Endocrine System - Part 3 (robbins)

Pathology (dr. Yabut) Endocrine Pathology – Part 3 (from Book) 09 January 08 ADRENAL INSUFFICIENCY (AI) 

Primary adrenal disease ( primary hypoadrenalism)



Decreased stimulation of the adrenals owing to a deficiency of ACTH (secondary hypoadrenalism)

2) Waterhouse-Friderichsen Syndrome 

Uncommon but catastrophic syndrome



Characteristics: 1.Overwhelming bacterial infection

Patterns of Adrenal Insufficiency

•

Usually associated with Neisseria meningitides septicemia

•

Occasionally by highly virulent organisms: Pseudomonas, pneumococci, Haemophilus influenza, or staph

1) Primary Acute AdrenocorticalInsufficiency 

Caused by any lesion of the adrenal 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 patients maintained on exogenous corticosteroids, owing to the inability of the atrophic adrenals to produce glucocortioid hormones Result of massive adrenal hemorrhage, 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 

Occurs at any age – BUT more common in children



Adrenal hemorrhage is uncertain 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 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 vasculitis 

Whatever the basis, the adrenals are converted to sacs of clotted blood virtually obscuring all underlying detail



Morphology: massive, bilateral adrenal hemorrhage, which begins in the medulla

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Histologic exam:

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Pathology – Endocrine Pathology by Dr. Yabut

Hemorrhage starts within the

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i.

medulla I relationships to thinwalled venous sinusoids  suffuses peripherally in the cortex  leaving islands of recognizable cortical cells 

Clinical course is usually devastatingly abrupt, and prompt recognition and appropriate therapy must be instituted immediately, or death follows within hours to a few days

Autoimmune polyendocrine syndrome type 1 (APS1) 

Also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED)

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Characterized by chronic mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy)

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Occurring in association with a combination of organ-specific autoimmune disorders resulting in immune destruction of target organ

3) Addison Disease/ Primary Chronic Adrenocortical Insufficiency 

Uncommon disorder



Progressive destruction of the adrenal cortex



Clinical manifestations appears until at least 90% of the adrenal cortex has been compromised

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All races and both sexes may be affected

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Certain cause of Addison (such as autoimmune adrenalitis) are much common in whites, particularly in women

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Pathogenesis:  90% of all cases are attributable to one of four disorders: 1.

a.

Autoimmune adrenalitis

b.

Autoimmune hypoparathyr oidism

c.

Idiopathic hypogonadis m

d.

Pernicious anemia

Autoimmune adrenalitis •

60% to 70% of cases of Addison disease

•

Most common cause of primary AI in developed countries

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Autoimmune destruction of steroidogenic cells

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Autoantibodies to several key steroidogenic enzymes (21-hydroxylase, 17-hydroxylase) are detected in these patients

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Occurs in 3 clinical settings:



ii.

Caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22

Autoimmune polyendocrine syndrome type 2 (APS2) 

Starts in early adulthood

Pathology – Endocrine Pathology by Dr. Yabut 

iii.

Presents as a combination of AI with autoimmune thyroiditis or type 1 diabetes



Characteristics of APS1 do not occur

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Unlike APS1, it is not a monogenic disorder, although some studies have suggested a possible association with polymorphisms in the HLA loci

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 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  Adrenals are a fairly common site for metastases in patients with disseminated carcinomas destroy enough adrenal cortex to produce a degree of AI

Isolated autoimmune Addison disease 

Presents with autoimmune destruction restricted to the adrenal glands

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Overlaps with APS2 in terms of age and linkage to HLA and other susceptibility loci

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 Carcinomas of the lung and breast are source of a majority of metastases in the adrenals, although many other neoplasms, including GI carcinomas, malignant melanoma, and hematopoietic neoplasms, may also metastasize to this organ 

 Includes adrenal hypoplasia congenital (AHC) and adrenoleukodystrophy

Variant of APS2

 Not commonly included in the causes of Addison disease

 Infections, particularly tuberculosis and those produced by fungi may cause Addison 

Tuberculous adrenalitis – once accounted for as much as 90% of Addison; become less common with development of antituberculous agents  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 is associated with active infection in other sites – lungs and genitor-urinary tract

Genetic disorders of AI



Morphology:  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 Dr. Yabut  In cases of tuberculous and fungal disease – adrenal architecture is effaced by a granulomatous inflammatory reaction identical to that encountered in other sites of infection  Caused by metastatic carcinoma – adrenals are enlarged, and their normal architecture is obscured by the infiltrating neoplasm

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ADRENAL NEOPLASMS 

Functional and nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of morphologic features



Morphology:

 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

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Yellow to yellow-brown on cut surface – presence of lipid within tumor cells

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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

Autoimmune adrenalitis – usually produces small glands, lipid depletion of adrenal cortex, and a variable lymphocytic infiltrate in cortex; medulla is spared 

Clinical course:  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 Adrenocortical 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 Characterized by deficient cortisol and androgen output but normal or nearnormal aldosterone levels

 Adrenocortical carcinomas – rare 

Occur at any age more likely to be functional than adenomas

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associated with virilism or other clinical manifestations of hyperadrenalism

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two rare inherited causes: LiFraumeni syndrome and Beckwith-Wiedermann syndrome

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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 

Corticotrophin deficiency may be isolated or associated with hypopituitarism

 Morphology: variable degrees of atrophy of the adrenal cortex, with sparing of the zona glomerulosa and medulla

Pathology – Endocrine Pathology by Dr. Yabut 

typically variegated, poorly demarcated lesions containing areas of necrosis, hemorrhage, and cystic change

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 Composed of specialized neural crest cells (chromaffin cells) and their supporting (sustentacular) cells 

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invasion of contiguous structures, including the adrenal vein and IVC, is common microscopically: welldifferentiated cells resembling those seen in 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 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 important diseases of the adrenal medulla are neoplasms 1. PHEOCHROMOCYTOMA (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”

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10% of PCM arise in association with one o several familial syndromes – includes MEN-2A and MEN2B syndromes, type 1 neurofibromatosis, vonHippel Lindau syndrome and Sturge-Weber syndrome

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10% of PCM are extraadrenal – occurs in sites such as the organ of Zuckerkandl and the carotid body

OTHER LESIONS OF THE ADRENAL 

Advancements in medical imaging and greater utilization of abdominal CT scans have led to the incidental discovery of adrenal masses in asymptomatic individuals

 Adrenal 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

− •

10% of nonfamilial adrenal PCM are bilateral – may rise to 70% in cases that are associated with familial syndromes

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10% of adrenal PCM are biologically malignant, although the associated hypertension represents a serious and potentially lethal complication of even “benign” tumors

 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 

Adrenal Medulla

Nonsecreting cortical adenomas

Usually called paragangliomas

−

Frank malignancy - more common

Pathology – Endocrine Pathology by Dr. Yabut (20-40%) arising in extra-adrenal sites

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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

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Metastasis most commonly to lymph nodes, live, lung, and bones

10% of adrenal pheochromocytomas arise in childhood – usually familial subtypes −

M>F

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Non-familial PCM occurs in adults between 40-60; F>M

 Morphology: •

Vary in size (1g -4kg)

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Cut surface appears usually pale gray or brown

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Associated with hemorrhage, necrosis, or cystic change

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Highly vascular

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Dichromate fixative ( e.g. Zenker) causes it to turn brown-black because of oxidation of catecholamines hence the term chromaffin

 Microscope: •

 Clinical features: •

•

Composed of polygonal to spindle-shaped chromaffin cells or chief cells

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Clustered with the sustentacular cells into small nests or alveoli (zallballen), by a rich vascular network

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Cellular and nuclear pleiomorphism (common)

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There is no single histologic feature that can reliably predict clinical behavior in PCMs

Hypertension – dominant clinical feature −

Abrupt, precipitous elevation in BP, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension

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May be assoc with organ dysfunction

Paroxysmal release of catecholamines −

•

Associated with episodic headache. Anxiety, sweating, tremor, visual disturbances, abdominal pain, and nausea

Cardiac complications – due to ischemic myocardial damage 2ndary to catecholamineinduced vasoconstriction  catecholamine cardiomyopathy

Pathology – Endocrine Pathology by Dr. Yabut •

Dx: based on lab studies – measuring urinary catecholamine and their metabolites, plasma catecholamine assays, and radiographic imaging studies

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 multiple endocrine organs, either synchronously (at the same time) or metachronously (at different times) 

 preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor

TUMORS OF EXTRA-ADRENAL PARAGANGLIA 

PCMs that develop in paraganglia other than the adrenal medulla

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Arise in any organ that contains paraganglionic tissue

 Carotid body tumors – tumor arising in the carotid body

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

tympanic body Common in teens to 20s

More aggressive and recur

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Wermer syndrome

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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%) 

10% metastasize widely

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Morphology: 

Usually firm

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1cm to 6cm lesion

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Densely adherent to adjacent tissues

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Composed of well-differentiated neuroendocrine cells arrayed in nests or cords

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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 iv.

Prominent fibrovascular stroma

Microscope: may contain mitotic figures and may exhibit substantial pleiomorphism

MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES 

Group of genetically inherited disease resulting in proliferative lesions (hyperplasia, adenomas, and carcinomas) of multiple organs

Additional tumors include duodenal gastrinomas, carcinoid tumors, and thyroid and adrenocortical adenomas

 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 − Recurrent hypoglycemia in insulinomas and recurrent peptic ulcers in patients with gastrinsecreting neoplasms (ZollingerEllison syndrome)

Distinct features: 

Px with MEN-1 syndrome develop varying degrees of islet cell hyperplasia  some progress to pancreatic tumors

1. MEN-1

 Chemodectomas – originating in the jugulo

multifocal

younger age 2. MEN-2

Pathology – Endocrine Pathology by Dr. Yabut

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 Subclassified into 3 distinct syndromes:

 In MEN-2A (as well as in

MEN-2A, MEN-2B, and familial medullary thyroid cancer i.

MEN-2B), germ-line mutations constitutively activate the RET receptor, resulting in gain of function.

MEN-2A, or Sipple syndrome

 Characterized by pheochromocytoma, medullary carcinoma, and parathyroid 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.

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40 to 50% of patients with MEN-2A have pheochromocytomas, which are often bilateral and may arise in extraadrenal sites.

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As in the case of pheochromocytomas in general, they may be benign or malignant.

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10 to 20% of patients have parathyroid hyperplasia and evidence of hypercalcemia or renal stones.

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ii.

clinically and genetically distinct from MEN-1 Linked to germ-line mutations in the RET (rearranged during transfection) protooncogene on chromosome 10q11.2.

MEN-2B 

significant clinical overlap with MEN-2A

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Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas

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Unlike in MEN-2A, primary hyperparathyroidism is not present

 Accompanied by neuromas or ganglioneuromas involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract, and a marfanoid 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. iii.

Familial medullary thyroid cancer 

variant of MEN-2A



There is a strong predisposition to medullary thyroid cancer but not the other clinical manifestations of MEN-2A or MEN-2B.

Pathology – Endocrine Pathology by Dr. Yabut 

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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.

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PINEALOMAS

 Divided into two categories, pineoblastomas and pineocytomas, based on their level of differentiation, which, in turn, correlates with their neoplastic aggressiveness 

Morphology:

 Pineoblastomas

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Pineal Gland 

Minute, pinecone-shaped organ

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100 to 180 mg

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lying between the superior colliculi at the base of the brain

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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 "third eye")

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Silver impregnation stains reveal that these cells have long, slender processes reminiscent of primitive neuronal precursors intermixed with the processes of astrocytic cells.

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Encountered mostly in the first two decades of life

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appear as soft, friable, gray masses punctuated with areas of hemorrhage and necrosis

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Typically invade surrounding structures, such as the hypothalamus, midbrain, and lumen of the third ventricle.

Histologically: 

they are composed of masses of pleomorphic cells 2-4 times the diameter of an erythrocyte

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Large hyperchromatic nuclei appear to occupy almost the entire cell, and mitoses are frequent.

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The cytology is that of primitive embryonal tumor ("small blue cell neoplasm") similar to medulloblastoma or retinoblastoma.

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Pineoblastomas, like medulloblastomas, tend to spread via the cerebrospinal fluid

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As might be expected, the enlarging mass may compress the aqueduct of Sylvius, giving rise to

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Internal hydrocephalus and all its consequences.

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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 pineal parenchymal origin

PINEACYOMAS

Pathology – Endocrine Pathology by Dr. Yabut 

occur mostly in adults and are much slower-growing than pineoblastomas

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well-circumscribed, gray, or hemorrhagic masses that compress but do not infiltrate surrounding structures

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Histologically:



may be pure pineocytomas or exhibit divergent glial, neuronal, and retinal differentiation

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composed largely of pineocytes having darkly staining, round-to-oval, fairly regular nuclei

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Necrosis is unusual, and mitoses are virtually absent.

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neoplastic cells resemble normal pineocytes in their strong immunoreactivity for neuro-specific enolase and synaptophysin

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Particularly distinctive are the pineocytomatous pseudorosettes rimmed by rows of pineocytes

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The centers of these rosettes are filled with eosinophilic cytoplasmic material representing tumor cell processes.

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These cells are set against a background of thin, fibrovascular, anastomosing septa, which confer a lobular growth pattern to the tumor

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Glial and retinal 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.

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

The manifestations are the consequence of their pressure effects and consist of visual disturbances, headache, mental deterioration, and sometimes dementia-like behavior.

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The lesions being located where they are, it is understandable that successful excision is at best difficult.