo hyperplasia in response to maternal
hyperglycemia.
Figure 15. Pancreatic islets in Type 1 DM. Islets of Langerhans are infiltrated by
small round cells without cytoplasm (these are lymphocytes); there is early
insulinitis – this is seen in Type 1 DM. Infiltration of lymphocytes, some atrophy
of pancreatic β cells.
Figure 16. Pancreatic islet in type 2 DM. Amyloidosis of pancreatic islet in type
2 DM. Islet of Langerhans are not infiltrated by lymphocytes. Instead, there are
acellular homogenous slightly pinkish areas which are the amyloid deposits.
These amyloid deposits will now exert pressure on the adjacent islet cells and
these will lead to atrophy hence causing amyloid deposition as well as islet cell
atrophy. Mild β cell depletion due to replacement of amyloid deposits. Amyloids
stain positive in congo red.
B. Kidney (Diabetic Nephropathy)
 The kidneys are prime targets of diabetes.
 Three lesions are encountered:
1. Glomerular lesions
2. Renal vascular lesions, principally arteriosclerosis
3. Pyelonephritis, including necrotizing papillitis
 Glomerular lesions
1. Capillary basement membrane thickening
 Widespread.
Page 6 of 14

 Begins as early as 2 years after the onset of type 1
diabetes.
 Thickening continues progressively and usually
concurrently with mesangial widening.
 Simultaneously, there is thickening of the tubular
basement membranes.
2. Diffuse mesangial sclerosis
 This lesion consists of diffuse increase in mesangial
matrix.
 There can be mild proliferation of mesangial cells early in
the disease process, but cell proliferation is not a
prominent part of this injury.
 The mesangial increase is typically associated with the
overall thickening of the GBM.
 The matrix depositions are PAS-positive.
 As the disease progresses, the expansion of mesangial
areas can extend to nodular configuration.
 The progressive expansion of the mesangium has been
shown to correlate well with measures of deteriorating
renal function such as increasing proteinuria.
Figure 17. Diabetic Glomerulosclerosis. The cortex in finely granular and there
is increase in adipose tissue in the renal pelvis. There seems to be pitted
triangular scars indicating probable chronic pyelonephritis which is an
important complication of diabetic mellitus.
Figure 18. Diabetic Glomerulosclerosis. There is diffuse increase in mesangial
matrix and characteristic acellular PAS-postive areas. Capillary loops are pinkish
and almost hypocellular; there is thickening of the Bowman’s capsule; the
arteriole is also thickened.
3. Nodular glomeruloscerosis
 This is also known as intercapillary glomerulosclerosis or
Kimmelstiel-Wilson disease.
 Due to non-enzymatic glycosylation of proteins causing an
increase in the mesangial matrix.
 The glomerular lesions take the form of ovoid or spherical,
often laminated, nodules of matrix situated in the
periphery of the glomerulus.
 The nodules are PAS-positive.
 Surrounded by patent peripheral capillary loops.
 At advanced stages, nodules may enlarge and compress
capillaries thereby obliterating tuft.
PATHOLOGY 6.3
 These nodular lesions are frequently accompanied by
prominent accumulations of hyaline material in capillary
loops (“fibrin caps”) or adherent Bowman’s capsules
(“capsular drops”).
 Afferent and efferent glomerular hilar arterioles show
hyalinosis.
 As a consequence of glomerular and arteriolar lesions, the
kidney suffers from ischemia, develops tubular atrophy
and interstitial fibrosis, and undergoes overall contraction
in size.
Figure 19. Nodular Glomerulosclerosis aka Kimmelstiel-Wilson disease (KW
lesion). Presence of pink hyaline nodules - due to increase in mesangial matrix;
non-enzymatic glycosylation of proteins.
4. Renal atherosclerosis and arteriosclerosis
 Hyaline arteriosclerosis affects both afferent and efferent
arterioles.
5. Pyelonephritis
 Acute or chronic inflammation of the kidneys that usually
begins in the interstitial tissue and then spreads to affect
the tubules.
 Common complication of renal diabetes
 Most are chronic because patients with diabetes are more
prone to infection
 Frequent complication of DM – since diabetics are prone
to infection due to decrease in the number and function
of lymphocytes and macrophages.
6. Papillary Necrosis
 Special pattern of acute pyelonephritis.
 Much more prevalent in diabetics than in nondiabetics
Figure 20. Papillary Necrosis. Pelvicalyceal system appears distorted and there
is fat deposition which results to the triangular shaped infarcts; The surface of
the kidney has indistinct corticomedullary markings; There is papillary necrosis,
the normal triangular appearance of papillary pyramids are gone because it is
affected by papillary necrosis.
C. Cardiovascular system
1. Atherosclerosis
 In diabetes there is accentuation or acceleration of the
atherosclerosis so that initially there is deposition of
cholesterol in the intima of blood vessels especially the
arteries and this eventually will form streaks, plaques, and
there will be complication of the plaques in the form of
ulceration, etc and is prone to thrombus formation.
 Affects vessels of all sizes but is most often macrovascular.
Page 7 of 14
 PATHOLOGY 6.3
 Pathogenesis is multifactorial:
o hyperlipidemia, qualitative changes in lipoproteins due
to increased non-enzymatic glycosylation affect
turnover and tissue deposition, low HDL levels in type 2
DM.
o Inc. platelet adhesion due to inc. thromboxane A2
synthesis and dec. prostacyclin, inc. incidence of HPN.

Figure 23. Diabetic retinopathy. (exudates - yellowish areas, small

hemorrhages - brown areas, most likely there are aneurysms but they cannot be
appreciated here)

Figure 21. Shows presence of atheromatous plaques and ulcerations. A rough

intima will lead to thrombogenesis which can lead to MI or gangrene in the
lower extremities.

2. Myocardial infarction and peripheral vascular insufficiency

gangrene of the lower extremities
 Caused by atherosclerosis of the coronary arteries.
 Most common cause of death in diabeteics.
3. Hyaline arteriosclerosis
 The vascular lesion associated with hypertension. Figure 24. Proliferative diabetic retinopathy (there are many blood vessels)
 Prevalent in both diabetics and non-diabetics.
 It takes the form of an amorphous, hyaline thickening of the
wall of the arterioles, which causes narrowing of the lumen.
 It is related to the chronicity of the disease and the
individual’s blood pressure.
4. Diabetic microangiopathy
 Diffuse thickening of capillary basement membranes (a
consistent morphologic feature of diabetes).
 Evident in capillaries of skin, skeletam muscle, retina, renal
glomeruli, and renal medulla.
 Underlies diabetic nephropathy and some neuropathy. Figure 25. Glaucoma with marked cupping of the optic disc.
 Due to nonenzymatic glycosylation of membrane protein.
 It should be noted that despite increase in thickness of the
basement membrane, diabetic capillaries are more leaky
than normal to plasma proteins. The microangiopathy
underlies the development of diabetic nephropathy,
retinopathy, and some forms of neuropathy.
D. Eyes
 Diabetes in an important cause of blindness.
1. Cataract formation due to sorbitol accumulation in lens.
2. Diabetic retinopathy
o Retinal exudates, edema, hemorrhages, and
microaneurysms of small blood vessels. Figure 26. Glaucoma with excavation of the optic disc.
o Two types:
 Proliferative retinopathy (usually leads to blindness).
 Non-proliferative retinopathy.
3. Glaucoma

Figure 27. Cataracts (sorbitol accumulation in the lens so it becomes thick and
white)

E. Nervous system
Figure 22. Normal retina on funduscopic examination.  Peripheral neuropathy (both somatic and sensory).
 Changes in the brain and spinal cord.
 Most frequent pattern is a peripheral, symmetric neuropathy of
lower exts. that affects both motor and sensory function.
Page 8 of 14
 PATHOLOGY 6.3
 Over half of gastrin producing tumors are locally invasive or
F. Liver have already metastasized at the time of diagnosis.
 Fatty Change  Associated with Zollinger-Ellison syndrome characterized by:
G. Skin o Marked gastric hypersecretion of HCL.
1. Xanthomas (collection of lipid-laden macrophages in the o Recurrent peptic ulcer (multiple duodenal, gastric and even
dermis). jejunal ulcers).
2. Furuncles and abscesses because of increased propensity to o Hypergastrinemia.
infection; frequent fungal infections, especially with Candida sp.

C. Causes of Death in Diabetes Mellitus

 In decreasing order of frequency:
1. myocardial infarction
2. renal failure
3. CVA
4. infections
5. ketoacidosis and hyperosmolar coma
Figure 30. Islet cell adenoma (Left) and Normal pancreas with islets (Right). If
V. PANCREATIC ENDOCRINE TUMORS insulin is produced  hypoglycemia. If gastrin is produced  multiple gastric
(ISLET CELL TUMORS) and duodenal ulcerations (Zollinger-Ellison syndrome).
A. Insulinoma (Cell tumor)
 most common islet cell tumor. VI. ADRENAL GLANDS
 may be benign or malignant.  Weighs 4-6 grams
 markedly increased secretion of insulin & circulating C-  These glands are also called suprarenal glands due to their
peptides (“hyperinsilunemia”). position in relation to the kidneys.
 characterized by Whipple’s Triad:  Cortex – yellowish peripheral layer.
O Episodic hypoglycaemia. o Synthesize three different steroids.
O Central nervous system (CNS) dysfunction temporally o Mineralocorticoids – most important of which is
related to hypoglycemia (confusion, anxiety, stupor, aldosterone; produced in the zona glomerulosa.
convulsions, coma). o Glucocorticoids – principally cortisol; produced in the zona
O Dramatic reversal of CNS abnormalities by glucose fasciculata; to a lesser degree of this is also synthesized in
administration. the zona reticularis.
o Sex steroids – estrogens and androgens; produced in the
zona reticularis.
 Medulla - reddish brown central layer.

Figure 31. Adrenal glands. Each weighing 4-6 grams and their colors vary
Figure 28. Insulinoma (cell tumor). Usually small, often <2cm, encapsulated,
from yellow to yellow orange.
pale to red brown nodules located anywhere in the pancreas.

VII. ADRENAL ENDOCRINE SYNDROMES

Figure 29. Insulinoma (Cell Tumor). Histologically, Insulinomas appear as giant
Islet’s, with monotonous cell appearance, intact cord arrangement and
vasculature. Desposition of amyloid extracellularly is a characteristic feature.
The Immunohistochemical stain for insulin in the islet cell adenoma shows
brown areas that indicate the presence of insulin.
B. Gastrinoma
 Often malignant
 May arise in the pancreas, peripancreatic region or the wall of
the duodenum (“gastrinoma triangle”).
A. Cushing Syndrome
 Characterized by excess of cortisol or glucocorticoid levels which
may be adrenal or pituitary in origin
 Usual Anatomic Lesion: mostly due to bilateral hyperplasia of
adrenal zona fasciculata secondary to hyperactivity of pituitary
corticotrophs or to ectopic ACTH-like production by a variety of
tumors (e.g. adrenal cortical adenoma)
 Divided into two causes: exogenous and endogenous
 Vast majority of this case is due to administration of exogenous
glucocorticoids (“iatrogenic” Cushing syndrome).
o Exogenous glucocorticoids inhibit normal adrenal function
causing atrophy of bilateral adrenal cortex.
 Endogenous causes are either ACTH dependent or ACTH
independent.
Page 9 of 14

o 70% of cases of endogenous hypercortisolism are due to
ACTH-secreting pituitary adenomas which cause bilateral
nodular cortical hyperplasia and elevated levels of ACTH.
o Secretion of ectopic ACTH by non-pituitary tumors (usually
small cell carcinoma of the lung, medullary thyroid carcinoma
and islet cell tumors) account for 10% of ACTH dependent
Cushing syndrome.
 Adrenal glands undergo bilateral cortical hyperplasia.
o Primary adrenal neoplasms, such as adrenal adenoma (10%)
and carcinoma (5%), are the common causes of ACTH-
independent Cushing syndrome.
 Biochemical sine qua non: elevated serum cortisol and
low ACTH.
 If the neoplasm is unilateral, the other adrenal gland
undergoes cortical atrophy due to suppression of ACTH
secretion from the pituitary.
Figure 32. Section of an Adrenal Gland with a Mass. Pink circle – normal color of
the adrenals. Green oval – points to the mass which is yellow brown in color
B. Hyperaldosteronism
 Generic term for conditions characterized by excess aldosterone
secretion; can be primary or secondary.
1. Primary Hyperaldosteronism
 There is decreased plasma renin activity due to autonomous
overproduction of aldosterone.
 Common manifestiation is elevated blood pressure, which is
caused by one of the three mechanisms:
o Bilateral idiopathic hyperaldosteronim (IHA)
 Characterized by bilateral nodular hyperplasia of the
adrenal glands and is the most common underlying cause
of primary hyperaldosteronims comprising 60% of the
cases.
o Adrenocortical neoplasm
 This is either an aldosterone producing adenoma (most
common) or adreno-cortical carcinoma (rare).
o Conn syndrome
 Solitary aldosterone secreting adenoma comprising 35%
of cases of primary hyperaldosteronism. This occurs
mostly in women than in men (ration 2:1).
C. Adrenal Virilism (Adrenogenital Syndrome)
Figure 33. Conn’s syndrome. Bright yellow, solitary, solid, small (<2cm) well
circumscribed lesion buried in the gland and do not produce visible enlargement.
Characteristic feature: spironolactone bodies – eosinophilic laminated
cytoplasmic inclusions found after treatment of anti-hypertensive drug
spironolactone.
PATHOLOGY 6.3
o Glucocorticoid-remediable hyperaldosteronism
 uncommon cause of primary familial hyperaldosteronism.
2. Secondary Hyperaldosteronism
 Aldosterone release occurs in response to activation of the
renin-angiotensin system.
 Plasma renin level is increased.
 Encountered in decreased renal perfusion, arterial
hypovolemia & edema, and pregnancy (due to estrogen
induced increase in plasma renin substrate).
 Morphology
o Aldosterone producing adenoma
 Always solitary, small (<2cm diameter), well
circumscribed lesions, more often found on the left
than on the right.
 Occurs between 30 and 40 y/o.
 Lesions are buried within the gland and do not produce
visible enlargement.
 Bright yellow on cut section.
 Composed of lipid laden cortical cells that more closely
resemble fasciculate cells than glomerulosa cells.
 Cells are uniform in size and shape and resemble
mature cortical cells
 Characteristic feature – spironolactone bodies;
eosinophilic, laminated cytoplasmic inclusion; found
after treatment with the anti-hypertensive drug
spironolactone.
o Bilateral idiopathic hyperplasia
 Diffuse and focal hyperplasia of the cells.
 Wedge shaped extending from the periphery toward
the center of the gland.
 Clinical course
o Hypertension.
o Long term effects of hyperaldosteronism – cardiovascular
compromise and increase in myocardial infarction and
stroke.
o Hypokalemia – mandatory feature but increasing numbers
of normokalemic patients are now diagnosed. This results
from renal potassium wasting and can cause a variety of
neuromuscular manifestations like weakness,
paresthesias, visual disturbances and frank tetany.
 Diagnosis
o Elevated ratios of plasma aldosterone concentration to
plasma renin activity.
o Aldosterone suppression test.
 Treatment
o Adenomas – surgical excision.
o Primary hyperaldosteronism d/t bilateral hyperplasia –
aldosterone antagonist such as spironolactone.
o Secondary hyperaldosteronism – correcting the underlying
cause that stimulates the renin-angiotensin system.
 Disorders of sexual differentiation, such as virilization or
feminization, can be caused by primary gonadal disorders,
several primary adrenal disorders and congenital adrenal
hyperplasia.
 In contrast to gonadal androgens, ACTH regulates adrenal
androgen formation thus, excess secretion can occur either as
a “pure” syndrome or as a component of Cushing disease.
 Due to adenoma, carcinoma or hyperplasia of zona reticularis
which causes Virilism in females and Precocious puberty in
males.
Page 10 of 14

 Adrenal hyperplasia from congenital enzyme deficiencies (21-
hydroxylase and 11-hydroxylase).
 There may be salt-wasting, hyponatremia, hyperkalemia and
hypotension due to lack of aldosterone production.
 There may be genital ambiguity, hirsutism, acne formation and
menstrual irregulatiries due to increased production of
testosterone in female patients.
D. Hypocorticism
 Also known as adrenocortical insufficiency or hypofunction of the
adrenals.
 Idiopathic adrenal atrophy
o Probably autoimmune etiology.
o Most common cause of Addison’s disease.
 Infection
o Waterhouse-Friderichsen syndrome.
 Adrenocortical Insufficiency or hypofunction.
 May be caused by primary adrenal disease (primary
hypoadrenalism).
 Decreased stimulation of the adrenals due to a deficiency of ACTH
(secondary hypoadrenalism)
VIII. TUMORS OF THE ADRENAL CORTEX
PF notes!!!
According to Robbin’s, Addison’s Disease and Waterhouse
Friedrichsen Syndrome are classified under Adrenocortical
Inssuficiency Syndromes. However in Dr. Bailon’s PPT, she
classified them as tumors. IDK WHY SHE DID THAT.
Tumors discussed by Robbin’s are:
Adrenocortical adenoma – usually clinically silent if non-
functional; functional adenomas may cause atrophy of the
unaffected ardrenal; it is a well-circumscribed nodular lesion
composed of cells similar to a normal adrenal cortex.
Adrenocortical carcinoma – usually functional, associated
with virilism and hyperadrenalism; large invasive lesions that
efface the adrenal gland with foci of haemorrhage, necrosis
and cystic change; strong tendency to invade adrenal vein,
vena cava and lymphatics.
A. Addison’s Disease
 A constellation of symptoms including “general languor and
debility, remarkable feebleness of the heart’s action, and a peculiar
change in the color of the skin.”
 A form of chronic adrenocortical insufficiency resulting from
progressive destruction of the adrenal cortex.
 Clinical manifestations do not appear until 90% compromise of
adrenal cortex.
 90% of all cases are attributable to: autoimmune adrenalitis (most
common), TB, AIDS, and metastatic cancers (usually lung and
breast).
 Manifestations include: Hypotension, Increased skin pigmentation,
Decreased serum Na, Cl, HCO3, and glucose, Increased serum K, and
gastrointenstinal disturbances.
o Hyperpigmentation is due to elevated levels of POMC which is
the precursor to ACTH and MSH.
PATHOLOGY 6.3
Figure 34. Addison’s disease. Adrenal atrophy (with either Addison’s disease or
long term corticosteroid therapy). Adrenals at the bottom with bilateral cortical
hyperplasia due to pituitary adenoma secreting ACTH (Cushing’s syndrome) from
ectopic ACTH production or idiopathic adrenal hyperplasia.
Primary Autoimmune cause of Addison’s show irregularly shrunken glands with
variable lymphoid infiltrate.
Metastatic carcinomas cause enlarged adrenal glands but with structure
obscured by the neoplasm.
B. Waterhouse-Friderichsen Syndrome
 It is more common in children, with an abrupt and devastating
clinical course.
 Overwhelming bacterial infection (Neisseria meningitidis,
Pseudomonas species, pneumococci, Haemophilus influenzae,
staphylococci)
 Rapidly progressing hypotension leading to shock.
 Rapidly developing adrenocortical insufficiency associated with
massive bilateral adrenal haemorrhage.
 Adrenal hemorrhage results from direct bilateral seeding of small
vessels in the adrenal, development of DIC, endotoxin induced
vasculitis, and hypersensitivity vasculitis.
IX. TUMORS OF THE ADRENAL MEDULLA
Adrenal Medulla
 Developmentally, functionally, and structurally distinct from the
adrenal cortex.
 Composed of specialized neural crest (neuroendocrine) cells,
termed chromaffin cells, and their supporting (sustentacular) cells.
 It is the major source of catecholamines (i.e. epinephrine,
norepinephrine) in the body.
A. Pheochromocytoma
 Chromaffin cell tumor that secretes cathecholamines & causes
hypertension.
 Paraganglioma if the source is from extra-adrenal chromaffin
cells.
 Often benign; 10% are malignant.
 Uncommon but important cause of surgically correctible HPN.
 Can be part of MEN type IIA or type IIB.
 Associated with neurofibromatosis / von Hippel-Lindau disease.
Figure 35. Pheochromocytoma. The tumor is enclosed within an attenuated
cortex and demonstrates areas of hemorrhage. On cut section, the surfaces are
yellow-tan. Larger lesions tend to be hemorrhagic, necrotic, and cystic and
typically efface the adrenal gland. Incubation of fresh tissue with a potassium
dichromate solution turns the tumor a dark brown color due to oxidation of
stored catecholamines, thus the term chromaffin.
Page 11 of 14
 PATHOLOGY 6.3
 Clinical Manifestations: granules containing catecholamines. The nuclei are usually round to ovoid, with
o Dominant clinical manifestation is hypertension, observed in a stippled “salt and pepper” chromatin that is characteristic of neuroendocrine
90% of patients. tumors.
o Approximately two thirds of patients with hypertension
demonstrate paroxysmal episodes, which are described as an
abrupt, precipitous elevation in blood pressure, associated with
tachycardia, palpitations, headache, sweating, tremor, and a
sense of apprehension.
o These episodes may also be associated with pain in the
abdomen or chest, nausea, and vomiting.
o Isolated paroxysmal episodes of hypertension occur in fewer
than half of patients; more commonly, patients demonstrate
chronic, sustained elevation in blood pressure punctuated by
the aforementioned paroxysms.
o Paroxysms may be precipitated by emotional stress, exercise, Figure 38. Electron micrograph of pheochromocytoma. Tumor contains
membrane-bound secretory granules in which catecholamines are stored.
changes in posture, and palpation in the region of the tumor.
Immunoreactivity for neuroendocrine markers (chromogranin and
o Patients with urinary bladder paragangliomas occasionally synaptophysin) is seen in the chief cells, while the peripheral sustentacular cells
precipitate a paroxysm during micturition. stain with antibodies against S-100, a calcium-binding protein expressed by a
o Elevations of blood pressure are induced by the sudden release variety of mesenchymal cell types.
of catecholamines that may acutely precipitate congestive heart
failure, pulmonary edema, myocardial infarction, ventricular
fibrillation, and cerebrovascular accidents.
o Cardiac complications have been attributed to what has been
called as catecholamine cardiomyopathy, or catecholamine-
induced myocardial instability and ventricular arrhythmias.
o Nonspecific myocardial changes, such as focal necrosis,
mononuclear infiltrates, and interstitial fibrosis, have been
attributed either to ischemic damage secondary to the
catecholamine-induced vasomotor constriction of the
myocardial circulation or to direct catecholamine toxicity.
o In some cases pheochromocytomas secrete other hormones,
such as ACTH and somatostatin, and may therefore be
associated with clinical features related to the secretion of these
or other peptide hormones. Figure 39. Pheochromocytoma. Tumor is composed of sheets/islands of tumor
cells (zellballen) which are polyhedral with eosinophilic cytoplasm separated by
vascular sinusoids. The tumors are composed of polygonal to spindle-shaped
chromaffin cells or chief cells, clustered with the sustentacular cells.

 Diagnosis:
Figure 36. Pheochromocytoma (below) and normal adrenal glands (on top).
Tumor ranges from small, circumscribed lesions confined to large hemorrhagic
masses weighing kilograms. The average weight of a pheochromocytoma is 100
gm. The larger tumors are well demarcated by either connective tissue or
compressed cortical or medullary tissue. Richly vascularized fibrous trabeculae
within the tumor produce a lobular pattern. In many tumors, remnants of the
adrenal gland can be seen, stretched over the surface or attached at one pole.
Figure 37. Pheochromocytoma. The cytoplasm has a finely granular
appearance, best demonstrated with silver stains, due to the presence of
o Increased urinary excretion of metanephrine and VMA
(vanillylmandelic acid) which are metabolites of
catechomamines.
o Increased plasma & urinary excretion of free catecholamines.
o Malignancy: distant metastases (most common on the liver).
o There is no histologic feature that reliably predicts clinical
behavior. Several histologic features, such as numbers of
mitoses, confluent tumor necrosis, and spindle cell morphology,
have been associated with an aggressive behavior and increased
risk of metastasis, but these are not entirely reliable.
o Tumors with “benign” histologic features may metastasize,
while bizarrely pleomorphic tumors may remain confined to the
adrenal gland.
o In fact, cellular and nuclear pleomorphism, including the
presence of giant cells, and mitotic figures are often seen in
benign pheochromocytomas, while cellular monotony is
paradoxically associated with an aggressive behavior. Even
capsular and vascular invasion may be encountered in benign
lesions.
o The definitive diagnosis of malignancy in pheochromocytomas
is based exclusively on the presence of metastases. These may
involve regional lymph nodes as well as more distant sites,
including liver, lung, and bone.
Page 12 of 14
 PATHOLOGY 6.3

Figure 42. Neuroblastoma. Spontaneously regress, leaving only a focus of

Figure 40. Pheochromocytoma demonstrating characteristic nests of cells
(“zellballen”) with abundant cytoplasm. Granules containing catecholamine are
not visible in this preparation. It is not uncommon to find bizarre cells even in
pheochromocytomas that are biologically benign.
 Treatment
o Surgical removal of tumor.
fibrosis or calcification in the adult.
Some neuroblastomas are often sharply demarcated by a fibrous pseudo-
capsule, but others are far more infiltrative and invade surrounding structures,
including the kidneys, renal vein, and vena cava, and envelop the aorta.
On transection, they are composed of soft, gray-tan, tissue. Larger tumors have
areas of necrosis, cystic softening, and hemorrhage. Occasionally, foci of
punctate intra-tumoral calcification can be palpated.
o Histologic/Microscopic Appearance:
Homer-Wright rosettes

B. Neuroblastoma
 Includes tumors of sympathetic ganglia and adrenal medulla.
 3rd most common extracranial malignant neoplasm of childhood
(80% < 5 yrs of age), median age of diagnosis at 18 months.
 Originate from primitive neural crest cells.
 Characterized by amplification of the N-myc oncogene.
 Most cases present as an abdominal mass.
 Hematogenous metastasis occurs early to bone (Hutchinson
type), and liver (Pepper type).
Figure 43. Neuroblastoma is composed of small, primitive-appearing cells with
 Extensive bone marrow involvement common. dark nuclei, scant cytoplasm, and poorly defined cell borders growing in solid
 Demonstrate certain characteristic features including sheets. Tumor cells are concentrically arranged about a central space filled with
spontaneous or therapy-induced differentiation of primitive neuropil (eosinophilic fibrillary material) thus forming the Homer-Wright
neuroblasts into mature elements, spontaneous tumor rosette.
regression, and a wide range of clinical behavior and prognosis,
which often mirror the extent of histologic differentiation.
 Germline mutations in the anaplastic lymphoma kinase (ALK)
gene have recently been identified as a major cause of familial
predisposition.
 Despite the remarkable progress made in the therapy of this
disease, long-term prognosis for the high-risk subsets remains
modest, with a 5-year survival in the range of 40%.
 Disseminated neuroblastomas may present with multiple
cutaneous metastases that cause deep blue discoloration of the
skin (“blueberry muffin baby”). Figure 44. Adrenal neuroblastoma. This tumor is composed of small cells
 Age and stage are the most important determinants of outcome. embedded in a finely fibrillar matrix.
 Diagnosis o Electron Microscope
o Gross Appearance  Dense-core neurosecretory granules
 Large, soft, hemorrhagic masses

Figure 45. Fluorescence in situ hybridization using a fluorescein-labeled

cosmid probe for N-myc on a tissue section. Amplification of the N-MYC
oncogene has the most profound impact on prognosis.
Figure 41. Neuroblastoma. Large hemorrhagic mass that pushes the liver to the
contralateral side. PF: C. Legaspi
Page 13 of 14
 PATHOLOGY 6.3

III. APPENDIX

Figure 9. Genetic Susceptibility and Environmental Factors in playing a role in the pathogenesis of type 1 Diabetes Mellitus. The most important is the contribution
of the HLA locus on chrom 6p21.

Page 14 of 14