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.
Hypercalcemia can be produced by a variety of disorders, but primary hyperparathyroidism and malignancy account for most cases. The symptoms and signs associated with hypercalcemia are typically independent of the etiology. What symptoms are seen with mild, moderate, and severe hypercalcemia?
Patients with mild hypercalcemia (calcium 14 mg/dL [3.5 mmol/L]), there is often progression of these symptoms.
PTH synthesis. What is the initial form, and what is the biologically active form?
PTH is synthesized as a 115- amino acid polypeptide called pre-pro-PTH, which is cleaved within parathyroid cells at the N-terminal portion first to pro-PTH (90 amino acids) and then to PTH (84 amino acids). The latter is the major storage, secreted, and biologically active form of the hormone. Calcium regulates not only the release but also the synthesis and degradation of PTH, in all its molecular forms.
What forms/fragments of PTH are secreted in hypocalcemia and hypercalcemia?
In addition to intact PTH, some inactive C-terminal fragments and small amounts of active N-terminal fragments of PTH are present in the parathyroid glands. During hypocalcemia, intracellular degradation of PTH decreases, and mostly PTH 1-84 is secreted; in comparison, during hypercalcemia mostly biologically inactive C-terminal fragments of PTH are secreted.
Circulating immunoreactive PTH in normal subjects comprises: intact PTH (__-__%), C-terminal fragments (__-__%), and N-terminal fragments (__%).
Circulating immunoreactive PTH in normal subjects comprises: intact PTH (5-30%), C-terminal fragments (70-95%), and N-terminal fragments (small percentage).
For the 4 forms of PTH (intact PTH, N-terminal PTH, mid-region PTH, C-terminal PTH), give biologic activity as + or -, and give half-life as short or long.
Intact PTH: +, short (plasma half-life of 2-4 min). N-terminal PTH: +, short. Mid-region PTH: -, long. C-terminal PTH: -, long (plasma half-life 5-10x longer than intact PTH).
What are causes of hypercalcemia?
PTH-mediated: primary hyperparathyroidism, familial (MEN-I and -IIa, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia), tertiary hyperparathyroidism. PTH-independent: hypercalcemia of malignancy, vitamin D intoxication, chronic granulomatous disorders, medications (thiazide diuretics, lithium, teriparatide, theophylline toxicity, excessive vitamin A), miscellaneous (hyperthyroidism, acromegaly, pheochromocytoma, adrenal insufficiency, immobilization, parenteral nutrition, milk-alkali syndrome).
What are causes of hypocalcemia?
Low PTH (hypoparathyroidism): genetic disorders, post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection), autoimmune, infiltration of the parathyroid gland (granulomatous, iron overload, metastases), radiation-induced destruction of parathyroid glands, hungry bone syndrome, HIV infection. High PTH (secondary hyperparathyroidism in response to hypocalcemia): vitamin D deficiency or resistance, parathyroid hormone resistance, renal disease, loss of calcium from the circulation (hyperphosphatemia, tumor lysis, acute pancreatitis, osteoblastic metastases, acute respiratory alkalosis, sepsis or acute severe illness. Drugs. Disorders of magnesium metabolism.
Metabolic acidosis can be categorized by presence or absence of anion gap. List causes from each category.
With increased AG (>12): ketoacidosis (diabetic, starvation, EtOH-associated), lactic acidosis, D-lactic acidosis, ingestions (methanol, ethylene glycol, diethylene glycol, propylene glycol, salicylate, toluene (if early or if kidney function is impaired)), pyroglutamic acid (5-oxoproline), CKD/uremia. With normal AG (<12): diarrhea or other intestinal losses, ureteral diversion, ketoacidosis posttreatment, carbonic anhydrase inhibitors, type 1 (distal) RTA, type 2 (proximal) RTA, type 4 RTA (hypoaldosteronism), toluene ingestion (if late and if renal function is preserved - dut to excretion of sodium and potassium hippurate in the urine), CKD and tubular dysfunction (but relatively preserved GFR).
Elevated plasma osmolal gap can be seen with or without metabolic acidosis. List causes of each category.
With anion gap metabolic acidosis: ingestion (ethylene glycol, methanol, formaldehyde, paraldehyde); lactic acidosis; diabetic ketoacidosis; alcoholic ketoacidosis; end-stage CKD (GFR <10 mL/min) without regular dialysis. Without metabolic acidosis: ingestion (ethanol, isopropyl alcohol, diethyl ether); infusion of nonconductive glycine, sorbitol, or mannitol solutions; severe hyperproteinemia; severe hyperlipidemia.
Metabolic alkalosis can be categorized by chloride responsive (U Cl 10). List causes of each.
Chloride responsive: diuretic therapy, vomiting, NGT suction, villous adenoma, carbenicillin, contraction alkalosis. Chloride resistant: hyperaldosteronism, Cushing syndrome, exogenous steroids, licorice (glyccrhizic acid), Bartter syndrome, milk-alkali syndrome.
Do pheochromocytomas (intra-adrenal) or paragangliomas (extra-adrenal) exhibit a higher risk of malignancy?
Paragangliomas.
Which are more often symptomatic: sympathetic (including pheochromocytomas) or parasympathetic paragangliomas?
Pheochromocytomas and most sympathetic paragangliomas are often associated with clinical symptoms, while only a small percentage of parasympathetic paragangliomas are symptomatic. Parasympathetic paragangliomas often lack tyrosine hydroxylase, the enzyme required for catecholamine synthesis, and are therefore usually nonfunctional.
At least 30% of paragangliomas and pheochromocytomas are associated with familial syndromes. Specific genotype-biochemical correlations highlight the importance of laboratory testing to characterize patterns of catecholamine excess. The biochemical profiles of tumors associated with mutations of genes encoding succinate dehydrogenase subunits, (collectively referred to as SDHx; x refers to all subunits, SDHA refers to subunit A, etc) are characterized by ___ and/or ___ production. VHL-related tumors are associated with ___ production. RET- and NF1-related tumors are associated with ___ production.
The biochemical profiles of tumors associated with mutations of genes encoding succinate dehydrogenase subunits, (collectively referred to as SDHx; x refers to all subunits, SDHA refers to subunit A, etc) are characterized by dopamine and/or norepinephrine production. VHL-related tumors are associated with norepinephrine production. RET- and NF1-related tumors are associated with epinephrine production.
In laboratory biochemical testing for pheochromocytomas and paragangliomas, why is measuring catecholamine metabolites superior to measurement of the parent catecholamine?
Catecholamines (dopamine, norepinephrine, and epinephrine) are not continuously secreted in normal conditions, and undergo intracellular methylation by the tumor cells the produce them. Biochemical testing for the O-methylated metabolites of dopamine, norepinephrine, and epinephrine (methoxytyramine, normetanephrine, and metanephrine, respectively) in plasma and/or urine is therefore superior to measurement of the parent catecholamines.
Patients with multiple paragangliomas (including multiple pheochromocytomas in the same adrenal gland) should be evaluated for the possibility of underlying genetic susceptibility and thus genetic testing for ___ (7) mutations should be considered.
Patients with multiple paragangliomas (including multiple pheochromocytomas in the same adrenal gland) should be evaluated for the possibility of underlying genetic susceptibility and thus genetic testing for RET (rearranged during transfection), NF1 (neurofibromin 1), VHL (von Hippel-Lindau), SDHx (succinate dehydrogenase subunits, (collectively referred to as SDHx; x refers to all subunits, SDHA refers to subunit A, etc)), TMEM127 (transmembrane protein 127), MAX (MYC-associated factor-X), and KIF1Bbeta (kinesin family member 1B) mutations should be considered.
What is a composite pheochromocytoma/paraganglioma?
The term composite is used when a tumor combines features of pheochromocytoma or paraganglioma with those of MPNST, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Corticomedullary tumors, cauda equina paragangliomas showing ependymal differentiation, as well as gangliocytic paragangliomas that include Schwann-like cells and ganglion cells do not qualify as composite tumors. Moreover, scattered mature ganglion cells seen in pheochromocytomas/paragangliomas should not be misinterpreted as a component of a composite tumor.
VHL-related pheochromocytomas/paragangliomas may have what unique histologic features?
VHL-related tumors often exhibit a thick vascular capsule, hyalinized and myxoid stroma, round tumor cells intermingled with small vessels, cells with predominantly amphophilic and clear cell cytoplasm, absence of intracytoplasmic hyaline globules, lipid degeneration, and lack of nuclear atypic or mitoses.
Adrenal medullary hyperplasia is a precursor lesion of pheochromocytomas arising in ___ syndrome and is characterized by a nodular and/or diffuse enlargement of the adrenal medulla.
Adrenal medullary hyperplasia is a precursor lesion of pheochromocytomas arising in MEN 2 syndrome and is characterized by a nodular and/or diffuse enlargement of the adrenal medulla. Other predisposing genetic syndromes are not usually associated with adrenal medullary hyperplasia.
IHC positivity for tyrosine hydroxylase, which is the rate limiting enzyme in the synthesis of catecholamines, is very helpful to distinguish paragangliomas from other neuroendocrine carcinomas, which can also be negative for CKs. But the positivity is usually weaker and more variable, and sometimes absent, in (sympathetic/parasympathetic) paragangliomas.
IHC positivity for tyrosine hydroxylase, which is the rate limiting enzyme in the synthesis of catecholamines, is very helpful to distinguish paragangliomas from other neuroendocrine carcinomas, which can also be negative for CKs. But the positivity is usually weaker and more variable, and sometimes absent in parasympathetic paragangliomas compared to sympathetic paragangliomas.
What is the utility of IHC for SDHB in paragangliomas?
Loss of succinate dehydrogenase B expression if regarded as a surrogate marker for some of the familial paraganglioma syndromes caused by SDHx (x refers to all subunits, SDHA refers to subunit A, etc) mutations. Moreover, the use of SDHB Ab not only allows the identification of SDHx-related tumors, but also provides prognostic data, owing to the high rate of malignancy associated with SDHB-driven paragangliomas.
What hormones does the kidney produce?
It secretes hormones that participate in the regulation of systemic and renal hemodynamics (renin, prostaglandins, and bradykinin), red blood cell production (erythropoietin), and calcium, phosphorus, and bone metabolism (1,25-dihydroxyvitamin D3 or calcitriol).
By what mechanisms are the following lab results seen in pregnancy: Decreased albumin and total protein. Increased transport proteins such as TBG. Increased GFR. Increased insulin resistance.
Decreased albumin and total protein result from hemodilution. Increased transport proteins such as TBG result from increased estrogen. Increased GFR is due to increased blood volume and is reflected in decreased BUN, Cr, and urate. Increased insulin resistance is due to hPL, which has anti-insulin effects similar to GH.
When in pregnancy does insulin resistance develop, and what is the cause?
Until the mid-2nd trimester, glucose tolerance actually improves. After that, however, relative insulin resistance emerges, reflected in prolonged elevations in postprandial serum glucose. The most important cause of this is hPL, which has anti-insulin effects similar to GH.
Is hypothyroidism or hyperthyroidism more common in pregnancy?
Hypothyroidism. In pregnancy there is increased demand placed upon the thyroid due to an estrogen-driven increase in TBG and the TSH-like stimulatory effect of hCG. Patients with borderline thyroid function or those with borderline availability of iodine will be unable to meet these demands.
What is the most common cause of hyperthyroidism in pregnancy?
Transient hyperthyroidism of hyperemesis gravidarum, due to high levels of hCG.
Why is hypocalcemia seen only in some patients with medullary thyroid carcinoma, despite high circulating calcitonin levels?
This has been attributed to a secondary increase in PTH, as well as resistance of the tissues to the effect of calcitonin.
Why can mercury toxicity sometimes mimic pheochromocytoma?
Since mercury blocks the degradation pathway of catecholamines (it is suggested to inactivate S-adenosyl-methionine, which is necessary for catecholamine catabolism by catechol-o-methyl transferase), epinephrine excess causes profuse sweating, tachycardia, salivation and elevated blood pressure. There are increased amounts of vanillylmandelic and homovanillic acid in urine.
What are some extrahepatic manifestations of HCV infection?
Hematologic diseases such as essential mixed cryoglobulinemia, lymphoma, and aplastic anemia. Renal disease, particularly membranoproliferative glomerulonephritis. Autoimmune disorders such as thyroiditis and the presence of autoantibodies. Dermatologic conditions such as porphyria cutanea tarda and lichen planus. Diabetes mellitus.
What are some secondary causes of a predominant hypercholesterolemia?
Hypothyroidism, DM, nephrotic syndrome, cholestasis, cyclosporine, thiazide diuretics, or loop diuretics.
What are some secondary causes of a predominant hypertriglyceridemia?
Heavy alcohol consumption, obesity, DM, hepatitis, pregnancy, renal failure, beta blockers, isotretinion, corticosteroids, nephrotic syndrome, and gout.
What are some secondary causes of a mixed hypertriglyceridemia and hypercholesterolemia?
Severe examples of DM, hypothyroidism, or nephrotic syndrome. Also, type III hyperlipidemia, thiazides, loop diuretics, and beta blockers.
In Hashimoto’s disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab. In Graves disease, __% have anti-thyroglobulin Ab and __% have anti-thyroid peroxidase Ab.
In Hashimoto’s disease, 90% have anti-thyroglobulin Ab and 95% have anti-thyroid peroxidase Ab. In Graves disease, 50% have anti-thyroglobulin Ab and 90% have anti-thyroid peroxidase Ab.
Structure of insulin?
Insulin is synthesized as proinsulin, a single amino acid chain 51 amino acids long. Though it is a single polypeptide chain, by convention the first (amino terminus) several amino acids are called the B-chain, the next several amino acids are called the C-peptide, and the carboxy-terminal amino acids are called the A-chain. Disulfide bonds form between the A and B chains, and the C-peptide is proteolytically cleaved posttranslationally to make insulin. When islet cells are induced to secrete, they secrete disulfide-linked A-B chains (insulin) and C-peptide simultaneously.
When islet cells are induced to secrete, they secrete disulfide-linked A-B chains (insulin) and C-peptide simultaneously. C-peptide and insulin are produced in equimolar quantities, but the ratio of C-peptide:insulin is 5-15:1. Why?
Because insulin is rapidly metabolized compared to C-peptide.
Continuous glucose monitors determine glucose levels on a continuous basis (every few minutes) by measuring the glucose level of interstitial fluid. Changes in interstitial glucose lag changes in blood glucose by how long?
(5-15?) to up to 30 min.
In patients with insulinomas, the absolute insulin concentration may be normal, but it is inappropriately high for the degree of hypoglycemia. Thus, the diagnosis depends on the insulin:glucose ratio, which is often ___ with insulinoma. Also useful are proinsulin levels, which will be greater than __% of that of immunoreactive circulating insulin.
In patients with insulinomas, the absolute insulin concentration may be normal, but it is inappropriately high for the degree of hypoglycemia. Thus, the diagnosis depends on the insulin:glucose ratio, which is often greater than 180 with insulinoma, whereas normal is less than 0.25. Also useful are proinsulin levels, which will be greater than 25% (or up to 90%) of that of immunoreactive circulating insulin, whereas normal is less than 10%.
When can anti-insulin antibodies be seen?
Anti-insulin Abs can be raised in response to exogenous insulin, but this is rare in the era of human (recombinant?) insulin administration. Anti-insulin Abs may rarely occur in patients never exposed to exogenous insulin, and may cause reactive hypoglycemia (autoimmune insulin syndrome). Also, anti-insulin Abs may be found rarely in patients with insulinoma.
Do anti-insulin receptor antibodies cause hypoglycemia or hyperglycemia?
Hyperglycemia more commonly than hypoglycemia.
List causes of hypoglycemia.
Insulinoma. Nesidioblastosis. ILGF-like hormone secreting tumors (sarcomas, HCC). Advanced malignancy. Anti-insulin receptor antibodies. Autoimmune insulin syndrome. Post-gastric surgery. Drug induced (insulin, sulfonylureas, alcohol, quinine, salicylates, haloperidol, beta blockers, quinolones, pentamidine, ACE inhibitors, IGF-1). Critical illness such as hepatic/renal/cardiac failure, sepsis, inanition (def: an exhausted condition resulting from lack of food and water or a defect in assimilation; starvation). Hormone deficiency (cortisol, glucagon and epinephrine in insulin-deficient DM). Inborn errors of metabolism (glycogen storage disease, hereditary fructose intolerance, galactosemia, carnitine deficiency). Starvation. Accidental, surreptitious, or malicious hypoglycemia.
Autoantibodies can be frequently detected in type 1 diabetes. What are some targets?
Insulin. Islet cells. Glutamic acid decarboxylase (GAD65). ZnT8 (zinc transporter of islet beta cells). Insulinoma-associated protein 2 (IA-2 and IA-2 beta).
What are the 2 categories of pre-diabetes and their lab value definitions?
Impaired glucose tolerance (IGT) – OGTT (75 g oral glucose load) results in a two-hour plasma glucose of 140 to 199 mg/dL (7.8 to 11.0 mmol/L). Impaired fasting glucose (IFG) – FPG 100 to 125 mg/dL (5.6 to 6.9 mmol/L).
What are lab value definitions of diabetes mellitus?
FPG 126 mg/dL (7.0 mmol/L) or greater. A1C 6.5% or greater. 2 hr plasma glucose 200 mg/dL (11.1 mmol/L) or greater in an OGTT. Random (or “casual”) plasma glucose 200 mg/dL (11.1 mmol/L) or greater in the presence of symptoms. The diagnosis based on one of the above findings must be confirmed on a subsequent day by repeat measurement, repeating the same test for confirmation.
What is the normal value for fasting plasma glucose?
FPG less than 100 mg/dL (5.6 mmol/L). Fasting is defined as no caloric intake for at least eight hours.
What is the process for screening for/diagnosing gestational diabetes?
Screening can be performed at the first prenatal visit for high-risk women, where a FPG of 126 mg/dL or random plasma glucose of 200 mg/dL is diagnostic of GDM. In the absence of early screening/testing or if early screening/testing is negative, universal screening is performed at 24 to 28 weeks of gestation. There are numerous approaches from numerous organizations: one step vs. two steps, 75g vs 100g oral glucose load, 2 hr test vs 3 hr test.
Women who have been diagnosed with gestational diabetes mellitus should be tested for nongestational diabetes at what time postpartum?
6-12 wks postpartum.
What initial and repetitive lab testing is done in diabetes?
Hg A1C testing is used to monitor glycemic control. The frequency of testing is often individualized, but the ADA recommends testing at least twice a yr in stable patients and more frequently in others, and recommends the A1C be less than 7%. Adult patients are screened annually for lipid disorders. Testing for microalbuminuria is performed annually. The serum Cr is measured annually for calculation of eGFR. Magnesium levels should be checked periodically, since hypomagnesemia is a common problem in diabetics, and appears to complicate glycemic control.
How is diabetic ketoacidosis diagnosed?
Hyperglycemia (glucose at least 200 mg/dL; normoglycemic DKA is rare), ketosis, and metabolic acidosis (venous pH less than 7.30 or bicarbonate less than 15 mmol/L) are the usual requirements for the diagnosis of DKA. Occasionally the diagnosis is made solely on the basis of the typical clinical presentation coupled with urine dipstick findings of glycosuria and ketonuria.
How are the proportions of the types of serum ketones altered in DKA?
Acetone, acetoacetic acid, and beta-hydroxybutyrate are the major serum ketones. These are in a dynamic balance with one another and undergo continual interconversion, and in normal circumstances these are present in roughly equimolar concentrations. In DKA, due to an altered metabolic milieu, acetone and acetoacetic acid account for 20% of serum ketones and beta-hydroxybutyrate accounts for 80%.
In DKA, due to an altered metabolic milieu, acetone and acetoacetic acid account for 20% of serum ketones and beta-hydroxybutyrate accounts for 80%, whereas normally these are present in equimolar concentrations. What causes the initial apparent increase in ketones in the treatment of DKA?
Ketones are measured by the nitroprusside technique, a semi-quantitative method that is sensitive to acetone and acetoacetic acid but not beta-hydroxybutyrate. The apparent increase in “ketones” is due to beta-hydroxybutyrate being converted to the other two forms as total serum ketones decrease.
What is the clinical utility of anti-microsomal antibody AKA anti-thyroid microsomal antibody?
High specificity (90%) and sensitivity (95%) for Hashimoto disease, although up to 50% of patients with Graves disease will have antibodies. Note: Anti-liver kidney microsomal type 1 antibody is different, and is found in autoimmune hepatitis.
What is the clinical utility of anti-thyroglobulin antibodies?
Hashimoto disease.
What is the clinical utility of anti-thyroid-stimulating antibodies?
Also called LATS, it is present in 90% of individuals with Graves disease.
What diseases are associated with the following HLA types: HLA-DR2, HLA-DR3, HLA-DR4, HLA-B27?
HLA-DR2: multiple sclerosis, narcolepsy, protective for IDDM. HLA-DR3: SLE, Sjogren syndrome, myasthenia gravis, Graves disease (The DR3-DQ2 linkage is associated with IDDM, dermatitis herpetiformis, and celiac disease). HLA-DR4: IDDM, RA, pemphigus vulgaris. HLA-B27: ankylosing spondylitis and other “reactive” arthritidies.
What autoimmune condition are each of the following triggering exposures correlated with: Coxsackie B virus infection; HBV infection; K. pneumoniae infection; aldomet; penicillamine; procainamide, hydralazine, and isoniazid.
Coxsackie B virus infection - development of IDDM. HBV infection - polyarteritis nodosum. K. pneumoniae infection - onset of ankylosing spondylitis. Aldomet - WAIHA. Penicillamine - systemic vasculitis. Procainamide, hydralazine, and isoniazid - drug-induced SLE.
What auto-antibodies are associated with Hashimoto disease, and how are they detected?
Anti-microsomal and anti-thyroglobulin. IIF on cryostat sections of thyroid tissue; latex agglutination.
What auto-antibodies are associated with Graves disease, and how are they detected?
Anti-TSH (TSI/LATS). Detected by bioassay.
What auto-antibodies are associated with IDDM, and how are they detected?
Anti-islet cell, anti-glutamic acid decarboxylase (GAD), anti-insulin receptor. IIF on cryostat sections of pancreas; ELISA; bioassay.
Although rare, appendiceal endocrine tumors are the most common neoplasm of the appendix, and are the second most frequently occuring digestive endocrine tumor. AETs are separated into 2 groups: classic appendiceal endocrine tumors and goblet cell carcinoids. Describe each group: presentation, incidence, location of tumor in the appendix, histologic appearance, treatment.
Most classic AETs are diagnosed incidentally during appendectomy. They are associated with, but not related to, acute appendicitis b/c most tumors are located at the tip of the appendix (60-75%) and do not induce obstruction. M:F = 1:2. Histologically, classic AETs have uniform tumor cells arranged in rounded, solid nests, with some peripheral palisading infiltrating the appendiceal wall. Treatment is local resection for tumors
What is seen on FNA of parathyroid cysts?
Aspirates of parathyroid cysts characteristically yield thin, clear, watery fluid. Epithelial cells are typically sparse, relatively uniform and bland, resembling thyroid follicular cells. Immunocytochemical staining for PTH and analysis of cyst fluid for PTH may be diagnostically helpful.
For the following thyroid disorders, what are %s for the presence of anti-thyroglobulin Ab, anti-microsomal Ab, and LATS/TSI (Long-Acting Thyroid-Stimulating/Thyroid-Stimulating Immunoglobulin, AKA TSH receptor) Ab: Hashimoto thyroiditis, other thyroiditis (de Quervain and lymphocytic), Graves disease, thyroid carcinoma?
Hashimoto thyroiditis: 60-100%, 80%, 0%. Other thyroiditis (de Quervain and lymphocytic): 30-50%, 50%, 0%. Graves disease: 30%, 60-80%, 100%. Thyroid carcinoma: 20-50%, 15%, 0%.
Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in ___% of cases.
Autoimmune/lymphoplasmacytic/sclerosing pancreatitis is associated with elevation of serum IgG4 in more than 70% of cases.
Although somatostatin is a normal product of endocrine cells in both the pancreas and duodenum, somatostatin-producing neuroendocrine tumors arising in these 2 sites tend to behave differently. How?
Pancreatic: usually in the head of the pancreas; are not associated with NF-1; contain fewer psammoma bodies; have poorer prognosis; more commonly have the somatostatinoma syndromes. Duodenal: 6 times more common than pancreatic; functional ones are distinctly unusual in the duodenum; duodenum and periampullary location is more common in patients with NF-1; psammoma bodies are seen in over half of sporadic tumors and all of the NF-1 associated ones.
Duodenal somatostatin-producing neuroendocrine tumor with psammoma bodies. What syndrome is it associated with?
NF-1.
Which thyroid tumors are galectin-3 pos, CK19 pos, HBME-1 pos?
Papillary carcinoma (92% positive for galectin-3, 86% positive for CK19, 77% positive for HBME-1). Papillary carcinoma, macrofollicular variant (100%, 86%, 100%). Papillary carcinoma, follicular variant (90%, 89%, 90%). Follicular adenocarcinoma (66%, 59%, 62%).
Which thyroid tumors are galectin-3 pos, CK19 neg, HBME-1 neg?
Atypical follicular adenoma (90% positive for galectin-3, 14% positive for CK19, 29% positive for HBME-1). Hyalinizing trabecular tumor (86%, 38%, 0%). Hurthle cell adenocarcinoma (86%, 39%, 20%). Anaplastic carcinoma (74%, 25%, 7%). Hurthle cell adenoma (60%, 0%, 33%).
How does Hashimoto’s thyroiditis stain with galectin-3, CK19, and HBME-1?
Galectin-3 positive in 20%, CK19 positive in 87%, and HBME-1 positive in 19%.
Which thyroid tumors are galectin-3 neg, CK19 neg, HBME-1 neg?
Well differentiated thyroid tumor of uncertain malignant potential (37% positive for galectin-3, 33% positive for CK19, 40% positive for HBME-1). Nodular goiter (19%, 37%, 3%). Follicular adenoma (18%, 32%, 11%). Papillary hyperplastic nodule (13%, 25%, 0%). Thyroid nodule hyperplasia (10%, 24%, 0%). Thyrotoxic hyperplasia (7%, 9%, 0%).
How does normal thyroid tissue stain with galectin-3, CK19, and HBME-1?
0% positive for galectin-3, 20% positive for CK19, 0% positive for HBME-1.
MEN1 gene (disease = MEN1, protein product = menin) and RET gene (disease = MEN2, protein product = proto-oncogene tyrosine-protein kinase receptor ret). Is MEN1 a porto-oncogene as well?
No. MEN1 gene is a tumor suppressor gene.
MEN1 and all MEN2 subtypes (MEN 2A, FMTC, and MEN 2B) are inherited in an ___ manner.
MEN1 and all MEN2 subtypes (MEN 2A, FMTC, and MEN 2B) are inherited in an autosomal dominant manner.
What % of cases of MEN1, MEN 2A, and MEN 2B are caused by a de novo pathogenic variant?
MEN1: 10%. MEN 2A:
What is the main MEN1-associated endocrinopathy?
Parathyroid tumors. Onset in 90% of individuals is between ages 20 and 25 years with hypercalcemia evident by age 50 years.
Familial isolated hyperparathyroidism (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies. MEN1 germline pathogenic variants have been reported in between __% and __% of families with FIHP.
Familial isolated hyperparathyroidism (FIHP) is characterized by parathyroid adenoma or hyperplasia without other associated endocrinopathies. MEN1 germline pathogenic variants have been reported in between 20% and 57% of families with FIHP.
The ductal system of the pancreas is subdivided into what 5 parts?
Centroacinar cells, intercalated ducts, intralobular ducts, interlobular ducts (large and small), and main ducts.
The ductal system of the pancreas is subdivided into 5 parts: Centroacinar cells, intercalated ducts, intralobular ducts, interlobular ducts (large and small), and main ducts. What are the centroacinar cells?
Small, relatively inconspicuous, flat to cuboidal cells with pale or lightly eosinophilic cytoplasm and central oval nuclei. Centroacinar cells are located in the middle of the acini, where they partially border the acinar lumina along with the acinar cells, to which they are joined by tight junctions. The lumen surrounded by acinar and centroacinar cells drains into the intercalated ducts.
Approximately 95% of all individuals with the MEN 2B phenotype have a single nucleotide variant (SNV) in the tyrosine kinase domain of RET at codon __ in exon __, which substitutes a threonine for methionine.
Approximately 95% of all individuals with the MEN 2B phenotype have a single nucleotide variant (SNV) in the tyrosine kinase domain of RET at codon 918 in exon 16, which substitutes a threonine for methionine.
What is RET/PTC?
The RET proto-oncogene on chromosome 10q11.2 encodes a cell membrane receptor tyrosine kinase. In some papillary thyroid carcinomas, the tyrosine kinase domain of RET is fused with a heterologous gene that provides the promoter and the 5’-coding region. The product of this rearrangement is a chimeric oncogene named RET/PTC. Since the original report, at least 11 types of RET/PTC variants have been isolated.
RET/PTC. The RET proto-oncogene on chromosome 10q11.2 encodes a cell membrane receptor tyrosine kinase. In some PTCs, the tyrosine kinase domain of RET is fused with a heterologous gene that provides the promoter and the 5’-coding region. The product of this rearrangement is a chimeric oncogene named RET/PTC. Since the original report, at least 11 types of RET/PTC variants have been isolated. What variants are most common?
Most of these rearrangements are between RET on chromosome 10 and genes located on different chromosomes. By contrast, RET/PTC1 and RET/PTC3 are intrachromosomal paracentric inversions because the genes involved H4 and RFG (also designated ELE1/ARA70/NCOA4) are also all located on chromosome 10. RET/PTC1 and RET/PTC3 account for the vast majority of the variants, while the others are very rare and have little clinical significance.
