Pathology (dr.

Yabut) Endocrine Pathology Part 3 (from Book) 09 January 0 ADRENAL INSUFFICIENCY (AI) Primary adrenal disease ( primary hypoadrenalism) Decreased stimulation of the adrenals owing to a deficiency of ACTH (secondary hypoadrenalism) !) "ater#ouse$Frideric#sen Syndro e

,ncommon but catastrophic syndrome Characteristics' -. %erwhelming bacterial infection ,sually associated with Neisseria meningitides septicemia ccasionally by highly %irulent organisms' Pseudomonas, pneumococci# Haemophilus influenza, or staph

Patterns of Adrenal Insufficiency 1) Pri ary Acute AdrenocorticalInsufficiency Caused by any lesion of the adrenal cortex that impairs corticosteroid production or may be secondary to corticotrophin deficiency ccur as a crisis in patients with chronic adrenocortical insufficiency precipitated by any form of stress ! immediate increase in steroid output from glands incapable of responding "n patients maintained on exogenous corticosteroids# owing to the inability of the atrophic adrenals to produce glucocortioid hormones $esult of massi%e adrenal hemorrhage# which destroys the adrenal cortex sufficiently to cause acute adrenal insufficiency ccurs in newborns following prolonged and difficult deli%ery with considerable trauma and hypoxia &ewborns are %ulnerable because they are often deficient in prothrombin Also occurs in' Patients maintained on anticoagulation therapy Postsurgical patients who de%elop D"C with conse(uent hemorrhagic infarction o the adrenals )aterhouse!*riderichsen +yndrome

/.$apidly progressi%e hypotension leading to shoc0 1.D"C with widespread purpura 2 +3"& 4.$apidly de%eloping adrenocortical insufficiency associated with massi%e bilateral adrenal hemorrhage ccurs at any age 2 5,T more common in children Adrenal hemorrhage is uncertain but could be attributable to' -.Direct bacterial seedling of small %essels in the adrenal /.De%elopment of D"C 1.6ndotoxin!induced %asculitis 4.+ome form of hypersensiti%ity %asculitis Whatever the basis, the adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail 7orphology' massi%e# bilateral adrenal hemorrhage# which begins in the medulla Histologic exam'

Pwets

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Pathology Endocrine Pathology by Dr. Yabut Hemorrhage starts within the medulla " relationships to thin! walled %enous sinusoids suffuses peripherally in the cortex lea%ing islands of recogni9able cortical cells Clinical course is usually de%astatingly abrupt# and prompt recognition and appropriate therapy must be instituted immediately# or death follows within hours to a few days i.

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Autoimmune polyendocrine syndrome type - (AP+-) Also 0nown as autoimmune polyendocrinopathy# candidiasis# and ectodermal dystrophy (AP6C6D) Characteri9ed by chronic mucocutaneous candidiasis and abnormalities of s0in# dental enamel# and nails (ectodermal dystrophy) ccurring in association with a combination of organ!specific autoimmune disorders resulting in immune destruction of target organ a. Autoimmune adrenalitis Autoimmune hypoparathyr oidism "diopathic hypogonadis m Pernicious anemia

%) Addison Disease& Pri ary C#ronic Adrenocortical Insufficiency ,ncommon disorder Progressi%e destruction of the adrenal cortex Clinical manifestations appears until at least :8; of the adrenal cortex has been compromised All races and both sexes may be affected Certain cause of Addison (such as autoimmune adrenalitis) are much common in whites# particularly in women Pathogenesis' :8; of all cases are attributable to one of four disorders' -. Autoimmune adrenalitis <8; to =8; of cases of Addison disease 7ost common cause of primary A" in de%eloped countries Autoimmune destruction of steroidogenic cells Autoantibodies to se%eral 0ey steroidogenic en9ymes (/-!hydroxylase# -=!hydroxylase) are detected in these patients ccurs in 1 clinical settings'

b.

c.

d.

Caused by mutations in the autoimmune regulator (A"$6) gene on chromosome /-(//

ii.

Autoimmune polyendocrine syndrome type / (AP+/) +tarts in early adulthood

Pathology Endocrine Pathology by Dr. Yabut Presents as a combination of A" with autoimmune thyroiditis or type diabetes Characteristics of AP+- do not occur ,nli0e AP+-# it is not a monogenic disorder# although some studies ha%e suggested a possible association with polymorphisms in the H>A loci

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Disseminated infections caused by Histoplasma capsulatum and Coccidioides immitis may result in Adisson disease Patients with A"D+ are at ris0 for de%eloping A" from se%eral infections (C7?# Mycobacterium aviumintercellulare) and non!infectious complications (3aposi sarcoma) Metastatic neoplasms in%ol%ing the adrenals are another potential cause of A" Adrenals are a fairly common site for metastases in patients with disseminated carcinomas ! destroy enough adrenal cortex to produce a degree of A" Carcinomas of the lung and breast are source of a maAority of metastases in the adrenals# although many other neoplasms# including B" carcinomas# malignant melanoma# and hematopoietic neoplasms# may also metastasi9e to this organ

iii.

"solated autoimmune Addison disease Presents with autoimmune destruction restricted to the adrenal glands %erlaps with AP+/ in terms of age and lin0age to H>A and other susceptibility loci ?ariant of AP+/

enetic disorders of !I "ncludes adrenal hypoplasia congenital (AHC) and adrenoleu0odystrophy &ot commonly included in the causes of Addison disease

Infections# particularly tuberculosis and those produced by fungi may cause Addison Tuberculous adrenalitis 2 once accounted for as much as :8; of Addison@ become less common with de%elopment of antituberculous agents )ith resurgence of tuberculosis in most urban centers and the persistence of the disease in de%eloping countries# howe%er# this cause of A" must be 0ept in mind )hen present# tuberculous adrenalitis is associated with acti%e infection in other sites 2 lungs and genitor!urinary tract

7orphology' Depends on the underlying disease AP+- 2 characteri9ed by irregularly shrun0en glands which is difficult to identify within the suprarenal adipose tissue Histologically' cortex contains only scattered residual cortical cells in a collapsed networ0 of connecti%e tissue@ a %ariable lymphoid infiltrate is present in the cortex and may extend into the subAacent medulla

Pathology Endocrine Pathology by Dr. Yabut "n cases of tuberculous and fungal disease 2 adrenal architecture is effaced by a granulomatous inflammatory reaction identical to that encountered in other sites of infection Caused by metastatic carcinoma 2 adrenals are enlarged# and their normal architecture is obscured by the infiltrating neoplasm !utoimmune adrenalitis 2 usually produces small glands# lipid depletion of adrenal cortex# and a %ariable lymphocytic infiltrate in cortex@ medulla is spared Clinical course' "ncludes wea0ness# fatigue# anorexia# hypotension# nausea# %omiting and cutaneous hyperpigmentation >aboratory %alues include ele%ated le%els of corticotrophin# hyper0alemia# and hyponatremia# associated with %olume depletion and hypotension ') Secondary Adrenocortical Insufficiency Caused by any disorder of the hypothalamus or pituitary causing a decreased corticotrophin production With secondary disease, the hyperpigmentation of primary !ddison disease is lac"ing because melanotropic hormone levels are lo# Characteri9ed by deficient cortisol and androgen output but normal or near! normal aldosterone le%els +e%er hyponatremia and hyper0alemia are & T features of /o adrenocortical insufficiency Corticotrophin deficiency may be isolated or associated with hypopituitarism 7orphology' %ariable degrees of atrophy of the adrenal cortex# with sparing of the zona glomerulosa and medulla

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$unctional and nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of morphologic features 7orphology' Adrenal adeno as 2 clinically silent

Typical cortical adenomas are well!circumscribed# nodular lesion up to /.Ccm in diameter that expands the adrenal "nc contrast to functional adenomas# which are associated with atrophy of the adAacent cortex# the cortex adAacent to nonfunctional adenomas is of normal thic0ness Dellow to yellow!brown on cut surface 2 presence of lipid within tumor cells 7icroscopically' composed of cells similar to those populating the normal cortex@ nuclei small# although some degree of pleiomorphism may be encountered e%en in benign lesions (Eendocrine atypiaF)@ cytoplasm of the neoplastic cells ranges from eosinophilic to %acuolated# depending on lipid content@ mitotic acti%ity is inconspicuous as 2 rare

Adrenocortical carcino

ccur at any age more li0ely to be functional than adenomas associated with %irilism or other clinical manifestations of hyperadrenalism two rare inherited causes' >i! *raumeni syndrome and 5ec0with!)iedermann syndrome large# in%asi%e lesions# may exceed /8 cm in diameter# that efface the nati%e adrenal gland typically %ariegated# poorly demarcated lesions containing

ADRENAL NE(PLAS)S

Pathology Endocrine Pathology by Dr. Yabut areas of necrosis# hemorrhage# and cystic change in%asion of contiguous structures# including the adrenal %ein and "?C# is common microscopically' well! differentiated cells resembling those seen in cortical!adenomas or bi9arre# monstrous giant cells@ cancers with moderate degrees of anaplasia# some composed predominance of spindle cells@ they may be difficult to differentiate from metstatic cells commonly in%ade the adrenal %ein# %ena ca%a# and lymphatics# with metastases to regional and periaortic lymph nodes and to %iscera# especially lung

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7ost important diseases of the adrenal medulla are neoplasms 1, P+E(C+R()(CY*()A (PC)) ,ncommon neoplasms composed of chromaffin cells Associated with catecholamine production and hypertension (account for 8.-;!8.1; of all cases of hypertension ,sually subscribe to a con%enient Erule of -8sF &'( of PCM arise in association #ith one o several familial syndromes 2 includes 76&!/A and 76&/5 syndromes# type neurofibromatosis# %on! Hippel >indau syndrome and +turge!)eber syndrome &'( of PCM are e)tra! adrenal 2 occurs in sites such as the organ of Guc0er0andl and the carotid body ,sually called paragangliomas

(*+ER LESI(NS (F *+E ADRENAL Ad%ancements in medical imaging and greater utili9ation of abdominal CT scans ha%e led to the incidental disco%ery of adrenal masses in asymptomatic indi%iduals !drenal myelolipomas % unusual benign lesions composed of mature fat and hetopoietic cells Histology' mature adipocytes are admixed with aggregates of hetopoietic cells belonging to all three lineages@ foci of myelolipomatous change may be seen in cortical tumors and in adrenals with cortical hyperplasia

&'( of nonfamilial adrenal PCM are bilateral 2 may rise to =8; in cases that are associated with familial syndromes &'( of adrenal PCM are biologically malignant, although the associated hypertension represents a serious and potentially lethal complication of e%en EbenignF tumors *ran0 malignancy ! more common (/8!48;) arising in extra!adrenal sites

!drenal incidentaloma % half!facetious moni0er that has crept into the medical lexicon as ad%ancements in medical imaging ha%e led to the incidental disco%ery of adrenal masses in asymptomatic indi%iduals Nonsecreting cortical adenomas

Adrenal )edulla Composed of speciali9ed neural crest cells (chromaffin cells) and their supporting (sustentacular) cells

&'( of adrenal pheochromocytomas

Pathology Endocrine Pathology by Dr. Yabut arise in childhood 2 usually familial subtypes 7H* &on!familial PC7 occurs in adults between 48!<8@ *H7

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atypical mitotic figures@ confluent (Esheetli0eF) tumor necrosis@ high cellularity and large tumor nest cells@ cellular monotony@ and spindle! cell morphology 7etastasis most commonly to lymph nodes# li%e# lung# and bones

7orphology' ?ary in si9e (-g !40g) Cut surface appears usually pale gray or brown Associated with hemorrhage# necrosis# or cystic change Highly %ascular Dichromate fixati%e ( e.g. Gen0er) causes it to turn brown!blac0 because of oxidation of catecholamines hence the term chromaffin

Clinical features' Hypertension 2 dominant clinical feature Abrupt# precipitous ele%ation in 5P# associated with tachycardia# palpitations# headache# sweating# tremor# and a sense of apprehension 7ay be assoc with organ dysfunction

7icroscope' Composed of polygonal to spindle!shaped chromaffin cells or chief cells Clustered with the sustentacular cells into small nests or al%eoli (9allballen)# by a rich %ascular networ0 Cellular and nuclear pleiomorphism (common) *here is no single histologic feature that can reliably predict clinical behavior in PCMs Aggressi%e tumor 2 large tumor@ extensi%e %ascular# capsular# or periadrenal adipose tissue in%asion@ inc. mitotic index (H1I-8hpf) or

Paroxysmal release of catecholamines Associated with episodic headache. Anxiety# sweating# tremor# %isual disturbances# abdominal pain# and nausea

Cardiac complications 2 due to ischemic myocardial damage /ndary to catecholamine! induced %asoconstriction catecholamine cardiomyopathy Dx' based on lab studies 2 measuring urinary catecholamine and their metabolites# plasma catecholamine assays#

Pathology Endocrine Pathology by Dr. Yabut and radiographic imaging studies *U)(RS (F E-*RA$ADRENAL PARA.AN.LIA PC7s that de%elop in paraganglia other than the adrenal medulla Arise in any organ that contains paraganglionic tissue Carotid body tumors 2 tumor arising in the carotid body Chemodectomas 2 originating in the Augulo! tympanic body Common in teens to /8s Multicentric (-C!/C;) Malignant (/8!48;) -8; metastasi9e widely 7orphology' ,sually firm -cm to <cm lesion iii. Densely adherent to adAacent tissues Composed of well!differentiated neuroendocrine cells arrayed in nests or cords Prominent fibro%ascular stroma i%. ii.

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preceded by an asymptomatic stage of endocrine hyperplasia in%ol%ing the cell of origin of the tumor Px with 76&!- syndrome de%elop %arying degrees of islet cell hyperplasia some progress to pancreatic tumors

More aggressive and recur

1, )EN$1 Wermer syndrome Characteri9ed by 1 PJs i. Parathyroid hyperplasia or multiple adenomas (:8!:C;) of cases 2 48 to C8 yIo Pancreatic lesions 2 endocrine tumors which may usually secrete a %ariety of peptide hormones (pancreatic peptide (most common)# gastrin and insulin (associated with clinical symptoms) Pituitary adenomas (-8!-C;) 2 usually prolactinoma Additional tumors include duodenal gastrinomas# carcinoid tumors# and thyroid and adrenocortical adenomas

7icroscope' may contain mitotic figures and may exhibit substantial pleiomorphism

6tiology 2 in%ol%es germ line mutations in the 76&!- gene on c!some --(--!-1 encoding for menin (<-8!a.a) Clinical manifestations 2 defined by the peptide hormones $ecurrent hypoglycemia in insulinomas and recurrent peptic ulcers in patients with gastrin! secreting neoplasms (Gollinger! 6llison syndrome)

)UL*IPLE END(CRINE NE(PLASIA ()EN) SYNDR()ES Broup of genetically inherited disease resulting in proliferati%e lesions (hyperplasia# adenomas# and carcinomas) of multiple organs Distinct features' younger age multiple endocrine organs# either synchronously (at the same time) or metachronously (at different times) multifocal

!, )EN$! +ubclassified into 1 distinct syndromes' M+N-,!, M+N-,-, and familial medullary thyroid cancer i, )EN$!A/ or Si00le syndro e

Pathology Endocrine Pathology by Dr. Yabut Characteri9ed by pheochromocytoma, medullary carcinoma, and parathyroid hyperplasia. 7edullary carcinomas of the thyroid occur in almost -88; of patients. They are usually multifocal and are %irtually always associated with foci of C! cell hyperplasia in the adAacent thyroid. The medullary carcinomas may elaborate calcitonin and other acti%e products and are usually clinically aggressi%e. 48 to C8; of patients with 76&!/A ha%e pheochromocytomas# which are often bilateral and may arise in extra! adrenal sites. As in the case of pheochromocytomas in general# they may be benign or malignant. -8 to /8; of patients ha%e parathyroid hyperplasia and e%idence of hypercalcemia or renal stones. clinically and genetically distinct from 76&!>in0ed to germ!line mutations in the $6T (rearranged during transfection) protooncogene on chromosome -8(--./. "n 76&!/A (as well as in 76&!/5)# germ!line mutations constituti%ely acti%ate the $6T receptor# resulting in gain of function. ii, )EN$!1

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significant clinical o%erlap with 76&!/A Patients de%elop medullary thyroid carcinomas# which are usually multifocal and more aggressi%e than in 76&!/A# and pheochromocytomas ,nli0e in 76&!/A# primary hyperparathyroidism is not present Accompanied by neuromas or ganglioneuromas in%ol%ing the s0in# oral mucosa# eyes# respiratory tract# and gastrointestinal tract# and a marfanoid habitus# with long axial s0eletal features and hyperextensible Aoints. A single amino acid change in $6T ($6T7et:-KThr)# appears to be responsible for %irtually all cases of 76&! /5 and affects a critical region of the tyrosine 0inase catalytic domain of the protein. edullary t#yroid

iii,

Fa ilial cancer

%ariant of 76&!/A There is a strong predisposition to medullary thyroid cancer but not the other clinical manifestations of 76&!/A or 76&!/5. 7aAority of cases of medullary thyroid cancer are sporadic# but as many as /8; may be familial. De%elop at an older age than those occurring in the full!blown 76&!/

Pathology Endocrine Pathology by Dr. Yabut syndrome and follow a more indolent course. 7orphology' Pineoblastomas

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6ncountered mostly in the first two decades of life appear as soft# friable# gray masses punctuated with areas of hemorrhage and necrosis Typically in%ade surrounding structures# such as the hypothalamus# midbrain# and lumen of the third %entricle.

Histologically' they are composed of masses of pleomorphic cells /!4 times the diameter of an erythrocyte >arge hyperchromatic nuclei appear to occupy almost the entire cell# and mitoses are fre(uent. The cytology is that of primiti%e embryonal tumor (Lsmall blue cell neoplasmL) similar to medulloblastoma or retinoblastoma. Pineoblastomas# li0e medulloblastomas# tend to spread %ia the cerebrospinal fluid As might be expected# the enlarging mass may compress the a(ueduct of +yl%ius# gi%ing rise to "nternal hydrocephalus and all its conse(uences. +ur%i%al beyond - or / years is rare.

Pineal .land 7inute# pinecone!shaped organ -88 to -K8 mg lying between the superior colliculi at the base of the brain composed of a loose# neuroglial stroma enclosing nests of epithelial!appearing pineocytes# cells with photosensory and neuroendocrine functions (hence the designation of the pineal gland as the Lthird eyeL) +il%er impregnation stains re%eal that these cells ha%e long# slender processes reminiscent of primiti%e neuronal precursors intermixed with the processes of astrocytic cells.

Pat#olo2y All tumors in%ol%ing the pineal are rare "nclude both germ cell tumors (resembling those arising in the gonads) and neoplasms of pineal parenchymal origin

PINEACY()AS occur mostly in adults and are much slower!growing than pineoblastomas well!circumscribed# gray# or hemorrhagic masses that compress but do not infiltrate surrounding structures

PINEAL()AS Di%ided into two categories# pineoblastomas and pineocytomas# based on their le%el of differentiation# which# in turn# correlates with their neoplastic aggressi%eness

Pathology Endocrine Pathology by Dr. Yabut Histologically' may be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation composed largely of pineocytes ha%ing dar0ly staining# round!to!o%al# fairly regular nuclei &ecrosis is unusual# and mitoses are %irtually absent. neoplastic cells resemble normal pineocytes in their strong immunoreacti%ity for neuro!specific enolase and synaptophysin Particularly distincti%e are the 0ineocyto atous 0seudorosettes rimmed by rows of pineocytes The centers of these rosettes are filled with eosinophilic cytoplasmic material representing tumor cell processes. These cells are set against a bac0ground of thin# fibro%ascular# anastomosing septa# which confer a lobular growth pattern to the tumor Blial and retinal differentiation is detectable by immunoreacti%ity for glial fibrillary acidic protein and retinal +!antigen# respecti%ely.

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successful excision is at best difficult.

The clinical course of patients with pineocytomas is prolonged# a%eraging = years. The manifestations are the conse(uence of their pressure effects and consist of %isual disturbances# headache# mental deterioration# and sometimes dementia!li0e beha%ior. The lesions being located where they are# it is understandable that