Endocrine Flashcards
Examples of pseudoneoplastic lesions in the endocrine system and their related neoplastic mimes.
Sclerosing and proliferative Hashimoto thyroiditis (differentiated and paucicellular anaplastic carcinomas). Nodular thyroid hyperplasia (thyroid adenomas and differentiated thyroid carcinomas). Nodular parathyroid hyperplasia (parathyroid adenoma). Nodular adrenal hyperplasia (adrenocortical adenoma). Adrenal myelolipoma (liposarcoma). Chronic tumefactive pancreatitis (low-grade pancreatic ductal adenocarcinoma).
IHC for adrenal cortical carcinoma vs pheochromocytoma?
Adrenal cortical carcinoma is synaptophysin +, chromogranin -, inhibin +, Melan-A +, calretinin +, S-100 -. Pheochromocytoma is synaptophysin +, chromogranin +, inhibin -, Melan-A -, calretinin -, S-100 reactive only in nuclei of sustentacular cells.
Intracytoplasmic eosinophilic hyaline globules are seen in up to __% of cases of pheochromocytoma, and up to __% of cases of adrenal cortical tumors.
Intracytoplasmic eosinophilic hyaline globules are seen in up to 45% of cases of pheochromocytoma, and up to 10% of cases of adrenal cortical tumors.
Papillary thyroid carcinoma, cribriform morular variant. What stains can be helpful? This variant is associated with (syndrome) ~25% of the time.
This variant’s unique histology and reactivity with thyroglobulin, TTF-1, and beta-catenin help to distinguish it. This variant is associated with FAP ~25% of the time.
Papillary thyroid carcinoma, diffuse sclerosing variant. In what age group does it occur? What is the histologic appearance?
A rare variant that occurs in children and young adults. It has conventional papillary architecture and PTC nuclear features, but has squamoid changes and abundant psammoma bodies, a dense lymphocytic and sclerotic background, and extensive lymphatic permeation.
Papillary thyroid carcinoma, oncocytic variant. What is the gross and histologic appearance?
This variant is grossly mahogany brown. Microscopically, while it has conventional papillary architecture, it is oncocytic with focally prominent nucleoli and often has psammoma bodies (about 33 %).
Will adrenal cortical carcinomas stain positive for cytokeratins?
Adrenal cortical carcinomas are negative for CKs in formalin-fixed tissue unless antigen retrieval techniques are utilized, and even then the tumors are only focally weakly positive.
___% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
15-20% of medullary thyroid carcinomas occur in a relatively young population in association with MEN2 syndrome; the remainder are sporadic and may occur at any age.
What is seen on FNAs in Hashimoto thyroiditis?
Smears from Hashimoto’s thyroiditis show a polymorphous lymphoplasmacytic infiltrate with germinal center formation. Lymphoid tangles, lymphohistiocytic aggregates, tingible body macrophages, and background lymphoglandular bodies may be the overwhelming findings on the smears. Multinucleated histiocytes may be seen. Oncocytic (Hurthle cell) metaplasia is usually prominent. Hurthle cells are epithelial cells with abundant, finely granular cytoplasm and enlarged, variably sized, typically round nuclei that may display prominent nucleoli.
How does medullary thyroid carcinoma appear on FNA?
FNA biopsy yields neoplastic neuroendocrine cells and amyloid in variable proportions. The cellularity of the smears is usually inversely proportional to the amount of amyloid produced by the tumor. The neoplastic cells are dispersed or form loose clusters, rarely forming microfollicles or papillae. MTC is a great mimicker. The tumor cells may have spindly, plasmacytoid, polygonal, hurthloid or giant cells appearances; may demonstrate mild pleomorphism; and may be bi- or multinucleated. The nuclei often have a “salt-and-pepper” or “speckled” chromatin pattern on Pap stain. Nucleoli may be seen, but are usually inconspicuous. Intranuclear cytoplasmic inclusions are frequently identified, and are morphologically identical to those seen in papillary thryoid cancer. Mitotic figures are present in 15% of cases. On Diff-Quik staining, red cytoplasmic granules, corresponding to neurosecretory granules containing calcitonin, may be seen.
What tumors are seen in the subtypes of MEN syndrome?
MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.
Both pancreatic endocrine neoplasms and solid pseudopapillary neoplasms are positive for what 2 immunostains?
CD56 and synaptophysin.
What immunostain can be used to differentiate paragangliomas from neuroendocrine tumors?
Cytokeratin. Paragangliomas generally do not stain with cytokeratins.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called ___ syndrome.
A small subset of cases of the polyostotic form of fibrous dysplasia (~3%) occurs along with endocrine abnormalities and coast of Maine cafe-au-lait spots, a triad called McCune-Albright syndrome.
Why do many patients with Addison disease/adrenal insufficiency have blood eosinophilia?
This association exists because glucocorticoids inhibit eosinophil proliferation and survival, an effect that is exploited clinically when steroids are used as treatment of reactive eosinophilias. In adrenal insufficiency, the converse occurs; low glucocorticoid levels allow increased eosinophil proliferation and survival. This scenario is especially important in critically ill patients, in whom eosinophilia due to adrenal insufficiency is common. Given the inverse relationship between glucocorticoid levels and eosinophil count, the standard evaluation of eosinophilia should include attention to clinical signs of adrenal insufficiency (orthostatic hypotension, skin discoloration); routine chemistries, which may be abnormal in Addison disease; and, in some cases, morning cortisol levels.
How to differentiate pancreatic neuroendocrine tumor from pancreatic solid-pseudopapillary neoplasm.
Cytologically, PanNET and SPN are both composed of fairly uniform round cells with uniform nuclei, but PanNET cells tend to have the speckled chromatin pattern typical of neuroendocrine neoplsms. While pseudopapillae may be present in PanNETs, their presence, along wiht foamy cells and hyaline globules, should favor the diagnosis of SPN. In cases where morphology is insufficient in differentiating the two, IHC should be performed. PanNET stains strongly for chromogranin and synaptophysin, and will generally stain for the expressed pancreatic hormone. SPN has variable staining for synaptophysin, it is typically much weaker than in PanNET, and does not stain for chromogranin. In addition, loss of E-cadherin is present in nearly all cases of SPN, but is variable in PanNET. CD56 and NSE are positive in both and provide little diagnostic utility between the two. Lack of PR staining is another useful diagnostic finding in PanNET. CD99 is positive in most PanNETs, but it has a membranous staining pattern that allows for easy differentiation from the staining pattern seen in SPN, which is a paranuclear dotlike pattern.
Peutz-Jeghers (hamartomatous) polyps overview.
Peutz-Jeghers polyps (hamartomatous polyps) are supported by broad bands of muscularis mucosa smooth muscle, which is thicker centrally, and resembles a Christmas tree at low power. The polyp has superficial columnar and goblet cells, but Paneth and endocrine cells at its base. Peutz-Jeghers polyps are large, pedunculated polyps of the gut almost always seen in association with Peutz-Jeghers syndrome. This rare autosomal dominant disorder is usually diagnosed at ages 20-30, with hamartomatous polyps in the small bowel (100%), stomach and colon (25%), and associated adenomatous lesions that may give rise to adenocarcinoma of the stomach, large or small bowel; adenoma malignum of the cervix, ovarian mucinous tumors, and carcinoma of the breast, lung and pancreas. The syndrome is also associated with sex-cord tumor with annular tubules (almost all patients) and melanotic pigmentation of the digits, genitalia, lips, oral mucosa, palms and soles. Peutz-Jeghers syndrome is caused by mutations in STK11/LKB1, a serine threonine kinase that may play a role in cell polarity.
What is the most common endocrine tumor associated with MEN1?
Gastrinoma.
Pancreatic endocrine tumors have similar histologic features irrespective of the type of hormone produced, with a few exceptions, which are ___.
Stromal amyloid is commonly seen in insulinomas. Somatostatinomas are peculiar for containing glandular structures with psammoma bodies, but the latter are typically seen in duodenal rather than pancreatic tumors.
WHO 2010 classification of neuroendocrine tumors in GI tract and pancreas.
Low grade (G1): 20 mitoses/10 HPF, OR >20% Ki-67 index.
How are neuroendocrine tumors graded in GI tract and pancreas, and for lung and thymus?
For GI tract and pancreas, WHO 2010 classification: Low grade (G1): 20 mitoses/10 HPF, OR >20% Ki-67 index. For lung and thymus, WHO 2004 classification: Low grade (G1): 10 mitoses/10 HPF.
When McCune-Albright syndrome is associated with intramuscular myxomas, it is called ___ syndrome.
When McCune-Albright syndrome (hyperfunctioning endocrinopathies, including precocious puberty, fluctuating thelarchy, hyperthyroidism, growth hormone excess, rickets/osteomalacia; as well as skin hyperpigmentation/cafe au lait spots) is associated with intramuscular myxomas, it is called Mazabraud syndrome.
Distinction between benign and malignant adrenal cortical tumors may be extremely difficult, and numerous authors have utilized various parameters in order to allow differentiation of these neoplasms. Medeiros and Weiss have proposed a system which utilizes histologic criteria only. What are the 9 features commonly associated with adrenal cortical carcinoma, according to these authors?
- High nuclear grade (Fuhrman criteria). 2. Mitotic rate exceeding 5 per 50 HPFs. 3. Atypical mitoses. 4. Eosinophilic tumor cell cytoplasm (>75% of tumor cells). 5. Diffuse architecture (>33% of tumor). 6. Necrosis. 7. Venous invasion (smooth muscle in wall). 8. Sinusoidal invasion (no muscle in wall). 9. Capsular invasion. The presence of two or fewer features portends low metastatic potential, while three or more features portend metastatic potential and/or recurrence. The three most important criteria according to Weiss are mitotic activity greater than 5 per 50 high-power field, atypical mitoses, and venous invasion.
What is the PTEN gene? In what tumors is it often mutated?
Phosphatase and tensin homolog (PTEN) gene is on chromosome band 10q23.31. In addition to its role as a tumor suppressor, it has important roles in embryogenesis and maintenance of physiologic functions in many organ systems and is constitutively expressed in normal tissues. It is one of the most frequently inactivated genes in sporadic cancer. Sporadic mutations of PTEN occur frequently in many tumors such as glioblastoma, breast carcinoma, endometrial carcinoma, thyroid neoplasms, skin neoplasms, and advanced prostate cancer.
Congenital adrenal hyperplasia is a group of autosomal recessive disorders characterized by impairment of cortisol biosynthesis, with or without impairment of aldosterone biosynthesis, and ~95% of cases are due to ___ deficiency.
Congenital adrenal hyperplasia is a group of autosomal recessive disorders characterized by impairment of cortisol biosynthesis, with or without impairment of aldosterone biosynthesis, and ~95% of cases are due to 21-hydroxylase (21-OHD) deficiency. CAH is manifested in a variety of clinical severities comprised of three subtypes: i) classic salt wasting, ii) classic simple virilizing, and iii) nonclassic (mild or late onset) forms.
What are the 2 isoenzymes of serum amylase?
Pancreatic and salivary. But when subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.
How many bands form when serum amylase is subjected to electrophoresis?
When serum amylase is subjected to electrophoresis, 6 bands result, with the first three being salivary and the slowest three being pancreatic.
Other than electrophoresis and monoclonal antibody assays, how can salivary and pancreatic amylase be differentiated?
An inhibition test: Salivary amylase is sensitive to inhibition by the wheat germ lectin, triticum vulgaris.
Serum amylase rises within __ to __ hours of the onset of acute pancreatitis and returns to normal in __ to __ days.
Serum amylase rises within 2 to 24 hours of the onset of acute pancreatitis and returns to normal in 2 to 3 days.
Up to 10% of cases of acute pancreatitis are associated with normal levels of amylase, with this finding most common in people with hypertriglyceridemia-associated acute pancreatitis. Why?
Triglycerides competitively interfere with the amylase assay.
How much overlap is seen in the range of levels of amylase for acute pancreatitis vs other causes?
The degree of elevation tends to be higher in acute pancreatitis, but there is considerable overlap in the ranges. Pancreatitis causes amylase in the range of 250-1000 Somogyi units, while other causes are 200-500.
What are 2 additional markers of acute pancreatitis other than amylase and lipase?
Serum and urine trypsinogen-2 and elastase-1.
What tests are available for measuring pancreatic exocrine function?
Invasive: Secretin-CCK/secretin-pancreozymin test. Noninvasive: Fecal fat. Fecal elastase-1. Fecal chymotrypsin (bentiromide).
What is the secretin-CCK test?
An endoscope is introduced, and the duodenal concentrations of pancreatic exocrine products (bicarbonate, amylase, lipase, trypsin) are measured after IV administration of secretin and CCK.
A fecal fat test (72 hour fecal fat quantitation) is positive in pancreatic exocrine dysfunction. What other conditions will also result in a positive fecal fat test?
Severe ileal diseases (such as Crohn disease) or ileal resection.
MEN1 manifests with pituitary adenomas, parathyroid adenomas, and pancreatic islet cell tumors. What are nonendocrine lesions associated with MEN1?
Facial angiofibromas, collagenomas, lipomas, and meningiomas.
There are 3 subtypes of MEN2: MEN 2A, MEN 2B, and FMTC. All are autosomal dominant, all are due to a mutation in RET, and all have a high risk for medullary thyroid carcinoma. While the histology of the medullary thyroid carcinoma in the syndrome is not distinctive, the appearance of the background thyroid is. What is seen?
C-cell hyperplasia and numerous small foci of medullary carcinoma.
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
What are the 3 possible haptoglobin phenotypes? Is there a disease association with any particular phenotype?
The haptoglobin genetic locus at 16q22 is polymorphic with two classes of alleles: type 1 and type 2. Based on these 2 alleles, the 3 haptoglobin phenotypes/protein products are: Hp 1-1, Hp 2-1, and Hp 2-2. The 2-2 phenotype is an independent risk factor for CV disease in DM.
What genetic disorders can cause hypokalemia?
Congenital adrenal hyperplasia (11-beta hydroxylase or 17-alpha hydroxylase deficiency). Glucocorticoid-remediable hypertension. Bartter syndrome. Gitelman syndrome. Liddle syndrome. Gullner syndrome. Glucocorticoid receptor deficiency. Hypokalemic periodic paralysis. Thyrotoxic periodic paralysis (TTPP). Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome).
What ovarian tumors are associated with paraendocrine hypercalcemia?
Small cell carcinoma (60%). Clear cell carcinoma (20%). Serous carcinoma, squamous cell carcinoma arising in a dermoid cyst, and dysgerminoma account for 10%.
What IHC stain can differentiate pheochromocytoma/paraganglioma from other endocrine tumors?
Immunostaining for enzymes involved in catecholamine biosynthesis such as tyrosine hydroxylase can differentiate it from other endocrine tumors.
When metastatic, what locations do pheochromocytoma and paraganglioma involve? Patients with paragangliomas are at __x the risk of metastasis as patients with adrenal tumors.
Bones, lung, liver, lymph nodes. Patients with paragangliomas are at 11x the risk of metastasis as patients with adrenal tumors.
In addition to colorectal polyps, ~__% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (__%), congenital hypertrophy of the retinal pigment epithelium (__%), desmoid-type fibromatosis (__%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (__x), duodenal carcinoma (__x), ampullary carcinoma (__x), nasopharyngeal adenofibroma (__x), thyroid carcinoma (__x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (__x), and pancreatic carcinoma (__x).
In addition to colorectal polyps, ~90% of patients with FAP also develop gastric and duodenal polyps. Other systemic manifestations of FAP include osteomas (80%), congenital hypertrophy of the retinal pigment epithelium (70-80%), desmoid-type fibromatosis (15%), and dental abnormalities. Risk of malignancy is increased relative to the general population for hepatoblastoma (847x), duodenal carcinoma (330x), ampullary carcinoma (123x), nasopharyngeal adenofibroma (25x), thyroid carcinoma (7.6x) (specifically, the cribriform morular variant of papillary thyroid carcinoma is strongly associated with APC gene mutations), brain tumors (7x), and pancreatic carcinoma (4x).
The effect of PTH on renal tubules causes (increased/decreased) calciium reabsorption and (increased/decreased) phosphate excretion.
The effect of PTH on renal tubules causes increased calciium reabsorption and increased phosphate excretion.
Primary hyperparathyroidism is characterized by increased calcium, decreased phosphate, increased chloride, and increased nephrogenous cAMP. The decreased phosphate is in contrast to many other forms of hypercalcemia, which often have increased phosphate. Why does this occur?
This is because PTH has a dual effect on renal tubules, where there is increased calciium reabsorption and increased phosphate excretion.
Primary hyperparathyroidism is caused by solitary parathyroid adenoma in __%, 4-gland hyperplasia in __%, and carcinoma in __%.
Primary hyperparathyroidism is caused by solitary parathyroid adenoma in 90%, 4-gland hyperplasia in 9%, and carcinoma in 1%.
The locus on chromosome 11 that, in germline form, leads to MEN1 has been found to contain somatic mutation in ~__% of sporadic parathyroid adenomas.
The locus on chromosome 11 that, in germline form, leads to MEN1 has been found to contain somatic mutation in ~25% of sporadic parathyroid adenomas.
A (decreased/increased) nephrogenous cAMP in the presence of (decreased/normal/increased) PTH is highly suggestive of humoral hypercalcemia of malignancy.
An increased nephrogenous cAMP in the presence of normal PTH is highly suggestive of humoral hypercalcemia of malignancy.
PTH and vitamin D. How do they differ in increasing/decreasing calcium and phosphate excretion/absorption by the kidneys?
PTH causes increased calcium reabsorption and increased phosphate excretion. Vitamin D causes increased calcium reabsorption and increased phosphate reabsorption.
What granulomatous disease can potentially cause hypercalcemia?
The histiocytes of sarcoidal granulomas appear to have the capacity to activate vitamin D to the active form (1,25 dihydroxy vitamin D). This phenomenon is rarely seen in other types of granulomatous disease.
