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Endocrine > Endocrine > Flashcards

Endocrine Flashcards

1
Q

List the circulating antibodies against thyroid antigens and their associated disorders

A

Hashimotos: Antithyroglobulin (TG), antithyroid peroxidase (TPO), antimicrosomal

Grave’s disease: TSH-receptor antibodies (TSHR-abs), 3 types (stimulating, blocking, neutral)

Other types of thyroiditis including post-partum, Riedel’s, focal lymphocytic: TPO, antimicrosomal

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2
Q

List 5 examples of malignant neoplasms and their associated paraneoplastic syndromes. Also name the underlying mechanims

A
  • Small cell lung CA
    • Cushing syndrome (ACTH)
    • Innapropriate ADH secretion (ADH)
    • Lambert-eaton myasthenia (autoimmmune)
  • Bronchogenic carcinoma:
    • Hypercalcemia (parathyroid hormone related protein)
    • Acanthosis nigracans (epidermal growth factor secretion)
    • Dermatomyositis (immunological)
    • Hypertrophic osteoarthropathy (?)
  • Pancreatic carcinoma:
    • Venous thrombosis (Trousseau)(tumor mucins activate clotting)
  • Fibrosarcoma
    • hypoglycemia (insulin)
  • Pulmonary carcinoid
    • carcinoid syndrome (serotonin)
  • RCC
    • polycythemia (erythropoeitin)
  • any advanced CA
    • non-bacterial thrombotic endocarditis (hypercoagulability)
  • Thymic CA
    • Red-cell aplasia (?)
  • Any CA
    • Nephrotic syndrome (tumor antigens/immune complex)
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3
Q

Classify tumors of the thyroid

A

Epithelial:

Benign: follicular adenoma, hyalizing trabecular adenoma

Malignant: Papillary Ca, Follicular Ca, Poorly differentiated Ca (insular), Undifferentiated ca (anaplastic), Medullary ca, Squamous cell ca, Mucoepidermoid ca, Mixed medullary/follicular, Spindle cell tumor with thymus-like differentiation (SETTLE), carcinoma showing thymus-like differentiation (CASTLE)

Others:

Primary lymphoma, Teratoma, Angiosarcoma, Leiyomyoma/sarcoma, Peripheral nerve sheath tumors, paraganglioma, SFT, follicular dendritic cell tumor, langerhans, metastatic

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4
Q

For the MEN1, MEN2a, MEN2B syndromes, give the characteristic findings and genetic alterations.

A

MEN1 (Wermer syndrome), Germline mutation in MEN1 (menin), a tumor suppressor gene (11q13)

  • Parathyroid (hyperparathyroidism due to hyperplasia or adenoma)
  • Pancreas (neuroendocrine tumors)
  • Pituitary (adenoma–prolactinoma)
  • Others: duodenal gastrinoma, thymic carcinoid, adrenocortical adenoma

MEN2a (Sipple syndrome), Germline activating mutation in RET protooncogene (10q11)

  • Pheochromocytoma
  • Medullary thyroid carcinoma/c-cell hyperplasia
  • Parathyroid hyperplasia

MEN2b (MEN3), Germline mutation in RET protooncogene

  • Pheochromocytoma
  • Medullary thyroid carcinoma
  • Marfanoid habitus
  • Neuromas/ganglioneuromas (skin, oral mucosa, eyes, respiratory tract)
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5
Q

What is the DDx and clinical significance of an intrathyroidal parathyroid nodule in a thyroidectomy specimen?

A

Histologic DDx:

  • Normal intrathyroidal parathyroid
    • hypoparathyroidism if others also removed
  • Parathyroid adenoma
    • cure of hyperparathyroidism, but r/o hyperplasia
  • Hyperplastic parathyroid
    • May need 2nd surgical procedure for other enlarged glands
  • Parathyroid carcinoma
    • vascular invasion, perineural invasion, capsular invasion and growth into supporting structures suggest, along with necrosis and atypical mitoses. Resection margins should be samples, LN examined for mets
  • ALso including follicular thyroid neoplasm, medullary thyroid carcinoma
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6
Q

List the indications for frozen section in parathyroid disease. Describe the handling of specimens for FS.

A

Indications:

  • Identify parathyroid tissue during surgery
  • Identify abnormal glands
  • Distinguish parathyroid adenoma from hyperplasia (in resected gland).
  • Rapid PTH assay not available intraoperatively

Specimen processing:

  • Determine if biopsy or entire gland
  • Measure and weigh (esp. resection) (n weight 30mg men, 35mg women) any gland >50mg=enlarged
  • Look for lesions (adenoma compresing normal gland), parenchyma/adipose tissue ratio
  • Submit small specimens entirely, if large, submit representative section
  • +/- Fat stain (oil red O)

Evaluation at frozen:

  • Is it parathyroid tissue?
  • Fat to parenchyma ratio
  • ? compressed rim normal parathyroid
  • Fibrous bands, invasive features, necrosis and other anomalies
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7
Q

Name morphologic variants of papillary thyroid carcinoma and their biological behaviour

A

Agressive: Tall cell variant, columnar cell variant, diffuse sclerosing variant, solid variant, hobnail variant

Average: follicular variant, macrofollicular variant, oncocytic variant, clear cell variant, papillary ca with fasciitis-like stroma

Good prognosis: papillary microcarcinoam

Others: cribriform morular (FAP/gardner syndrome), combined papillary-medullary (determined by medullary)

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8
Q

List 3 common diagnostic pitfalls with papillary thyroid carcinoma

A
  • Papillary hyperplasia (lacks nuclear features)
  • Encapsulated follicular variant of PTC mimicking follicular adenoma
  • Hashimoto’s thyroiditis: follicular epithelium with some features of PTC (focal)
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9
Q

List 5 cytologic features of papillary thyroid carcinoma on FNA (cytology)

A
  • Hypercellular aspirate
  • Neoplastic epithelial cells in monolayer sheets and papillae
  • Enlarged, molded nuclei with nuclear grooves, fine pale chromatin, small nucleoli
  • Chromatin clearing and nuclear pseudoinclusions
  • Background thick colloid, multinucleate giant cells, psammoma bodies
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10
Q

List 4 clinicopathologic prognostic factors for papillary thyroid carcinoma

A
  1. Patient age (<45)
  2. Tumor size (<1cm)
  3. Extrathyroidal extension (bad prognosis)
  4. Histologic type (aggressive variants), including tall cell, columnar, solid, hobnail
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11
Q

List 3 possible genetic alterations seen in papillary thyroid carcinoma

A
  1. RET/PTC rearrangement
  2. BRAF mutation
  3. RAS mutation
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12
Q

What is the prognosis for papillary thyroid carcinoma? List factors affecting prognosis

A

Excellent prognossi, 10 yr survival >90%. Spread by lymphatic channels to regional LN, rarely hematogenous spread to lungs/bone

Factors affecting prognosis:

Age (>45)

Tumor size

Extrathyroidal extension

Lymph node mets

Aggressive histologic types

Completeness of resection (margin status)

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13
Q

Describe the clinical features of medullary thyroid carcinoma

A
  • age: 5th-6th decade
  • painless nodule
  • 50% lymph node mets
  • 70% sporadic
  • mass effect (hoarseness)
  • hereditary MTC: MEN2b, childhood/adolescence
  • paraneoplastic syndromes: Cushing’s, carcinoid
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14
Q

List 3 characteristic histologic features of medullary thyroid carcinoma

A
  • Architecture: trabeculae or nests
  • Cell morphology: polygonal, spindled, plasmacytoid cells
  • Nuclei: round, fusiform, oval with salt n pepper chromatin
  • Amyloid deposit in stroma (congo red)
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15
Q

What ancillary studies/stains can be used in the diagnosis of medullary thyroid carcinoma?

A
  • Histochemistry: Congo red for amyloid
  • IHC: cam 5.2+, calcitonin +, CEA +, synaptophysin +, chromogranin +, TTF1 +, TGB-
  • EM: cytoplasmic electron-dense, membrane-bound secretory granules
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16
Q

Anaplastic thyroid carcinoma: List 3 clinical and 3 histologic differential diagnoses

A

Clinical DDx:

  • Lymphoma
  • Metastatic CA
  • Acute hemorrhage in a retrosternal goiter

Histologic DDx:

  • Metastatic CA
  • Primary sarcoma
  • Medullary CA
  • melanoma
  • lymphoma
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17
Q

If clinical and radiologic findings confirm thyroid derivation, which ancillary studies can be used to diagnose anaplastic thyroid ca?

A

IHC:

positive: Cam 5.2, EMA, vimentin, p53
neg: TTF-1, thyroglobulin, calcitonin, desmin, myogenin, CD31, CD34, S100, HMB45, MelanA, CD45

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18
Q

List 4 ddx for follicular neoplasms of the thyroid

A

Hyperplastic nodule in multinodular goiter: lacks complete fibrous capsule separating it from surrounding tissue

Follicular adenoma: demarcated from surounding parenchyma by fibrous capsule, without invasion of capsule or vascular invasion. No PTC nuclear features.

Minimally invasive follicular carcinoma: capsular/vascular invasion. No PTC nuclear features.

Follicular variant of PTC: encapsulated, follicular neoplasm with elongated follicles and thick colloid. Lining epithelium with PTC nuclear features, may be attenuated.

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19
Q

What is the role for FS in the diagnosis of thyroid nodules?

A
  • Diminished role since FNA; should be done pre-operatively
  • Usually done to assess for parathyroid tissue, LN for metastases
  • NO INDICATIONS FOR FS ON thyroid nodules if preoperative FNA shows benign/malignant diagnosis
  • For suspicious nodules/encapsulated nodules: Do touch prep.
  • NEVER do FS on lesions less than 1 cm
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20
Q

What is the histologic classification of thyroiditis?

A
  • Accute suppurative thyroiditis (bacterial, fungal)
  • Chronic lymphocytic thyroiditis (Hashimoto, silent)
  • Subacute granulomatous thyroiditis (De Quervain)
  • Subacute lymphocytic (painless)
  • Granulomatous (infectious, sarcoid, vasculitis-associated)
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21
Q

What are the clinical characteristics of Hashimoto’s thyroiditis?

A
  • Painless enlargement of thyroid gland in middle-aged women
  • Circulating autoantibodies to TTG, thyroid peroxidase
  • May be associated with transient thyrotoxicosis, but hypothyroidism develops over time
  • Increased risk for other autoimmune disease and B-cel non-hodgkin’s lymphoma (MALT)
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22
Q

Classify hyperparathyroidism

A

Primary hyperparathyroidism: parathyroid lesion such as hyperplasia, adenoma, carcinoma

Secondary: usually due to renal failure, but also inadequate dietary calcium, vitamin D, or malabsorption

Tertiary: autonomous parathyroid activity in renal failure

Familial hypocalciuric hypercalcemia: AD disorder with inreased parathyroid due to decreased sensitivity to extracellular calcium (renal excretion problem)

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23
Q

List the clinical manifestations of hyperparathyroidism

A
  • No symptoms
  • Symptoms including: (bones, stones, groans…)
  • Bone pain, fractures, osteoporosis
  • Nephrolithiasis
  • Polyuria/polydipsia due to renal insufficiency
  • consipation, nausea, PUD, pancreatitis, gallstones
  • CNS: depression, lethargy, seizures
  • Neuromuscular: weakness, fatigue
  • Cardiac: aortic/mitral valve calcification
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24
Q

Describe the histologic manifestations in the affected organs of patients with hyperparathyroidism:

A

Parathyroid: adenoma w/ delicate capsule, inconspicuous fat. Usually only chief cells, but occasional oxyphil adenomas, compressed rim normal parathyroid

Bone: increased osteoclast activity with erosion of bone matrix. Increased bone resorption with increased bone formation. Rarified trabecullae, with fibrosis of marros space with hemorrahge and cysts (osteitis fibrosa cystica)

Kidneys: nephrolithiasis, calcification of intersitium and tubules

SKin: calcification of walls of small blood vessels, skin necrosis (calciphylaxis)

Others: metastatic calcification in any organ

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25
Q

Describe the role of parathyoid hormone (PTH) in calcium metabolism

A
  1. Enhances gastrointestinal absorption of calcium
  2. Increases renal tubular reabsorption of calcium
  3. Increase urinary phosphate excretion and lowers the serum phosphate level
  4. Increases conversion of vitamin D to dihydroxy vitamin D in kidneys
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26
Q

What are the gross and microscopic morphologic features of pancreatic neuroendocrine tumors (including VIPoma)?

A
  • All NETs share gross/histo features; functional nomenclature (VIPoma, Insulinoma) should only be used in the setting of a clinical hormone syndrome
  • Gross: solitary, well-circ., unencapsulated, pink-tan-grey cut surface
  • Micro: organoid (trabecular, ensted, tubuloacinar, gyriform, pseudorosette)
  • Neoplastic cells are round, oval , plasmacytoid with eosinophilic granular cytoplasm and round nuclei with salt n peper chromatin
  • marked nuclear atypia uncommon
  • mitotic rate usually low
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27
Q

What is the IHC profile of pancreatic NETs?

A

Positive: chromogranin, synaptophysin, CD56, PGP, CK 8, CK18

PDX1, ISL1 (pancreatic origin)

VIP in 87% of diarrheaogenic VIPomas

CK19=agressive behaviour

***Positive IHC for a specific peptide hormone in pancreatic NET may reflect cell type, but not specific!!!

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28
Q

What is the most commonly produced hormon in functioning pancreatic NETs?

A

Insulin

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29
Q

List genetic syndromes associated with functioning pancreatic NETs

A

MEN1: pituitary adenoma, parathyroid adenoma, pancreatic NET, adrenocortical adenoma, foregut NET

Von-Hippel-Lindau: CNS hemangioblastoma, clear cell RCC, pheochromocytoma, pancreatic NET, endolymphatic cell tumor

Neurofibromatosis 1: pancreatic NET (insulinoma)

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30
Q

List features predictive of behaviour/prognosis in pancreatic NETs.

A
  • Stage
  • Grade
    • G1=<1 mitoses/HPF, ki67 0-2%
    • G2=2-20 mitoses/HPF, ki67 3-20%
  • Size (<1 cm, >2cm)
  • Functioning (earlier diagnosis)
  • Poor prognostic factors:
    • Mitoses >20/HPF (carcinomas)
    • Necrosis
    • Loss of PGR expression
    • Aneuploidy
    • upregulated CD44
    • CK19 expression by IHC
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31
Q

List 4 types of neuroendocrine tumors of the lung

A

Typical carcinoid

Atypical carcinoid

Large cell neuroendocrine carcinoma

Small cell carcinoma

Tumorlet

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32
Q

List 3 IHC stains used in diagnosis of neuroendocrine tumors of lung

A

chromogranin, synaptophysin, CD56

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33
Q

What are EM findings in neuroendocrine tumors?

A

Dense core neurosecretory granules in cytoplasm

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34
Q

List histologic features of pheochromocytoma

A
  • Alveolar, nested, trabecular or solid growth
  • Balls of chief cells (zellballen), surrounded by vascular sustentacular stroma
  • Chief cells are polygonal with basophilic cytoplasm and nuclei with salt n pepper chromatin
  • PAS positive intracytoplasmic hyaline globules
  • Mitotic figures rare
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35
Q

What features predict malignancy in pheochromocytoma?

A
  • Capsular invasion
  • Vascular invasion
  • Invasion of periadrenal tissue
  • Diffuse growth pattern
  • Necrosis
  • Increased cellularity
  • Spindle-cell morphology
  • Severe nuclear pleomorphism
  • Cellular monotony (small cells/high NC ratio)
  • Nuclear hyperchromasia
  • Increased mitoses
  • Atypical mitoses
  • Absence of hyaline globules

*** Metastases only real indicator

PASS score (>4 is concerning). Give 1point for first 4, 2 for rest.

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36
Q

What are the clinical features of pheochromotycoma and underlying mechanism?

A

Triad of sweating attacks, tachycardia and headaches is relatively specific for pheochromocytoma

  • related to catecholamine hypersecretion (usually norepinephrine > epinephrine); usually hypertension (abrupt; with tachycardia, palpitations, headaches, tremor, sense of apprehension and weight loss; unresponsive to treatment; isolated paroxysmal episodes of hypertension in < 50%)
  • increased urinary excretion of catecholamines or metabolites (vanilllylmandelic acid-VMA or total metanephrines); elevated serum chromogranin A levels
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37
Q

List useful IHC stains in diagnosis of pheochromocytoma

A

Chromogranin, Synaptophysin: positive in chief cells

S100: positive in sustentacular cells

Cytokeratin, melan A=negative (r/o neuroendocrine tumor, adrenocortical)

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38
Q

List genetic syndromes associated with pheochromcytoma

A
  • MEN2A (RET)
  • MEN2B (RET)
  • VHL (mutation VHL gene chromosome 3)
  • NF1 (neurofibromin)
  • Familial paragnaglioma 1 & 4 (Succinate dehydrogenase (SDH) A, B, C, D)
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39
Q

What is the most common cell type of gastric NETs?

A

Non-functioning enterochromaffin-like cell carcinoids

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40
Q

What is the most common hormone secreted by ileal NETs?

A

Serotonin

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41
Q

What test can be useful to detect ileal (serotonin secreting) NETs?

A

urine testing for 5-HIAA

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42
Q

List 4 clinical mainfestations of carcinoid syndrome

A
  • Episodic cutaneous fluishing
  • Abdominal cramps and diarrhea
  • Bronchospasm
  • Righ-sided endocardial fibrosis>pulmonary stenosis>tricuspid regurgitation
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43
Q

What are the indications for hemicolectomy in appendiceal NETs?

A
  • Size greater than 2 cm
  • Deep invasion into mesoappendix
  • Location at base of appendix/involvement of surgical margin/cecum
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44
Q

List 3 causes of HYPOparathyroidism

A
  • Surgical removal of parathyroid glands (i.e. for thyroid surgery)
  • Autoimmune polyendocrine syndrome type 1 (APS1): hypoparathyroidism, primarly adrenal insufficiency, mucocutaneous candidiasis
  • Autosomal dominant hypoparathyroidism due to gain-of-function mutations in Calcium sensing receptor CASR gene
  • Familial isolated hypoparathyroidism
  • Congenital absence of parathyroids
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45
Q

Name 6 clinical manifestations of hypercalcemia

A

Asymptomatic

Abdo pain, constipation, nausea, vomitting

Impaired renal concentration: poluria/dypsia

CNS: depression, psychosis, coma, confusion

Skeletal muscle weakness

Nephrolithiasis, ARF, nephrocalcinosis

Peptic ulcer, pancreatitis

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46
Q

List 4 causes of endogenous hypercortisolism

A

ACTH dependent: pituitary adenoma (Cushign disease), Ectopic ACTH secretion from small cell ca lung

ACTH independant: Adrenal cortical adenoma, adrenal cortical carcinoma, macronodular adrenal corticla hyperplasia, primary pignmened nodular adrenal diseae, McCune-Albright syndrome

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47
Q

List 3 causes of hypocortisolism

A
  • Primary adrenocortical insufficiency:
    • Congenital adrenal hypoplasia
    • Adrenoleukodystrophy
    • Autoimmune adrenal insufficiency (APS1, APS2), infection (AIDS, TB, Waterhouse-Friderichsen syndrom)
    • Amyloidosis
    • Sarcoidosis
    • Metastatic CA
  • Secondary adrenocortical insuffiency:
    • Hypothalamic pituitary disease (neoplasm, infection)
    • Hypothalamic pituitary suppression (steroid therapy)
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48
Q

What features indicate malignancy in adrenal cortical neoplasms?

A
  • Gross: size >100g, fleshy/rubbery, hemorrahge, necrosis, fibrosis calcification, degeneration, invasion into large veins/adjacent tissues
  • Micro (3 or more, modified Weiss criteria):
    • high nuclear grade (Fuhrman)
    • > 5 mitoses/50 HPF
    • Atypical mitoses
    • less than 25% clear cell component
    • Diffuse architecture (>33% tumor)
    • Necrosis
    • Venous invasion
    • Sinusoidal invasion
    • Capsular invasion
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49
Q

List 3 causes of hypercalcemia with NORMAL PTH

A
  • Hypercalcemia of malignancy
  • Vitamin D toxicity
  • Immobilization
  • Thiazide diuretics
  • Sarcoidosis
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50
Q

List 4 genetic syndromes associated with hypercalcemia

A

MEN1, MEN2a, Hyperparathyroidism/Jaw syndrome, Familial hypocalciuric hypercalcemia

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51
Q

Which genetic diseases are associated with medullary thyroid carcinoma and what is the gene involved?

A

MEN2a, MEN2b, familial medullary thyroid carcinoma (FMTC)

RET protooncogene on chromosome 10

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52
Q

What are the implications for relatives of a patient with medullary carcinoma of thyroid?

A
  • High risk of familial syndrome (MEN2a or 2b); if 2B, more aggressive and worse prognosis
  • Family should be offered genetic testing for RET gene mutation + counselling
  • Prophylactic thyroidectomy to affected family members
  • Regular screening for pheochromocytoma (MEN2a/2b) and hyperparathyroidism (MEN2a) for patient and family members
53
Q

How frequently is medullary thyroid ca associated with familial syndromes?

A
  • Majority sporadic
  • 25% heritable
  • assiciated with MEN2A, MEN2B, familial medullary thyroid carcinoma
  • Underlying RET protooncogene mutations are AD
54
Q

Name histologic variants of medullary thyroid carcinoma

A
  • Usual MTC has solid, trabecular, insular pattern with polygonal, plasmacytoid or spindle cell morphology with amyloid in stroma
  • Papillary variant
  • follicular variant
  • small cell variant
  • giant cell variant (ddx anaplastic ca)
  • clear cell variant (ddx rcc)
  • oncocytic variant (ddx hurthle cell neoplasm)
  • melanotic variant
  • mucin producing
  • encapsulated
  • mixed medullary/follicular
  • mixed medullary/papilary
55
Q

What is the clinical course of medullary thyroid carcinoma?

A
  • Clinical presentation: firm, painless nodule
  • 5 yr survival 83%, 10 year 3%
  • 50% mets at diagnosis
  • Distant mets (lung, liver, bone) in 25%
  • Poor prognosis: older age, male, local invasion, distant mets
56
Q

Diagnosis?

A

Thyroglossal duct cyst

57
Q

Thyroid lesion. Diagnosis?

A

Anaplastic ca thyroid

58
Q

Thyroid lesion. Diagnosis?

A

Columnar cell variant PTC

59
Q

Type of thyroiditis

A

De Quervains

60
Q

Diagnosis?

A

Grave’s disease

61
Q

Thyroid. Diagnosis?

A

Hashimotos’

62
Q

Thyroid neoplasm

A

Hurtle cell neoplasm

63
Q

THyroid lesion

A

Hyalinizing trabecular adenoma

64
Q

Thyroid lesion. Diagnosis?

A

Medullary carcinoma

65
Q

Parathyroid lesion

A

Adenoma/hyperplasia

66
Q

Parathyroid lesion

A

hyperplasia

67
Q

Thyroid lesion

A

Tall cell variant PTC

68
Q

Describe the effects of corticosteroids and their mechanisms

A
  • Effects:
    • Affect stress response, immune response, carbohydrate, lipid and protein metabolism
    • Produced in adrenal cortex
  • Mechanisms:
    • inflammation: bind to glucocorticoid receptor and enter nucleus, downregulate genes involved with inflammation and upregulate genes in anti-inflam.
    • Metabolism: stimulates gluconeogenesis in liver, moblizes amino acids from tissue, inhibits glucose uptake by adipose tissue, stimulates fatty acid release and fat breakdown
    • CNS: binds receptors in CNS to regulate blood pressure, salt excretion and sympathetic activation
    • Embryogenesis: promotes surfactant synethesis
69
Q

List the long-term complications of steroid use

A

Immunodeficiency: decreased function and number of lymphocytes, neutrophils, macrophages predisposing to infection

Adrenal insufficiency crisis: sudden withdrawl of long-term steroids

Cushing syndrome: bilateral adrenal cortical atrophy from exogenous steroids, decreased ACTH

Hyperglycemia, DM, insulin resistance

Osteoporosos

Cataracts

HTN

Hypothyroid

Growth failure

Glaucoma

Slow wound healing

70
Q

What conditions are included in autoimmune polyendocrinopathy syndrome type 1?

A
  • Chromosome 21, APS1
  • Mucocutaneous candidiasis
  • Ectodermal dystrophy
  • Pernicious anemia
  • Hypoparathyroid
  • Primary adrenal insufficiency
  • Idiopathic hypogonadism
71
Q

What are the features of autoimmune polyendocrinopathy syndrome, type 2?

A
  • Not monogenic
  • Adrenal insufficiency

Autoimmune thyroiditis

DM, type 1

72
Q

What are the lesions associated with Carney syndrome?

A
  • Spotty pigmentaiton
  • Psammomatous melanotic schwannoma
  • Endocrine overactivity (adrenal cortical hyperplasia, Cushing disease, GH pituitary adenoma)
  • Cardiac myxoma
  • Myxoid breast fibroadenomas
  • Large cell calcifying Sertoli cell testicular tumors
73
Q

What is Carney triad?

A
  • Pulmonary hamartoma
  • GIST
  • Extra-adrenal paraganglioma
74
Q

Conditions included in McCune-Albright syndrome

A
  • Irregular skin pigmentation
  • Polyostotic fibrous dysplasia
  • Precocious sexual development
75
Q

Name 5 pituitary cell types and their hormone

A

somatotrophs: growth hormone (AP)
lactotrophs: prolactin (AP)
corticotrophs: ACTH (AP)
thyrotrophs: TSH (AP)
gonadotrophs: FSH (AP)

*** oxytocin and ADH formed by hypothalamus and released into posterior pituitary

76
Q

What are 3 manifestations of pituitary disorders?

A
  • Hyperpituitarism (excess secretion of trophic hormones, due to adenoma/hyperplasias/carcinoma)
  • Hypopituitarism (deficiency in trophic hormone, due to ischemia, surgery, radiation, non-functional adenoma)
  • Local mass effect (radiologic abnormality of sella turcica; presents with visual field defects (bitemporal hemiaopsia) and features of raised ICP)
77
Q

Classify pituitary adenomas by cell type, hormone and associated syndrome

A
  1. corticotroph: ACTH, cushing syndrome
  2. Somatotroph, GH, gigantism/acromegally
  3. lactotroph: prolactin, galactorrhea amenorrhea, infertility
  4. mammosomatotroph: prolactin+GH, combined features of GH & prolactin
  5. Thyrotroph: TSH, hyperthyroidism
  6. Gonadotroph: FSH, hypogonadism, mass effect, hypoituitarism
78
Q

What is the clinical presentation of a pituitary adenoma?

A
  • adults, age 35-60
  • may be incidental (especially microadenomas less than 1cm)
  • can present with bitemporal hemianopsia, or raised ICP with H/A, N/V
  • may or may not be functional with hormonal disregulation
79
Q

Name 4 genetic alterations in pituitary adenomas, their mechanism and primary pituitary subtype

A

G-protein mutations most comon; activating leading to GH adenomas

  1. Protein kinase A; germline inactivating mutations of PRKARI in Carney’s complex leading to gain of function, GH adenoma
  2. Cyclin D1: overexpression in agressive adenomas
  3. HRAS: activating mutation in pituitary carcinomas
  4. MENIN: germ-line inactivating mutations in MEN1; GH, prolactin and ACTH adenomas
  5. CDKN1B: inactivating mutation, ACTH adenoma
  6. Retinoblastoma RB protein; methylation of promoter leading to loss of function, aggressive adenomas
80
Q

Name 4 genes causing familial pituitary adenomas:

A

MEN1

CDKN1B

PRKAR1A

AIP

81
Q

What are the gross and histologic features of pituitary adenoma, and what IHC stains can be useful?

A
  • soft, well circumscribed lesion within sella turcica, but may erode bone and neighbouring tissue
  • macroadenomas >1cm may have hemorrhage/necrosis
  • compoed of uniform, polygonal cells arrayed in sheets/cords with SPARSE reticulin
  • cytoplasm may be acidophilic, basophilic or chromophobic

(can be distinguished from normal pituitary by lack of reticulin and monomorphic appearance)

  • atypical adenomas: ki67 >3% or p53 staining
82
Q

organ?

A

pituitary

83
Q

Diagnosis?

A

pituitary adenoma

84
Q

Pituitary lesion

A

pituitary adenoma

85
Q

40yr pituitary, diagnosis

A

pituitary adenoma. Note electron-dense secretory granules and granular endopalsmic reticulum

86
Q

What are the histologic and clinical features of prolactinomas?

A
  • Most fequent hyperfunctioning pituitary adenoma
  • histologically weakly acidophilic/chromophobic cells + prolactin IHC
  • may have psammoma bodies/calcs
  • present with amenorrhea, galactorrhea, loss of libido, infertility
87
Q

What are the clinical and histologic features of somatotroph (GH) adenomas

A
  • 2nd most common
  • stimulate hepatic secretion of insulin-like growth factor 1, causing clinical manifestations
  • generalized increase in body size (kids), growh in visceral organs, hands and feet in adults with prognathism
  • also gonadal dysfunction, diabetes mellitus, muscle weakness, hypertension, CHF
  • usually acidophilic (densely granulated), cytokeratin perinuclear dot, IHC+ GH but also sparesely granulated with chromophobe cells and weaker GH staining
88
Q

What are the clinical and histologic features of ACTH cell adenomas

A
  • Usually small microadenomas at diagnosis
  • present with hypercortloism (Cushing disease), hyperpigmentation because of melanocyte stimulation
  • usually basophilic and stain positive for ACTH, PAS
89
Q

How much pituitary must be lost to have symptoms of hypopituitarism and what would make you suspect hypothalamic failure?

A
  • 75% must be lost if intrinsic to pituitary
  • if hypopituitarism+ evidence of posterior pituitary dysfunction (i.e. diabetes insipidus), then likely hypothalamus is problem
90
Q

Name 8 causes of hypopituitarism

A
  1. Tumor/mass lesion compressing pituitary cells
  2. traumatic brain injury/subarachnoid hemorrhage
  3. radiation/pituitary surgery
  4. pituitary apoplexy (hemorrhage into gland, with excruciating H/A, diploplia, cardiovascular collapse)
  5. Sheehan syndrome (ischemic necrosis; due to enlargement during pregnancy and subsequent ischemia)
  6. Rathke cleft cyst: cuboidal epithelium + goblet cells

7 .empty sella syndrome

  1. genetic defects (POUF1 deficiency)
  2. hypothalamic lesions
  3. inflammation and infections (sarcoid/TB)
91
Q

What are 2 posterior pituitary syndromes?

A
  • Diabetes insipidus
  • Syndrome of inappropriate ADH secretion
92
Q

What are the features of craniopharyngeomas?

A
  • arise in the suprasellar region, derived from Rathke’s pouch
  • BImodal age distribution (childhood 5-15 aned adults>65)
  • presents with H/A and visual distrubance
  • B-catenin mutations reported
  • 2 types: adamantinomatous and papillary
  • adamantinomatous: nests/cords of stratified squamous epithelium embedded in spongy reticum with palisading, Wet keratin and dystrophic calcificaations; may form cysts and contain cholesterol-rich “machine oil” fluid
  • papillary: solid sheets/papillae lined by well-differentiated squamous epithelium, without keratin, calcs or cysts. Lack peripheral palisading
  • tumors <5cm have good prognosis, SCC rare if radiated
93
Q

lesion in the sella turcica

A
  • Craniopharyngeoma, adamantinomatous type
94
Q

Adrenal glands: What is the normal combined weight, what are the layers of the cortex and their hormones, and what sections would you take if grossing a resection?

A
  • Normal combined weight should not exceed 6g
  • Layers of cortex: glomerulosa (aldosterone), fasciculata (cortisol), reticularis (sex steroids)
  • If adrenlolectomy for primary process, orient, weigh, measure, ink periphery. Serial section:

for diffuse hyperplasia: representative sections

for mass lesion: give size, circumscription. colour, necrosis, hemorrhage, take sections of tumor including capsule, relationship to adrenal gland, relationship to soft tissue etc. Photograph

95
Q

Neuroblastoma in pediatrics: How would you handle adrenal gland?

A
  • Follow the COG (Children’s Oncology Group) protocol
  • 1g of snap frozen tissue (store rest at -70)
  • fresh tissue for cytogenetics
  • air dried slides for FISH
  • label as primary or metastatic
96
Q

What are the 3 most common sites of adrenal cortical heterotopias in males?

A
  • Spermatic cord
  • Inguinal hernia sac
  • Periepididymal soft tissues
  • celiac axis
97
Q

Besides adrenal heterotopias, name 3 other congenital abnormalities of the adrenal gland

A
  • Adrenal fusion
  • Adrenal cytomegally
  • Intraadrenal heterotopies
  • Congenital adrenal hyperplasia
98
Q

What is adrenal cytomegally and with what condition is it associated?

A
  • Adrenal cytomegaly is chaacterized by the presence of foci of bizarre cells with eosinophilic granular cytoplasm and large hyperchromatic nuclei with pseudoinclusions
  • Seen in Beckwith-Wiedemann syndrome
99
Q

What is the incidence of non-functional cortical nodules, what is their gross appearance and histologic features?

A
  • Non-functional adrenal cortical nodules in 1-10% of autopsies
  • Yellow, well-circumscribed nodules
  • Usually fascicular-type cells, myelolipomatous metaplasia, osseus metaplasia, +/- hyalinization or calcification; pigmented nodules possible (lipofuschin)
100
Q

Name 4 causes of primary adrenal cortical insufficiency

A
  1. Autoimmune destruction of adrenal cortex (most common)
  2. Infection (TB, Meningococcus, Pseudomonas, CMV, HSV, toxoplasmosis), including Waterhouse-Fridreichson
  3. Adrenoleukodystrophy (x-linked peroxisomal disorder)
  4. Amyloidosis
  5. Congenital adrenal hypoplasia
  6. drug related (mitotane)
101
Q

Describe 5 features of autoimmune adrenal cortical insufficiency (Addison’s)

A
  • Destruction of the adrenal cortex by T-cells
  • 80% of cases in developed countries
  • Destruction of cortex with lympohcytes, plama cells and histiocytes + germinal centres, intact medulla
102
Q

Congenital Adrenal hyppoplasia: Name 5 features

A
  • Uncommon, seen at fetopsy, 1:12 500 births
  • defined as combined adrenal weights of <2g at term
  • 3 cytomorphologic patterns: cytomegally type (X-linked), anencephalic type (w/o CNS defects), miniature type with attenuated fetal cortex
103
Q

How is adrennal cortical insufficiency categorized?

A

Primary: i.e. adrenal cortical insufficiency (problem with adrenal cortex itself)

Secondary: Failure of pituitary gland to secrete ACTH

Tertiary: Failure of hypothalamus to secrete CRH

  • All present with small glands/atrophy
104
Q

Name 5 features of congenital adrenal hyperplasia

A
  • Autosomal recessive caused by deficiency of enzymes required for biosynthesis of glucocorticoids/mineralcorticoids
  • 1 of 5 enzymatic defects resulting in failure of cortisol synthesis; 21-hydroxylase deficiency is most common (95%)
  • glands enlarged bilaterally with cerebriform appearance
  • zona fasiculata cells are lipid depleted, with conversion into zona reticularis (eosinophilic) cells
  • may give rise to adrenal cortical neoplams-

presents with virilization/ambiguous genitalia in females

105
Q

Name 4 non-neoplastic forms of adrenal cortical hyperplasia

A
  • Diffuse
  • nodular
  • Primary pigmented nodular adrenocortical disease (PPNAD)
  • Adrenal cortical hyperplasia with hyperaldosteronism
106
Q

What are the histologic features of diffuse adrenocortical hyperplasia and what are 5 causes?

A

Both glands symmetrically enlarged, zone fasciulata and reticularis are expanding; fasciculata lipid depleted

Causes include: Hyperfunctional pituitary (ACTH secreting adenoma), Hypothalmic CRH secreting tumor, Neoplasms including small cell carcinoma, carcinoid, medullary thyroid, pancreatic endocrine, pheo

107
Q

Describe 5 features of nodular adrenal cortical hyperplasia.

A
  • ACTH independant
  • Markely inlarged glands (>15-20g)
  • yellowish nodules 2mm-4cm
  • Fasciculata type, reticularis type, or mixture
  • Glomerulosa in nodules with cortical atrophy=McCune Albright in CHildren
108
Q

Name 5 features of primary pigmented nodular adrenocortical disease

A
  • ACTH-independant nodular hyperplasia
  • 2nd decade of life, no other Carney’s complex stigmata
  • heterozygous inactivation of PRKR1A
  • Normal size glands with pigmented micronodules
  • Uniform compact cells with eosinophilic cytoplasm and balloon cells w/ intracytoplasmic lipofuscin
  • Synaptophysin + but Chromogranin -
109
Q

Describe the features of Conn syndrome

A
  • Adrenal cortical hyperplasia with hyperaldosteronism
  • Due to adenoma in 70%, Absence of adenoma in 30% due to bilateral cortical hyperplasia
  • Size/weight/appearance may be within normal range
  • Zona glomerulosa ha tongue-like projections towards fasciculata
110
Q

What is the classification of tumors of the adrenal gland?

A
  • Adrenal cortical tumors: cortical adenoma, carcinoma
  • Adrenal medullary tumors: benign pheo, malignant pheo, composite pheo
  • Others: adenomatoid, sex-cord, soft tissue (myelolipoma, teratoma, schwannoma, ganlioneuroma, angiosarcoma, leiyomyoma)
  • metastatic

(Note: some classifications put the neuroblastomas with the medullary tumors; therefore neuroblastoma, ganglioneuroblastoma, ganglioneuroma) etc.

111
Q

What is the WHO classification of extra-adrenal paragangliomas?

A
  • Jugulotympanic
  • Vagal
  • Laryngeal
  • ORbital/nasopharyngeal
  • Carotid body
  • Aorticopulmonary
  • Gangliocytic
  • Cauda equine
  • Cervical paravertebral
  • Intrathoracic
  • Intraabdominal
  • Superior paraaortic
  • Inferior paraaortic
  • Urinary bladder
112
Q

What are features of adrenal cortical adenomas, including specific features of subtypes

A
  • Functionning adenomas present with Cushing syndrome (60%), mineralcorticoids-androgens (20%), and lesser proportions of others
  • Hyperaldosterone secreting: usually adenoma, <2cm, yellowish-encapsulated with ZF, ZR and ZG-type cells. If treated with aldosterone, SPIRONOLACTONE bodies are present: eosinophilic, 2-6 concentric rings, halos.
  • Cushing: sharply-demarcated, homogenous yellow-golden, larger than normal cortical cells. Compressed residual cortex.
  • Adrenogenital: more often cortical carcinomas producing estrogens, sharply demarcated with reticularis-type cells
113
Q

What are some rare variants of adrenal cortical adenomas?

A
  • Black (pigmented adenoma): lipofushin
  • Oncocytic neoplasms
  • Myxoid neoplasms (myxoid-mucoid with cords/nest/pseudoglands) with spindled/epithelioid cells
  • ectopic adrenal cortical denoma
114
Q

Adrenal Cortical Carcinoma: What are criteria in the modified Weiss system for malignancy? What features are definitely indicative of malignancy?

A
  • Mitotic rate>5/50HPF
  • Dense eosinophilic cytoplasm in more than 75% of tumor
  • Atypica/bizarre mitoses
  • Necrosis
  • Capsular invasion

Uniquivocal malignant features: invasion into soft tissue/adjacent organs, invasion of a major vessel, metastasis to regional LN or distant site

115
Q

What is the staging of adrenal cortical carcinomas?

A
  • T1 <5cm, no extraadrenal invasion
  • T2 >5cm, no extraadrenal invaion
  • T3= extraadrenal invasion
  • T4 any size invading adjacent organs
116
Q

What is the differential diagnosis of adrenal cortical carcinoma and what IHC stains are positive?

A
  • Ddx: pheochromocytoma, metastatic renal cell carcinoma, HCC, Pecoma, Angiomyolipoma, epithelioid leiyomyosarcoma, epithelioid mesothelioma, epithelioid GIST

IHC: vimentin, inhibin, melan-A, adrenoal cortical antigen, calretinin

117
Q

What are the criteria needed to call adrenal cortical carcinoma in pediatric age group?

A
  • Weiss criteria do not apply
  • Neoplasms weighing in excess of 400g likely to behave malignant
118
Q

What syndromes are associated with adrenal cortical carcinomas?

A
  • Li-Fraumeni syndrome or SBLA (sarcoma; breast and brain tumors; leukemia, laryngeal carcinoma and lung cancer; and adrenal cortical carcinoma) p53
  • Beckwith-Weidmann syndrome CDK1C
  • MEN1
  • Gardner’s syndrome APC
119
Q

Name 4 syndromes associated with pheochromocytomas

A
  • MEN 2 (RET/10q)
  • NF1 (NF1/17q)
  • VHL (VHL/3p)
  • pheochromocytoma-paraganglioma SDHD/11q syndrome 1
  • pheochromocytoma-paraganglioma SDHD/1q

syndrome 2

120
Q

What is the difference between adrenal medullary hyperplasia and pheochromocytoma?

A
  • Cutoff of 1 cm
  • AMH often adjacent to pheo
  • Both associated with MEN 2A, 2B, Beckwith-Wiedemann, neurofibromatosis, carcinoid tumors, Cystic fibrosis, sudden infiant death syndroe
  • familial paragnlioma: succinate dehydrogenase subunit B mutations also seen in AMH
121
Q

What is the criterion for malignancy in pheochromocytoma?

A
  • Metastasis to bone, LN, liver, lungs
  • 10% are malignant
122
Q

What are features and locations of parasympathetic paragangliomas?

A
  • Predilection for head and neck
  • Cranial nerves 9 and 12

60% are carotid body tumors (at bifurcation of external and internal carotid arteries)

  • also glomus jugulare, glomus tympanicum, glomus vagale
  • Rare sites include larynx, paranasal sinuses, salivary gland, orbit, oral cavity
  • usually 1-6cm, grey-tan

Compressed spindle cells at periphery corresponding to sustentacular cells

  • positive on IHC for chromogranin, synaptophysin, CD56 and focally cyclin D1
123
Q

What are features of sympathetic paragangliomas?

A
  • Present in abdomen-retroperitoneum i 80%; superior paraaortic, adrenal gland/renal hilum, inferior paraortic, organ of Zuckerkandl or bladder
  • More likely to be functional with higher catecholamine concentrations
  • more often malignant (25-65%) with metastatic potential exceeding adrenal pheos
  • Malignant featurs include size >100g, confluent necrosis, mitotic and proliferative activity, absence of hyaline globules, small cell morphology
124
Q

What are features of adrenal myelolipoma

A
  • <5% of primary adrenal tumors
  • detected incidentally
  • 3-5cm
  • varying proportions of mature adipose tissue admixed with normal trilineage hematopoesis
  • DDx lipoma, angiomyolipoma, angiosarcoma
125
Q

What are features of adenomatoid tumor in adrenal?

A
  • well-circumscribed, solid, 0.5-9cm incidentiloma
  • tubules, cysts, papillary structures, and occasional solid sheets of low cuboidal cells +/- cytoplasmic vacuoles
  • Same IHC profile as mesothelial cells; CK7+, vimentin +, calreinin + WT-1+
  • DDx lymphangioma, metastatic carcinoma, vascular tumors (epithelioid angiosarcoma)
126
Q

What is the T staging for anaplastic thyroid carcinoma?

A

pT4a: Intrathyroidal anaplastic carcinoma
pT4b: Anaplastic carcinoma with gross extrathyroid extension

127
Q

What is the T staging for thyroid carcinomas (except anaplastic)

A

pT0: No evidence of primary tumor
pT1: Tumor size 2 cm or less, limited to thyroid
pT1a: Tumor 1 cm or less in greatest dimension limited to the thyroid.
pT1b: Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid

pT2 Tumor more than 2 cm, but not more than 4 cm, limited to thyroid
pT3 Tumor more than 4 cm limited to thyroid or any tumor with minimal extrathyroid extension (eg, extension to sternothyroid muscle or perithyroid soft tissues)
pT4a Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerve

pT4b Very advanced disease. Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

128
Q

What is the “whipple triad” in B-cell endocrine neoplasms of the pancreas?

A

characteristic of this tumor consists of: (1) mental confusion, weakness, fatigue, and convulsions; (2) fasting blood glucose levels below 50 mg%; and (3) relief of symptoms by the administration of glucose.

129
Q
A

Endocrine (1 decks)

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