Pathology (dr. Yabut) Endocrine Pathology – Part 3 (from 09 January 08
ADRENAL INSUFFICIENCY (AI)
Prima Primary ry adre adrena nall disea disease se ( prima primary ry hypoadrenalism)
2) Waterhous Waterhouse-F e-Frider riderichse ichsen n Syndrome Syndrome
Uncom Uncommon mon but but catast catastro rophi phic c syndro syndrome me
Char Charac acte teri rist stic ics: s:
Decreased Decreased stimulati stimulation on of the adren adrenals als owing owing to a deficiency of ACTH (secondary hypoadrenalism)
1.Overwhelming bacterial infection
Patterns of Adrenal Insufficiency
•
Usually associated with Neisseria meningitides meningitides septicemia
•
Occasionally by highly virulent organisms: Pseudomonas, pneumococci, Haemophilus influenza, or staph
1) Primary Primary Acute Adrenocort AdrenocorticalI icalInsuffi nsufficiency ciency
Caused Caused by by any any lesio lesion n of the the adr adrena enall cortex that impairs corticosteroid production or may be secondary to corticotrophin deficiency
Occur 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
2.Rapidly progressive hypotension leading to shock 3.DIC with widespread purpura – SKIN
In patie patients nts main maintai tained ned on on exoge exogeno nous us corticosteroids, owing to the inability of the atrophic adrenals to produce glucocortioid hormones Result Result of massi massive ve adre adrenal nal hemorr hemorrhage hage,, which destroys the adrenal cortex sufficiently to cause acute adrenal insufficiency Occurs
in newborns following prolonged and difficult delivery with considerable trauma and hypoxia
4.Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage
Occur Occurs s at any any age age – BUT BUT more more commo common n in children
Adrenal Adrenal hemorrh hemorrhage age is uncertai uncertain n but but could be attributable to: 1.Direct bacterial seedling of small vessels in the adrenal
Newborns
are vulnerable because they are often deficient in prothrombin
2.Development of DIC 3.Endotoxin-induced 3.Endotoxin-induced vasculitis
Also
occurs in:
•
•
•
Pwets
Patients maintained on anticoagulation therapy Postsurgical patients who develop DIC with consequent hemorrhagic infarction o the adrenals Waterhouse-Friderichsen Syndrome
4.Some form of hypersensitivity hypersensitivity vasculitis
Whatever the basis, the adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail
Morphol Morphology ogy:: massiv massive, e, bilate bilateral ral adrenal adrenal hemorrhage, which begins in the medulla
Hist Histol olog ogic ic exam exam::
1 of 10
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut Hemorrhage starts within the medulla I relationships to thin-
walled venous sinusoids suffuses peripherally in the cortex leaving islands of recognizable cortical cells
Clinical Clinical course course is usually usually devastati devastatingl ngly y abrupt, and prompt recognition and appropriate therapy must be instituted immediately, or death follows within hours to a few days
Page 2 of 10
i. Autoi toimmu mmune polyendocrine syndrome type 1 (APS1)
Also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED)
Characterized Characterized by chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy)
Occurring in association with a combination of organ-specific autoimmune disorders resulting in immune destruction of target organ
3) Addiso Addison n Disease Disease// Primary Primary Chron Chronic ic Adrenocortical Insufficiency
Unco Uncomm mmon on dis disor orde derr
Progre Progressiv ssive e destru destruction ction of the the adren adrenal al cortex
Clinical Clinical manifest manifestation ations s appea appears rs until until at least 90% of the adrenal cortex has been compromised
All races and both sexes sexes may may be be affecte affected d
Certai Certain n caus cause e of Add Addiso ison n (such (such as autoimmune adrenalitis) are much common in whites, particularly in women
Path athoge ogenesi esis:
90% of all cases are attributable to one of four disorders: 1.
a.
Autoimmune adrenalitis
b.
Autoimmune hypoparathyr oidism
c.
Idiopathic hypogonadis m
d.
Pernici icious anemia
Auto Autoim immu mune ne adren adrenal alit itis is •
•
•
•
•
60% to 70% of cases of Addison disease Most common cause of primary AI in developed countries Autoimmune Autoimmune destruction of steroidogenic cells Autoantibodies Autoantibodies to several key steroidogenic enzymes (21-hydroxylase, 17-hydroxylase) are detected in these patients Occurs in 3 clinical settings:
Caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22
ii. Autoi toimmu mmune polyendocrine syndrome type 2 (APS2)
Starts in early adulthood
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
Presents as a combination of AI with autoimmune thyroiditis or type 1 diabetes
Characteristics Characteristics of APS1 do not occur
Unlike APS1, it is not a monogenic disorder, although some studies have suggested a possible association with polymorphisms in the HLA loci
Page 3 of 10
Disseminated infections caused by Histoplasma capsulatum and Coccidioides immitis may result in Adisson disease
Patients with AIDS are at risk for developing AI from several infections (CMV, Mycobacterium aviumintercellulare ) and non-infectious complications (Kaposi sarcoma)
Metastatic neoplasms involving the adrenals are another potential cause of AI
iii. iii. Isol Isolat ated ed auto autoim immu mune ne Addison disease
Presents with autoimmune destruction restricted to the adrenal glands
Overlaps with APS2 in terms of age and linkage to HLA and other susceptibility susceptibility loci
those produced by fungi may cause Addison Tuberculo uberculous us adren adrenaliti alitis s – once once accounte accounted d for as much as 90% of Addison; become less common with development of antituberculous agents
Adrenals are a fairly common site for metastases in patients with disseminated carcinomas destroy enough adrenal cortex to produce a degree of AI
Carcinomas of the lung and breast are source of a majority of metastases in the adrenals, adrenals, although many other neoplasms, including GI carcinomas, malignant melanoma, and hematopoietic neoplasms, may also metastasize to this organ
Genetic disorders of AI
Includes adrenal hypoplasia congenital (AHC) and adrenoleukodystrophy
Not commonly included in the causes of Addison disease
Variant of APS2
Infections, Infections , particularly tuberculosis and
With resurgence of tuberculosis in most urban centers and the persistence of the disease in developing countries, however, this cause of AI must be kept in mind When present, tuberculous adrenalitis adrenalitis is associated with active infection in other sites – lungs and genitor-urinary tract
Morpho phology ogy:
Depends on the underlying disease
APS1 – characterized by irregularly shrunken glands which is difficult to identify within the suprarenal adipose tissue •
Histologically: cortex contains only scattered residual cortical cells in a collapsed network of connective tissue; a variable lymphoid infiltrate is present in the cortex and may extend into the subjacent medulla
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
In cases of tuberculous and fungal disease – adrenal architecture is effaced by a granulomatous inflammatory reaction identical to that encountered encountered in other sites of infection Caused by metastatic carcinoma carcinoma – adrenals are enlarged, and their normal architecture is obscured by the infiltrating neoplasm
Page 4 of 10
ADRENAL NEOPLASMS
Functional and nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of morphologic features
Morpho phology ogy:
Autoimmune adrenalitis – usually produces small glands, lipid depletion of adrenal cortex, and a variable lymphocytic infiltrate in cortex; medulla is spared
Adrenal adenomas – clinically silent
Typical cortical adenomas are well-circumscribed, nodular lesion up to 2.5cm in diameter that expands the adrenal
Inc contrast to functional adenomas, which are associated with atrophy of the adjacent cortex, the cortex adjacent to nonfunctional adenomas is of normal thickness
Yellow to yellow-brown on cut surface – presence of lipid within tumor cells
Clin Clinic ical al cour course se:: Includes weakness, fatigue,
anorexia, hypotension, nausea, vomiting and cutaneous hyperpigmentation Laboratory
values include elevated levels of corticotrophin, hyperkalemia, and hyponatremia, associated with volume depletion and hypotension
4) Secondary Secondary Adrenocort Adrenocortical ical Insufficiency Insufficiency
Caused by any disorder of the hypothalamus or pituitary causing a decreased corticotrophin production
With secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low Character Characterized ized by deficien deficientt corti cortisol sol and androgen output but normal or nearnormal aldosterone levels
Adrenocortical carcinomas – rare
Occur at any age more likely to be functional than adenomas
associated with virilism or other clinical manifestations of hyperadrenalism
two rare inherited causes: LiFraumeni syndrome and Beckwith-Wiedermann syndrome
large, invasive lesions, may exceed 20 cm in diameter, that efface the native adrenal gland
Sever hyponatremia and hyperkalemia are NOT features of 2o adrenocortical insufficiency
Corticotr Corticotroph ophin in defic deficienc iency y may may be isolated isolated or associated with hypopituitarism hypopituitarism
Morphology: variable degrees of atrophy of the adrenal cortex, with sparing of the zona glomerulosa and medulla
Microscopically: composed of cells similar to those populating the normal cortex; nuclei small, although some degree of pleiomorphism may be encountered even in benign lesions (“endocrine atypia”); cytoplasm of the neoplastic cells ranges from eosinophilic to vacuolated, depending on lipid content; mitotic activity is inconspicuous
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
typically variegated, poorly demarcated lesions containing areas of necrosis, hemorrhage, and cystic change
Page 5 of 10
Composed of specialized neural crest cells (chromaffin cells) cells) and their supporting (sustentacular) (sustentacular) cells
invasion of contiguous structures, including the adrenal vein and IVC, is common microscopically: welldifferentiated cells resembling those seen in cortical-adenomas cortical-adenomas or bizarre, monstrous giant cells; cancers with moderate degrees of anaplasia, some composed predominance of spindle cells; they may be difficult to differentiate differentiate from metstatic cells commonly invade the adrenal vein, vena cava, and lymphatics, with metastases to regional and periaortic lymph nodes and to viscera, especially lung
Most importan importantt diseases diseases of the adrenal adrenal medulla medulla are neoplasms 1. PHEOCH PHEOCHROM ROMOCY OCYTOM TOMA A (PCM) (PCM) Uncommon neoplasms composed of chromaffin cells Associated with catecholamine production and hypertension (account for 0.1%-0.3% of all cases of hypertension
Usually subscribe to a convenient “rule of 10s” •
association with one o several familial syndromes – includes MEN-2A and MEN2B syndromes, type 1 neurofibromatosis, vonHippel Lindau syndrome and Sturge-Weber syndrome
OTHER LESIONS OF THE ADRENAL
Advan Advancem cement ents s in medica medicall imagin imaging g and greater utilization of abdominal CT scans have led to the incidental discovery discovery of adrenal masses in asymptomatic individuals •
Adrenal myelolipomas – unusual – 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
Adrenal Medulla
Nonsecreting cortical adenomas
10% of PCM are extraextra adrenal – occurs in sites such as the organ of Zuckerkandl and the carotid body −
Usually called paragangliomas
•
10% of nonfamilial adrenal PCM are bilateral – may rise to 70% in cases that are associated with familial syndromes
•
10% of adrenal PCM are
Adrenal incidentaloma – half-facetious moniker that has crept into the medical lexicon as advancements in medical imaging have led to the incidental discovery of adrenal masses in asymptomatic individuals
10% of PCM arise in
biologically malignant, although the associated hypertension represents a serious and potentially lethal complication of even “benign” tumors −
Frank malignancy - more common
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut (20-40%) arising in extra-adrenal sites •
Page 6 of 10
•
10% of adrenal pheochromocytomas arise in childhood – childhood – usually familial subtypes −
−
M>F Non-familial PCM occurs in adults between 40-60; F>M
•
Morphology: •
•
•
•
Cut surface appears usually pale gray or brown
•
Associated with hemorrhage, necrosis, or cystic change
•
•
Hypertension – dominant clinical feature
Highly vascular Dichromate Dichromate fixative ( e.g. Zenker) causes it to turn brown-black because of oxidation of catecholamines hence the term chromaffin
−
•
•
features:
−
Microscope: •
Metastasis most commonly to lymph nodes, live, lung, and bones
Vary in size (1g -4kg) Clinical
•
Aggressive tumor – large tumor; extensive vascular, capsular, or periadrenal adipose tissue invasion; inc. mitotic index (>3/10hpf) or atypical mitotic figures; confluent (“sheetlike”) tumor necrosis; high cellularity and large tumor nest cells; cellular monotony; and spindlecell morphology
Composed of polygonal to spindle-shaped chromaffin cells or chief cells
Cellular and nuclear pleiomorphism (common) There is no single histologic feature that can reliably predict clinical behavior in PCMs
•
May be assoc with organ dysfunction
Paroxysmal release of catecholamines −
Clustered with the sustentacular cells into small nests or alveoli (zallballen), by a rich vascular network
Abrupt, precipitous elevation in BP, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension
Associated with episodic headache. Anxiety, sweating, tremor, visual disturbances, abdominal pain, and nausea
Cardiac complications – due to ischemic myocardial damage 2ndary to catecholaminecatecholamineinduced vasoconstriction catecholamine cardiomyopathy
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut •
Dx: based on lab studies – measuring urinary catecholamine catecholamine and their metabolites, plasma catecholamine catecholamine assays, and radiographic imaging studies
Page 7 of 10
multiple endocrine organs, organs , either synchronously (at the same time) or metachronously (at different times)
multifocal
preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor
TUMORS OF EXTRA-ADRENAL PARAGANGLIA PARAGANGLIA
PCMs that develop develop in in paragan paraganglia glia other other than than the adrenal medulla
Arise Arise in any any organ organ that conta contains ins parag paragangl anglioni ionic c tissue
Carotid body tumors body tumors – tumor arising in the carotid body
Px with MEN-1 syndrome develop varying degrees of islet cell hyperplasia some progress to pancreatic tumors
More aggressive and recur
1. MEN-1
Chemodectomas – originating in the jugulotympanic body
Comm Common on in teen teens s to to 20s 20s
Wermer syndrome
Characterized Characterized by 3 P’ s
i. Parathyroid hyperplasia or
Multicentric (15-25%)
multiple adenomas (90-95%) of cases – 40 to 50 y/o
Malignant (20-40%) Malignant (20-40%)
10% 10% met metas asta tasi size ze wid widel ely y
Morp orphology logy::
Usually firm
1cm to 6cm lesion
Densely adherent to adjacent tissues
Composed of well-differentiated neuroendocrine cells arrayed in nests or cords
ii. Pancreatic lesions – endocrine tumors which may usually secrete a variety of peptide hormones (pancreatic peptide (most common), gastrin and insulin (associated with clinical symptoms)
iii. Pituitary adenomas (10-15%) – usually prolactinoma
Microsco Microscope: pe: may may contai contain n mitotic mitotic figur figures es and and may exhibit substantial pleiomorphism
Group Group of geneti geneticall cally y inherite inherited d disease disease resul resulting ting in in proliferative lesions (hyperplasia, adenomas, and carcinomas) of multiple organs
Etiology – involves germ line mutations in the MEN-1 gene on c-some 11q11-13 encoding for menin (610-a.a)
Clinical manifestations – defined by the peptide hormones −
Dist Distin inct ct feat featur ures es::
Addi Additio tional nal tum tumors ors includ include e duodenal gastrinomas, carcinoid tumors, and thyroid and adrenocortical adenomas
Prominent fibrovascular stroma
MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES
iv. iv.
younger age 2. MEN-2
Recurrent hypoglycemia in insulinomas and recurrent peptic ulcers in patients with gastrinsecreting neoplasms (ZollingerEllison syndrome)
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
Page 8 of 10
Subclassified into 3 distinct syndromes: MEN-2A, MEN-2B, and familial medullary thyroid cancer i. MENMEN-2A, 2A, or or Sippl Sipple e synd syndro rome me
Characterized Characterized by pheochromocytoma, medullary carcinoma, and parathyroid hyperplasia. hyperplasia. Medullary carcinomas of the thyroid occur in almost 100% of patients. They are usually multifocal and are virtually always associated with foci of Ccell hyperplasia in the adjacent thyroid. The medullary carcinomas may elaborate calcitonin and other active products and are usually clinically aggressive.
40 to 50% of patients with MEN-2A have pheochromocytomas, which are often bilateral and may arise in extraadrenal sites.
As in the case of pheochromocytomas in general, they may be benign or malignant.
10 to 20% of patients have parathyroid hyperplasia and evidence of hypercalcemia or renal stones.
ii.
clinically and genetically distinct from MEN-1 Linked to germ-line mutations in the RET (rearranged during transfection) protooncogene on chromosome 10q11.2.
iii. iii.
In MEN-2A (as well as in MEN-2B), germ-line mutations constitutively constitutively activate the RET receptor, resulting in gain of function. function .
MEN-2B
significant clinical overlap with MEN-2A
Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas
Unlike in MEN-2A, primary hyperparathyroidism is not present
Accompanied by neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory respiratory tract, and gastrointestinal gastrointestinal tract, and a marfanoid habitus, habitus , with long axial skeletal features and hyperextensible joints.
A single amino acid change in RET (RETMet918Thr ), appears to be responsible for virtually all cases of MEN2B and affects a critical region of the tyrosine kinase catalytic domain of the protein.
Familia amiliall medul medullar lary y thyro thyroid id cancer
variant of MEN-2A There is a strong predisposition to medullary thyroid cancer but not the other clinical manifestations manifestations of MEN-2A or MEN-2B.
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
Majority of cases of medullary thyroid cancer are sporadic, but as many as 20% may be familial. Develop at an older age than those occurring in the full-blown MEN-2 syndrome and follow a more indolent course.
Page 9 of 10
PINEALOMAS
Divided into two categories, pineoblastomas pineoblastomas and pineocytomas , based on their level of differentiation, which, in turn, correlates with their neoplastic aggressiveness
Morphology:
Pineoblastomas
Encountered mostly in the first two decades of life
appear as soft, friable, gray masses punctuated with areas of hemorrhage and necrosis
Pineal Gland
Minu Minute, te, pine pinecon cone-s e-shap haped ed org organ an
100 to 180 mg
lying lying between between the super superior ior collic colliculi uli at at the base base of the brain
composed composed of of a loose, loose, neuro neuroglia gliall stroma stroma enclos enclosing ing nests of epithelial-appearing epithelial-appearing pineocytes, cells with photosensory and neuroendocrine functions (hence the designation of the pineal gland as the "third eye")
Silver Silver impreg impregnati nation on stains stains reveal reveal that these these cells cells have long, slender processes reminiscent of primitive neuronal precursors intermixed with the processes of astrocytic cells.
Histologically:
they are composed of masses of pleomorphic pleomorphic cells 2-4 times the diameter of an erythrocyte
Large hyperchromatic nuclei appear to occupy almost the entire cell, and mitoses are frequent.
The cytology is that of primitive embryonal tumor ("small blue cell neoplasm") similar to medulloblastoma medulloblastoma or retinoblastoma.
Pineoblastomas, like medulloblastomas, tend to spread via the cerebrospinal fluid
As might be expected, the enlarging mass may compress the aqueduct of Sylvius, giving rise to
Internal hydrocephalus and all its consequences.
Survival beyond 1 or 2 years is rare.
Pathology
All tumors involving the pineal are rare
Include both germ cell tumors (resembling those arising in the gonads) and neoplasms of of pineal parenchymal origin
Typically invade surrounding structures, such as the hypothalamus, midbrain, and lumen of the third ventricle.
PINEACYOMAS
Pathology – Endocrine Pathology by Pathology by Dr. Dr. Yabut
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
Histologically:
may be pure be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation
composed largely of pineocytes having darkly staining, round-to-oval, fairly regular nuclei
Necrosis is unusual, and mitoses are virtually absent.
neoplastic cells resemble normal pineocytes in their strong immunoreactivity for neuro-specific neuro-specific enolase and synaptophysin
Particularly distinctive are the pineocytomatous pseudorosettes 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 background of thin, fibrovascular, anastomosing septa, which confer a lobular growth pattern to the tumor Glial and retinal differentiation differentiation is detectable by immunoreactivity for glial fibrillary acidic protein and retinal S-antigen, respectively.
The clinical course of patients with pineocytomas is prolonged, averaging 7 years.
Page 10 of 10
The manifestations are the consequence of their pressure effects and consist of visual disturbances, headache, mental deterioration, deterioration, and sometimes dementia-like behavior.
The lesions being located where they are, it is understandable that successful excision is at best difficult.
