ENDOCRINE PATHOLOGY

PITUITARY

NORMAL

Adenohypophysis

• § Somatotrophs GH
• § Lactotrophs PRL[1]
• § Corticotrophs ATCH
• § Thyrotrophs TSH
• § Gonadotrophs LH

Neurohypophysis

• § Axons from hypothalamus

HYPERPITUITARISM

Etio

• § Primary: pituitary adenoma (by far no1), rarely carcinoma
• § Secondary: hypothalamic hyperfunction

HYPOPITUITARISM

Etio

• § Primary:
• § Secondary
  • Ø Ischemia[2]: DIC, sickle cell anemia, increased intracranial pressure, trauma, shock
  • Ø Pituitary apoplexy: sudden hemorrhage in pituitary gland (mostly in pituitary adenoma)
  • Ø Radiation
  • Ø Inflammation
  • Ø Nonfunctioning neoplasms or cysts[3] compressing sella
  • Ø Surgery: excessive removal of pituitary tissue during adenoma resection
  • Ø Sarcoidosis, TB
  • Ø Amyloidosis
• § Empty sella syndrome
  • Ø Primary: defect in diaphragm sellaeà herniation
  • Ø Secondary: mass, radiation, surgery

Genetics

• § Pit-1 mutation

Clinical

• § >75% parenchymal destruction needed to become symptomatic
• § Supraoptic (ADH) and paraventricular (oxytocin) nuclei of hypothalamus
• § Polydipsia, hyperNa
• § Head trauma, tumors, inflammation of hypothalamus and pituitary, surgery
• § HypoNa, cerebral edema
• § Ectopic secretion of ADH by tumors (SCLC) or non-tumors (TB) or local injury to pituitary or hypothalamus

POSTERIOR PITUITARY SYNDROME

DIABETES INSIPIDUS

SIADH

PITUITARY ADENOMA

Clinical

• § 30-60, hormonal effects, compressive effects
• § Any adenoma can cause mild increase in PRL due to stalk effect (interference with dopamine inhibition)

Genetics

• § Mutation in α-subunit of Gs[4]
• § MEN1[5]

Micro

• § Single cell population
• § Sheets, cords, nests, papillae
• § Scanty reticulin network
• § Atypia, necrosis, hemorrhage not imply malignancy
• § Can invade (called invasive adenoma)

Cutoff point for microadenoma vs macroadenoma

• § 1cm

EM

• § Membrane-bound secretory granules

GH ADENOMA

Clinical

• § No2 most common
• § GHà stimulates IGF-1[6] secretion by liverà gigantism or acromegaly

Micro

• § Acidophilic granular or chromophobic cytoplasm

Variants

• § Juxtanuclear “fibrous body” (CK+)

PROLACTINOMA

Clinical

• § No1 functional pituitary adenoma
• § Most macroadenomas
• § Characterized by efficiency[7] and proportionality
• § Amenorrhea, galactorrhea, loss of libido, infertility

Micro

• § Granular acidophilic or chromophobic cytoplasm
• § IHC required for identification
• § HyperT4

THYROTROPH CELL ADENOMA

CORTICOTROPH CELL ADENOMA

Clinical

• § Usually microadenomas

Micro

• § Basophilic or chromophobic cytoplasm
• § Crooke hyaline change[8]
• § Most often silent gonadotroph cell adenomas
• § Mostly non-functioning
• § Diagnosis requires metastasis

GONADOTROPH CELL ADENOMA

NULL CELL ADENOMA

PLURIHORMONAL (mixed)

PITUITARY CARCINOMA

GANGLIOCYTOMA

CHORDOMA

MENINGIOMA

GRANULAR CELL TUMOR

METS

SUPRASELLAR LESIONS

GLIOMAS

CRANIOPHARYNGIOMA

Clinical

• § Derived from vestigial Rathke pouch
• § Slow-growing
• § Most suprasellar but can be intrasellar
• § Mostly in childhood or adolescence
• § Endocrine deficiencies, growth retardation, visual disturbances

Micro

• § Cystic, calcified (75%)
• § Squamous epithelium
• § Reticular stroma
• § Wet keratin (compact lamellar keratin, cholesterol-rich, thick brown fluid)à machinery oil appearance
• § Rarely malignant

THYROID

NORMAL

Normal weight

• § 40g
• § TSH stimulates
  • Ø Conversion of TG to T4/T3[9] by thyroid follicular epithelium
  • Ø Release of T4/T3
• § T4/T3 are
  • Ø Bound to thyroxin-binding globulin (TBG)
  • Ø Provide feedback inhibition on thyroid
  • Ø T4 deiodinated peripherally to T3
• § Binding of T3 with nuclear thyroid hormone receptor (TR) results in formation of hormone-receptor complex that binds to thyroid hormone response elements (TRE) in target genes regulating their transcriptionà increases carbohydrate and lipid catabolism, stimulates protein synthesisà increased basal metabolism

NECK DISSECTION

Types: which 3 items? (hint: JAS)

• § Selective: LN[10] and soft tissue only
• § Radical: LN, soft tissue, IJV, spinal accessory nerve, SCM
• § Modified-radical: same as radical except preserving any one of three
• § Extended radical: same as radical with any additional structures (paratracheal LN, carotid artery)

CONGENITAL ANOMALIES (hint: branchial)

HETEROTOPIA

• § Anywhere along thyroglossal duct: intralingual, sublingual (no1), thyroglossal cyst, mediastinal and substernal[11]
• § Also cervical LN, larynx, trachea, esophagus, heart and great BV (Steinberg, Rosai)
• § Can be intramuscular and simulates muscle invasion

ULTIMOBRANCHIAL BODY REMNANTS (solid cell nests)

Clinical

• § Associated with C-cell development
• § Inconsequential
• § Small nests (≈0.1mm) of bland cells
• § Oval nuclei, nuclear grooves
• § Never in isthmus

THYROGLOSSAL DUCT CYST

Clinical: where, name 2 complications, who,

• § Anterior midline at or immediately below hyoid bone (between tongue and above sternum!)[12]
• § Secondary infection[13] or cancer[14]
• § Mostly in kids and young adults

Gross

• § Mucoid, purulent

Micro

• § Respiratory or squamous lining[15]
• § Fibrosis
• § Chronic inflammation
• § Thyroid tissue visible in 2/3 cases

Treatment

• § Must remove middle 1/3 of hyoid for complete excision

DD

• § Epidermoid cyst
• § Degenerated adenomatoid nodules
  • § Black pigments in follicular cells and colloid
  • § Minocycline and tetracycline

BLACK THYROID (melanosis thyroidi)

DD

• § Hemochromatosis
• § Onchronosis
• § Ceroid storage disease

HYPOFUNCTION

ATROPHY

Etio

• § Idiopathic, old age, radiation, pituitary or hypothalamic dysfunction

Lab

• § Euthyroid or hypothyroid

Micro

• § Small fibrotic gland
• § Small follicles with lymphocytes

CRETINISM

What 2 systems affected?

• § Neuroskeletal

2 forms

• § Endemic: dietary deficiency
• § Sporadic: defective hormonal synthesis

MYXEDEMA

INFLAMMATION

ACUTE THYROIDITIS

Clinical

• § Immunocompromised or trauma
• § Euthyroid, sudden onset of pain
• § Rare but by large infectious (viral, bacterial, fungal, pneumocystis)

2 possible pathways of spread?

• § Direct seeding (via fistula from piriform sinus[16], trauma)
• § Hematogenous

Micro

• § PMN + necrosisà if abscess drain surgically
• § Culture

SUBACUTE THYROIDITIS (granulomatous thyroiditis, de Quervain)

Clinical

• § Painful[17], sudden or gradual
• § Hyperthyroid  (2-6wks)à hypothyroid (2-8wks)à euthyroid (always back to normal)
• § Asymmetric, firm, vaguely nodular, entire gland involved
  • § 3x females, 50
  • § Self-limiting but may recur

Etio: 2 possibilities?

• § Viral infection/post-inflammatory response[18] vs AI[19]

Lab

• § Transient hyperT4 with complete loss of radioiodine uptake in early stage (Rosai)

Micro[20]***

• § Early: disruption of thyroid follicles with PMN[21] infiltrate
• § Late: mononuclear cells (l, p, h) and MGC around collapsed follicles, non-necrotizing granulomas surround naked pools of colloid fragments
• § Resolution: follicular regeneration, little fibrosis remains
• § No bug found

DD

• § Other causes of granulomatous inflammation (TB, sarcoid, fungi, post-operative, palpation)
• § Microscopic granulomatous[22] foci, follicle-centered, due to rupture of follicles
• § Similar to subacute thyroiditis but smaller and scattered, also no PMN

PALPATION THYROIDITIS

RIEDEL’S THROIDITIS

Clinical

• § Adults, elderly, profound dyspnea, “iron collar”
• § Mediastinum, lung, RP, biliary tree, pancreas, kidney, subcutis
• § Leads to vascular damage, hypoPTH, recurrent laryngeal nerve damage
• § 5x females, 50
• § Glandular atrophyà hypoT4
• § Characterized by fibrous tissue penetrating inwards to thyroid parenchyma and extending outwards to surrounding tissues

Micro

• § Dense fibrosis (sometimes with entrapment of skeletal muscle) + minor inflammatory component (mononuclear)à destructive
• § Residual entrapped thyroid follicle at peripheryà atrophic follicles
• § Occlusive phlebitis[23] characteristic
• § Infiltrating margin

HASHIMOTO’S THRYROIDITIS (chronic lymphocytic thyroiditis, struma lymphomatosa, lymphadenotoid goiter)

Clinical

• § HLA-DR3 and DR5[24]
• § Transient hyperthyroidism[25] then hypothyroidism
• § At risk for other AI diseases[26]
• § 5x females[27], mid-aged 45-65[28]
• § Mild hyperT4 followed by hypoT4
• § Diffuse painless symmetrical[29] goiter
• § Progressive depletion of thyrocytes with replacement by mononuclear infiltrate and fibrosis

Mechanism

• § Concept of inter-evolution of Graves and Hashimoto (hashitoxicosis)[30][31]
• § Sensitization of CD4 helpers to thyroid antigensà different mechanism of thyrocyte death
  • Ø CD8+ T mediated-cytotoxicity
  • Ø Cytokine-mediated cell death (interferon-γ)
  • Ø AB-dependent cell-mediated cytotoxicity (ADCC)[32][33]

Complications: name 3***

• § AI disorders (DM1, adrenalitis)
• § Non-endocrine disorders (SLE, MG, Sjogren)
• § Lymphoma (80x)

Gross

• § Diffusely enlarged[34] thyroid, paler than normal[35]
• § Nodules or fibrous bands if long-standing or fibrous variant[36][37][38]

4 key features in micro?

• § Hurthle cells[39][40][41] (oncocytic follicular cells)
• § Dense lymphoplasmacytic infiltrate with germinal centers
• § Follicular atrophy[42]
• § Squamous metaplasia common[43]
• § All non-neoplastic thyroiditis should not have LEL! (Rosai)

IF

• § Antimicrosomal antibody deposition (Osler)

Variants

• § Fibrous[44][45]: more fibrosis[46], minimal inflammation, small thyroid

AutoAB

• § Thryoglobulin[47]
• § Thyroid peroxidase[48]
• § TSH-R (most specific)

Cytology

• § Polymorphous inflammation (plasma cells, lymphocytes)
• § Hurthle cells

Treatment

• § No treatment for mild disease to decompressive subtotal thyroidectomy to total thyroidectomy to avoid confusion with tumor (Rosai)

DD

• § PTC
• § Maltoma: rapid enlargement[49], quite diffuse infiltrate, requires IHC and flow cytometry, clonality study
• § Riedel thyroiditis (vs fibrous variant)
• § Non-specific lymphocytic thyroiditis

AMYLOID GOITER

Clinical

• § Most from secondary amyloidosis (AA> AL)
• § Mass-forming with compression (sometimes quite rapid)
• § Euthyroid
• § Associated with JRA, familial Mediterranean fever, lymphomas

Gross

• § Wavy, diffuse enlargement (can be nodular)

Micro

• § Angiocentric deposit mostly (BV walls)
• § Follicular atrophy
• § Chronic inflammation, squamous metaplasia, fat tissue[50]
• § +/-MGC

IHC

• § Crystal violet: metachromatic
• § Thioflavin T
• § Congo red: apple-green birefringence under polarization

HYPERPLASTIC

1. GRAVES DISEASE (diffuse toxic goiter, diffuse HP)

Clinical

• § Triad: exopthalmos[51], pretibial myxedema, goiter
• § Thyroid storm: tachycardia, palpitations, tremors, anxiety, HTNà treated with beta-blockers
• § Associated with other AI disorders including Hashimoto, pernicious anemia and RA
• § 7x females, 20-40

Mechanism

• § HLA-B8, DR3 polymorphism in cytotoxic T-lymphocyte-associated-4 (CTLA-4) locusà loss of helper T toleranceà production of anti-TSH AB
• T-cell mediated autoimmunity against orbital preadipocyte FB expressing TSH receptorà infiltrative ophthalmopathy

Complications: any risk for cancer?

• § No

EM

• § IC at follicular BM (Rosai)

AutoAB[52]

• § TSI (thyroid stimulating immunoglobulin)[53]
• § TBII (TSH-binding inhibitor immunoglobulin)[54]
• § Anti-thyroid peroxidase: less concentrated than in Hashimoto

Gross

• § Mild, diffuse but symmetrical (unlike MNG) enlargement[55]
• § Beefy red

Treatment

• § Antithyroid drugs[56]

Micro

• § Diffuse hyperplasia[57]à papillary infoldings[58][59]
• § Little colloid
• § Diffuse hypertrophyà columnar with pink granular cytoplasm, round basal nuclei, only slightly enlarged nuclei, dense chromatin, scalloping[60],
• § Patchy chronic inflammation, mild fibrosis[61][62], increased vascularity in interfollicular parenchyma
• § Intraluminal dystrophic calcification[63]

Micro of infiltrative ophthalmopathy

• § Lymphocytic infiltration[64]
• § Hydrophilic GAG (glycosaminoglycans) accumulation behind eyes
• § Edema, and swelling of extraocular muscles
• § Fatty infiltration (increased numbers of adipocytes

Micro of infiltrative dermopathy

• § Lymphocytic infiltrate
• § Accumulation of hydrophilic GAG

Lab

• § Decreased TSH, increased T3/4[65]

Imaging

• § Diffuse iodine uptake

Cytology

• § Hypercelllular smear
• § Minimal/no colloid
• § Sheets of follicular cells
• § Flame cells[66]

DD

• § PTC: nuclear overlapping, loss of basal nuclear polarity, larger nuclei, irregular nuclei, psammoma, fine powdery chromatin
• § Toxic nodular goiter (Plummer’s disease)
• § Hashimoto: more lymphocytes (often with germinal centers), Hurthle cells, follicular atrophy

2. DIFFUSE AND MULTINODULAR GOITER (diffuse non-toxic goiter, nodular HP)

Clinical

• § Precursor for MNG: diffuse non-toxic goiter (Robbins)
• § Building blocks for MNG: adenomatoid nodule (nodular goiter, goiter nodule)[67] (Goldblum)
• § 8x females, young adults
• § Most euthyroid, can be hyperthyroid
• § Can be substernal “plunging goiter”

Genetics

• § Dominant nodule in MNG often monoclonal (Rosai).

Etio

• § Endemic: iodine deficiency[68], goitrogens
• § Sporadic: idiopathic[69]

Lab

• § High TSH, low T3/4[70]

Gross:

• § Multiple nodules[71], variable size
• § Degeneration common: hemorrhage, central scars, fibrous pseudocapsule, calcification, metaplastic bone formation, cystic cavitations[72]

Micro

• § Large follicles distended by colloid, lined by flat to cuboidal epithelium (because inactive!)
• § Dark nuclei, very round[73]
• § No capsule but rather pushing border[74][75]
• § May have Hurthle cells
• § Mainly macrofollicular but sometimes focal hypercellurity (microfollicular or solid patterns)
• § Secondary change (hemorrhage, hemosiderin) common
• § +/-papillary infoldings
• § Cellular nodules=adenomatoid nodules
• § Sometimes cystic metastasis to LN simulating lymphangioma or branchial cleft cyst!
• § Can have parasite nodules (still attached by inconspicuous fibrous stalk)

Describe stages (Robbins)

• § Hyperplastic stage[76]
  • Ø Gross: diffuse, symmetric enlargement
  • Ø Hypertrophy and HP of follicular epithelium with scant colloid
• § Colloid involution[77]
  • Ø Gross: colloid goiter (large but colloid-rich gland)
  • Ø Colloid accumulation (large follicles distended by colloid), variably atrophic or inactive follicular epithelium (flat to cuboidal epithelium)

Cytology

• § Hypocellular[78]
• § Abundant thin colloid (scratches, waves, cracks)
• § Sheets of follicular epithelium (honeycomb)
• § Hemosiderin-laden macrophages

Variants

• § Toxic MNG (aka Plummer’s disease)

DD

• § PTC
• § FA/FTC[79]: mainly based on solitary nature, presence of capsule and microfollicular patterns. Also less degeneration, different cytology from surrounding thyroid
• § Metastatic thyroid carcinoma vs parasite nodule

Treatment

• § Surgery for cosmetic or suspicion for neoplasm or toxic nodule
• § Thyroxin to suppress nodules
• § Painless
• § Postpartum
• § Self-limited
• § HyperT4à normal or hypoT4
• § Lasts about 8wks
• § Inflammatory disorder of unknown etiology

SUBACUTE LYMPHOCYTIC THYROIDITIS

Micro

• § Nonspecific lymphocytic infiltrate but no plasma cells or germinal centers

3. DYSHORMONOGENETIC GOITRE

Etio

• § Genetic mutations leading to thyroid hormone synthesis defectà hypothyroidism

Clinical

• § Young 16
• § Bad
  • Ø Permanent hypoT4[80]
  • Ø +/-cretinism
  • Ø Diffuse goiterà nodular with time

Mechanism

• § Genetic defects in thyroid hormone production-> increased TSH-> increased FTC (Fletcher, Rosai)

Gross

• § Multiple nodules, hemorrhage
• § Very large (up to 600g), asymmetric

Micro

• § Hypercellular follicles (solid, microfollicular, minimal colloid), columnar epithelium ≈Graves
• § Prominent fibrosis
• § Marked atypia, sometimes striking
• § Mitoses

Treatment

• § T4 supplement
• § Surgery is cosmetic

DD

• § FTC

TUMORS

ADENOMAS AND RELATED TUMORS

1. FOLLICULAR ADENOMA

• § Benign[81] encapsulated with follicular cell differentiation
• § Females, 50-60
• § Solitary nodule
• § Hematogenous spread to liver, bone and lung
• § Usually cold[82]

Cytology

• § Cellular smears
• § Colloid present
• § No nuclear features of PTC
• § Cannot separate from nodular goiter[83] or FTC

Gross

• § Different texture and coloration from surrounding thyroid
• § Encapsulated (by definition)
• § Absence of multinodularity in adjacent thyroid (Robbins)
• § Focal cystic change[84]

Mechanism*

• § Activating somatic mutation in TSH receptor itself or α-subunit of Gsà chronic cAMP pathway stimulationà growth advantageà clonal expansion

Micro: name 3 patterns

• § Microfollicular[85], normofollicular[86], trabecular, solid (Robbins)
• § Colloid present[87]
• § Looks different from adjacent normal thyroid
• § No invasions
• § Inspissated intraluminal calcifications
• § Cuboidal cells[88]
• § Round regular nuclei, coarse chromatin
• § Hürthle cell variant exists

Treatment: why remove it?

• § Lobectomy because needs to evaluate invasions

DD

• § Cellular dominant goiter nodule[89]: no capsule, multiple nodules, much more colloid and degenerative changes
• § FTC
• § PTC
• § Mets

2. HYALINIZING TRABECULAR TUMOR[90]

Micro

• § Trabecular, insular, organoid growth
• § Intracellular and extracellular hyalinization
• § +/- fibrous capsule[91]
• § Calcified bodies
• § Medium to large, polygonal to spindle cells
• § Variable cytoplasm +/-yellow paranuclear bodies
• § Prominent nuclear grooves, perinuclear halos
• § Prominent intranuclear cytoplasmic inclusions
• § Hyalinized stroma
  • § Minimal/no colloid
  • § Perpendicular cells
  • § Associated lymphocytic thyroiditis

Gross

• § Solitary, solid, encapsulated, usually small

CARCINOMAS

PTC (80%)

Clinical

• § Good prognosis, local infiltration bad, cervical lymph node involvement ok.
• § Malignant thyroid neoplasm with evidence of follicular differentiation and distinctive nuclear features
• § >98% 20 year survival!
• § 4x females, 20-50
• § Mass-forming, rarely compressive

Imaging

• § Cold nodule[92]
• § Solid or cystic
• § CT useful for clinical staging prior to surgery
• § Sometimes calcifications

RF

• § Previous radiation

Micro[93]

• § Papillae with FV cores[94]
• § Large nuclei[95], increased N/C
• § Grooves[96]
• § Nuclear overlapping/crowding[97]
• § Eosinophilic INCI[98]
• § Orphan Annie nuclei[99]
• § Psammomas
• § +/-squamous metaplasia

Cytology

• § Papillae[100] or monolayered sheets
• § Cuboidal cells with large and overlapping nuclei
• § Powdery chromatin, grooves
• § Intranuclear inclusion
• § Heavy bubble-gum colloid[101]

Treatment (Goldblum)

• § Lobectomy or thyroidectomy with radioiodine

IHC

• § TG+: cytoplasm of follicular cells and colloid

FTC

Clinical

• § Cold/warm single nodule
• § Rarely compressive
• § 3x females, 50

Imaging

• § Solid or cystic
• § CT useful for clinical staging

Gross

• § Single nodule[102]
• § Encapsulated

Micro

• § Slightly larger cells than normal
• § Follicular, trabecular or solid[103]
• § Degree of invasion separates minimally vs widely invasive
• § Capsular[104] or vascular[105] invasion[106][107]
• § +/-Hurthle cells[108]

Variants

• § Minimally invasive
• § Widely invasive
• § Oncocytic: >75% of tumor composed of Hurthle cellsà no difference in management although more in elderly, larger size and more nodal mets (Goldblum)

Cytology

• § Cellular smears
• § Microfollicular pattern mainly
• § Scant colloid

Outcome

• § >90% 20-year survival

IHC

• § TTF-1
• § Thyroglobulin
• § LMK

Genetics

• § RAS point mutations

Treatment

• § Lobectomy or thyroidectomy, with radioidone

DD

• § Follicular adenoma: no capsular/extracapsular invasion or BV invasion (also capsular/extracapsular)

PDTC[109]

ATC (undifferentiated carcinoma, pleomorphic carcinoma)

Clinical: RF?

• § Hot nodule
• § 1.5x in females, >60 (elderly)
• § Long history of thyroid disease
• § Compressive
• § More in areas of endemic goiter (Robbins)
• § >90% death[110] within <6 months

Gross

• § Rapidly expanding mass single nodule

Micro: name 3 histologic patterns (Robbins)***

• § Large anaplastic HG cells or
• § Sarcomatoid spindle cells (VIM+) or
• § Epithelioid cells or
• § Small round blue cells or
• § Tumor giant cells and osteoclast-like giant cells
• § Mitoses
• § Necrosis
• § Hemorrhage

IHC

• § VIM+: nearly in all cases (Goldblum)
• § Stain calcitonin to rule out MTC
• § TG and TTF1 rarely+

Genetics

• § P53 mutations

DD

• § Mets
• § Primary sarcomas
• § Lymphomas
• § Can occur in thyroid due to embryologic origin
• § Caveat: can occur in thyroid because of embryonic origin of thyroid from stomodeum (Osler)
• § Origin: metaplastic follicular cells (Fletcher)
• § Prognosis: better prognosis than MEC (Osler)

SCC

MUCOEPIDERMOID CARCINOMA

Variants (WHO)

• § Carcinoma, mucoepidermoid, sclerosing, with eosinophilia

SCLEROZING MUCOEPIDERMOID CARCINOMA WITH EOSINOPHILIA

MUCINOUS CARCINOMA

MTC

Origin

• § C cells[111] or parafollicular cells (NE cells)

Clinical: how to screen for familial MTC?

• § Increased calcitonin, locally infiltrative mass
• § More females, 50-60 for sporadic, 30 for familial[112]
• § Often LN+
• § Can be functional with peptide product (diarrhea from calcitonin or VIP)
• § Screened using serum calcitonin (Robbins)

Imaging

• § MIBG scan+

Prognosis[113] (Goldblum)***

• § Staging
• § Familial better
• § Small size
• § Confined to thyroid
• § LN negative better
• § <40 better
• § Females better
• § Calcitonin rich better
• § Abundant amyloid better

Gross

• § Sporadic (80%): single nodule
• § Familial: both lobes and multifocal
• § Calcifications often[114]
• § Tan-yellow, soft, encapsulated
• § Never in isthmus

Micro

• § Various patterns: glandular, papillary, trabecular, organoid, sometimes follicular! (Robbins)
• § Various cell morphology: round, oval, spindled, plasmacytoid, squamoid
• § Stippled to salt-and-pepper chromatin
• § Often entraps normal thyroid tissue at periphery
• § Basophilic[115] granular cytoplasm
• § INCI commonà don’t interpret as PTC
• § Mitoses and necrosis rare
• § Amyloid in 80% cases
• § Densely hyalinized stroma
• § ssC-cell HP[116][117]

Cytology

• § Single cells and small loose cohesive clusters
• § No colloid but amyloid[118] present!
• § Round, oval, spindle, polygonal, plasmacytoid[119]
• § Bi- and multinucleated cells
• § Metachromatic red cytoplasmic granules on air-dried
• § Stippled to salt-and-pepper chromatin

IHC

• § Calcitonin+: very dark cytoplasmic stain, good stain
• § NE markers+
• § CEA+
• § CK+
• § TTF1+ but TG-[120]!!!

Genetics

• § -RET (encodes a RTK) is a protooncogene ® point mutations in RET (mutated in 95% of MENIIb)
• § -MEN IIb and IIc (familial medullary ca→indolent)

Treatment

• § Total thyroidectomy with radical neck dissection[121] (Goldblum)
• § CK+ in both spindle and epithelial cells
• § TG-
• § TTF1-
• § Calcitonin-
• § CEA-
• § S100-
• § CK+ and CD5+ in CASTLE cells
• § TG-
• § TTF1-
• § Calcitonin-
• § CEA-
• § S100-

MIXED MTC AND FTC

SPINDLE CELL TUMOR WITH THYMUS-LIKE DIFFERENTIATION (“SETTLE”[122])

12. CARCINOMA SHOWING THYMUS-LIKE DIFFERENTIATION (“CASTLE”)

OTHERS

1. TERATOMA

2. PRIMARY LYMPHOMA/PLASMACYTOMA

Clinical

• § Most arise in background of lymphocytic thyroiditis or Hashimoto thyroiditis
• § 2% of thyroid tumors and 5% of extranodal lymphomasà so non-negligible
• § 5x females, 70
• § Often compressive
• § Mainly Maltoma and DLBCL

Micro

• § Effacement of thyroid by sheets of neoplastic cells
• § Interspersed areas of lymphocytic thyroiditis always present
• § Atypical small lymphocytes, centrocytes, centroblasts, monocytoid B[123] and plasma cells[124]
• § Dutcher bodies[125], Russell bodies
• § LEL: atypical lymphocytes within follicular epithelium

IHC

• § CD20+, CD79a+
• § Kappa and lambda light chain restriction
• § CK useful to highlight LEL

Prognosis

• § Stage
• § Grade
• § Chief cells: main component, polygonal cells with central nuclei
• § Fat
• § Just outside of thyroid capsule
• § Lower pair from 3^rd pouch along with thymus[126] whereas upper pair from 4^th pouch
• § Oxyphil cells[127]: oncocytic, mitochondria
• § -secrete PTH in response to ↓ serum Ca++
• § 2-10 glands
• § Combined weight 120-140mg[128]
• § <5mm
• § 4 cell types
  • Ø Chief: basic functional cells
  • Ø Oxyphilic: increases with age
  • Ø Water-clear: rare
  • Ø Transitional: in between
  • Ø Fat: increases with age

3. ECTOPIC THYMOMA

4. ANGIOSARCOMA

5. SMOOTH MUSCLE TUMORS

6. PERIPHERAL NERVE SHEATH TUMORS

7. PARAGANGLIOMA

8. SFT

9. FOLLICULAR DENDRITIC CELL TUMOR

10. LANGERHANS CELL HISTIOCYTOSIS

11. METS

PARATHYROIDS

NORMAL

CONGENITAL ANOMALIES

AGENESIS

Etio

• § Congenital
• § Surgical
• § Traumatic

Clinical

• § HypoCa
  • Ø Neuromuscular: tetany, muscle cramps
  • Ø Cataracts
• § Thyroid, thymus, pericardium, esophagus, mediastinum

ECTOPIC PARATHYROID

 

PARATHYROID CYST

• § Clear watery fluid (think of water clear cells)
• § Adenoma (80%)> HP[129] (15%)> carcinoma (5%)

PRIMARY HYPERPARATHYROIDISM

2 presentations

• § Asymptomatic
• § Symptomatic
• § usu secondary to chronic renal insufficiency
• § → results in ↓ PO4 excretion
• § → (↑serum PO4 suppresses Ca++ levels)
• § → ↓ Ca++ levels stimulates PTH secretion

SECONDARY HYPERPARATHRYOIDISM

PRIMARY PARATHYROID HP

Clinical

• § Non-neoplastic increase without known stimulus
• § 3x females, 50-70
• § Bones, stones[130], abdominal moans not often seen
• § HyperCa, hypoPO4

 

Etio

• § Sporadic
• § Familial (1/5): MEN1, MEN2a

Gross

• § Diffuse or nodular enlargement
• § All four glands affected although not to same degree[131]
• § All glands <1.0g?

Micro

• § Increased parenchyma but decreased fat
• § Increased cellularity
• § Both increased chief cells[132] and oncocytes
• § Solid, follicular[133] or cords
• § Secondary change common

Treatment

• § Surgery with auto-transplantation

DD

• § Parathyroid adenoma
• § Parathyroid carcinoma
• § Metastatic RCC

SECONDARY/TERTIARY PARATHYROID HP

Clinical

• § CRF patients[134]
• § Skeletal deformities, BV calcification
• § 3x females
• § Same histology as primary HP
• § GNAS1[135] mutationsà loss of response to PTH in target tissuesà hypoCa, compensatory parathyroid hyperfunction, skeletal[136] and developmental abnormalities
• § Rare

HYPOPTH

PSEUDOHYPOPTH

PARATHYROIDITIS

TUMORS

PARATHRYOID ADENOMA

Gross

• § Solitary but other parathyroid glands normal or shrunken (feedback inhibition)
• § Smooth delicate capsule
• § Usually <1g

Clinical

• § No1[137] cause of primary hyperPTH
• § 3x females, 50-60

Micro

• § Can have atypia and mitoses
• § Encapsulated with fibrous capsule[138]
• § Fatless
• § Either chief cells or oncocytic cells[139]
• § Distinct appearance from surrounding parathyroid
• § Atrophy or compressed parathyroid parenchyma
• § Pseudoglandular pattern with colloid-like secretion more common than in HP

Cytology

• § ≈thyroid follicular lesions
• § Clear cytoplasm and distinct cell borders helpful hints

IHC

• § TTF1-
• § Calcitonin-
• § PTH+
• § CG+

PARATHRYOID CARCINOMA

Clinical

• § 5% of primary hyperPTH
• § Death from adverse effects of hyperCa on cardiovascular system
• § Nephrolithiasis, bone brown tumors

Micro

• § Only reliable indicator local invasion[140] and metastasis
• § Remember clear cells (clear cytoplasm)
• § Tumor comedonecrosis
• § Thick acellular fibrous bands
• § Tumor cell monotony[141] although extreme pleomorphism can be seen
• § High N/C
• § Spindling
• § Pink macronucleoli
• § Mitoses (>2/HPF), atypical forms

IHC

• § CG+
• § PTH+
• § CK+
• § 2-4g, up to 10g if stressed
• § Cortex is mesodermal but medullar from neural crest
• § Very large in fetus
• § ZG
  • Ø Controlled by serum K, renin-angiotensin system
  • Ø Abundant lipid
• § ZF[142]
  • Ø Controlled by ACTH[143]
  • Ø Bulkiest of 3 layers
  • Ø Abundant lipid
• § ZR[144] (mainly androgen but some estrogens)
  • Ø Deeply pink with lipochrome pigment
  • Ø Controlled by ACTH
  • Ø For maintenance of secondary sex characteristics
• § Medulla[145]
  • Ø Pleomorphic
  • Ø Deeply blue cytoplasm

METS

ADRENAL GLANDS

NORMAL

IHC

• § Cortex
  • Ø CG-
  • Ø SYN+
  • Ø MELA+
  • Ø CAL+
  • Ø INH+
• § Medulla
  • Ø CG+
  • Ø SYN+
• § Along celiac axis, broad ligament, kidney, spermatic cord
• § Incidental, inconsequential

CONGENITAL ANOMALIES

ACCESSORY/HETEROTOPIA

Micro

• § Medulla may or may not be present

DD

• § RCC
• § Rare

FUSION

APLASIA/HYPOPLASIA

CYTOMEGALY

Micro

• § Marked atypia in cortical cells but still low N/C
• § All or focal

Clinical

• § Inconsequential
• § In premature stillbirths, often with Beckwith-Weidemann[146]

DD

• § ACC
• § Inherited disorders due to enzymatic deficiencies required for glucocorticoid and mineralocorticoid synthesis by cortex
• § 21-hydroxylase deficiency (90%), 11β-hypdroxylase deficiency (8%)

STORAGE DISEASE

ADRENAL CORTICAL HYPERFUNCTION

CONGENITAL ADRENAL HP[147][148] (excess androgen)

21-hydroxylase deficiency (2 variants)

• § Classic salt wasting
  • Ø Deficiency in both cortisol and aldosterone[149] secretion but increased androgen[150]
  • Ø Short adult stature
• § Simple virilizing
  • Ø Mineralocorticoid unaffected
  • Ø Symptoms associated with excess androgen (genital ambiguity in females)

11 β -hydroxylase deficiency

• § Increased androgens (so same as in 21-hydroxylase)
• § But high mineralocorticoidsà HTN unlike hypotension in 21-hydroxylase

17-hydroxylaseà no need to know because too rare

• § Rare… HTN due to excess aldosterone
• § Not much androgen excess (so no genital ambiguity)

Gross

• § Bilateral large adrenals, cerebriform[151]
• § Light brownà no longer yellow

Micro

• § Highly convoluted
• § Increased lipid-depleted cells with compact eosinophilic cytoplasmà dark pink

CUSHING SYNDROME (excess cortisol)

Etio

• § Exogenous: CTSD
• § Endogenous
  • Ø Hypothalamus-hypophysis disease
  • Ø Adrenal adenoma, nodular HP or carcinoma[152][153]
  • Ø Ectopic secretion[154]: SCLC, carcinoid of bronchus or pancreas, MTC, islets cell tumors of pancreas

Test

• § Dexamethasone suppression test
• § Defined as pituitary[155] hypersecretion of ACTH
• § 5x females, young
• § No1 cause of endogenous Cushing syndrome
• § Bilateral adrenal HP

CUSHING DISEASE

ADRENAL CORTICAL HP

PRIMARY PIGMENTED NODULAR ADRENOCORTICAL DISEASE

HYPERALDOSTERONISM (excess aldosterone)

CONN SYNDROME

ADRENAL CORTICAL HYPOFUNCTION

AUTOIMMUNE ADRENALITIS (ADDISON)

Clinical

• § Females, peak 40
• § Basically is chronic adrenal insufficiency
• § Primary: hyperpigmentation/vitiligo[156], salt craving[157]
• § Weakness, irritability, abdominal pain, diarrhea, depression, anorexia, menstrual abnormalities
• § Hypotension, hypoglycemia, hypoNa, hyperK, dehydration[158], metabolic acidosis
• § Treated with CTSD repletion
• § Requires >90% loss of both adrenal cortices to develop adrenal insufficiency symptoms

Etio

• § AI[159]
• § TB (3^rd countries)
• § Radiation, chemotherapy
• § Adrenal hemorrhages in neonates

Micro

• § Atrophic cortex (thin and dicontinuous)
• § Mostly composed of compact eosinophilic cytoplasm (lipid-depleted)
• § +/-lymphocytes, plasma cellsà check for organisms

INFECTIONS

Gross

• § Large usually[160]

Clinical

• § TB
• § Fungal: histoplasma[161]
• § Viruses: CMV[162], HSV

WATERHOUSE-FRIDERICHSEN SYNDROME

Clinical***

• § Fever (infection), nausea, vomiting, petechiae, shock, hypoglycemia

Etio

• § Severe stress (burns, hypovolemia, shock)
• § Iatrogenic (abrupt steroid withdrawal)
• § Infections (not only menogococcus[163])
• § Any chronic inflammation

AMYLOIDOSIS

ADRENAL CYSTS

• § Mostly incidental finding
• § If >5cm and symptomatic, do surgery to rule out malignancy
• § Remember this

VASCULAR CYST (45%)

Micro

• § Multiloculated
• § Flattened endothelium
• § Hemorrhagic to clear fluid
• § Irregular contour
• § Unilocular
• § No epithelial lining
• § Brown hemorrhagic content
• § Small incidental, serous fluid
• § Cuboidal or ciliated columnar lining
• § Echinococcal[164]

PSEUDOCYST (40%)

TRUE CYST (10%)

PARASITIC CYST (5%)

ADRENAL CORTICAL TUMORS

Functional classification (WHO)

1. Hyperfunction

• Ø Cushing[165]
  • § Truncal obesity, abdominal striae, menstrual abnormalities, protein wasting, loss of muscle strength, hirsutism, emothional disturbances, osteoporosis, impaired glucose tolerance, hypoK
  • Ø Conn[166]
    • § Polyuria, polydipsia, nocturia, weakness, paresthesia, tetany, HTN, hypoK, alkalosis, hyperNa
    • § Spinorolactone bodies[167] because treated by spironolactone
    • Ø Virilization: male pattern baldness, clitomegaly, voice deepening
    • Ø Feminization: loss of libido, testicular atrophy, gynecomastia
    • Ø Mixed

2. Non-functional

3. Unknown

Genetics

• § Oncogenes
  • Ø G protein
  • Ø RAS
  • Ø Calcium-dependent protein kinase C activity
  • Ø ACTH receptor deletions
• § Tumor suppressors
  • Ø P53
  • Ø MEN1
  • Ø P57
  • Ø H19
• § Growth factors
  • Ø IGFII overexpression

PARANEOPLASTIC SYNDROMES IN ADRENALS

What is the classification of endocrinopathies and 2 neoplasms and cause assoc/ each?

Cushing’sà ACTH or ACTH-like substance

• § “ACTH PALS”
• § Lung (SCLC, carcinoid) or Pancreas: HG NE tumor

SIADH (hint: “SI”)

Small cell lung

• Ø Intracranial neoplasms
• § HyperCaà PTH-related pep (hints: Ca++ (lots of C’s))
  • Ø Squamous cell ca
  • Ø Renal cell ca
  • Ø Breast ca
  • Ø Adult T cell lymp/leuk
• § Hypoglycemiaà insulin/insulin-like
  • Ø Fibrosarcoma
  • Ø Sarcoma
  • Ø HCC
• § Carcinoid syndromeà 5-HT, bradykinin

PG Carcinoids

• § Pancreatic ca
• § Gastric ca
• § Carcinoids
• § Polycythemiaà Epo
  • Ø Renal cell ca
  • Ø Cerebellar hemangioma
  • Ø HCC

ADRENAL CORTICAL NODULE

Clinical

• § Benign non-functioning nodule of adrenal cortexà non-neoplastic
• § Incidental finding
• § No treatment needed

Gross

• § Typically bilateral and multiple[168]
• § Variable size but usually <1cm

Micro

• § WC but no capsule
• § Abundant microvesiculated cytoplasm resembling zona fasciculata
• § Normal adrenal cortex between nodules

DD

• § ACA: impossible when only one dominant adrenal cortical nodule
• § Nodular adrenal cortical HP (Cushing): diffuse nodularity without discrete nodules, no residual normal cortex visible

ADRENAL CORTICAL ADENOMA

Micro

• § One single cell population[169]: lipid-filled microvesiculated cytoplasm resembling ZFà remember clear cells
  • Ø Cords
  • § Interspersed compact deeper pink cells
    • Ø Intracytoplasmic eosinophilic globules
    • § Compressed normal adrenal in periphery
    • § Black pigment if black adenoma
    • § +/-spironolactone bodies[170]

Clinical

• § 50yo
• § 75% of Conn (ACA is no1 cause[171], HP is no2, ACC least common)
• § 15% of Cushing
• § Virilization and feminization rare

Gross

• § <5cm, <100g
• § WC, yellow[172]
• § Controlateral atrophic adrenal if functional adenoma

DD

• § Dominant nodule of adrenal nodular HP: requires radiologic correlation of controlateral adrenal
• § Non-functional adrenal cortical nodule: requires radiologic correlation of controlateral adrenal
• § ACC: mitoses, diffuse growth, hypercellularity, necrosis, invasion
• § Any metastatic clear cell tumors such as RCC: PAS+ (glycogen), EMA+, CD10+, RCC+, melanA-, inhibin[173]-

ADRENAL CORTICAL CARCINOMA

Clinical

• § Hyperfunctioning usually (Osler) à hirsutism
  • Ø Cortisol> androgen> mineralocorticoid>> estrogen)
  • § Much larger
  • § Bimodal onset: 10 and 60

Gross

• § >10cm, >100g

Micro (Goldblum)

• § Invasion (capsule, cortex, BV, fat)
• § Fibrous bands
• § Comedonecrosis
• § Cellular tumors
  • Ø Trabecular, alveolar, solid, pseudoglnadular, fascicular
  • § Increased N/C
  • § From uniform to pleomorphic multinucleated giant tumor cells
  • § Vacuolated or eosinophilic cytoplasm
  • § Variable mitoses, atypical mitoses
  • § +/-calcifications
  • § Surrounded by thin or thick capsule
  • § Adjacent cortex often atrophic from endogenous steroid release

IHC

• § CK7-/20-
• § VIM+
• § INH+
• § MelanA+
• § CAL+
• § CK: weak and focal+
• § NF: weak and focal+
• § S100: weak and focal+
• § CG-
• § SYN+?

DD

• § ACA
• § HCC
• § RCC
• § Pheochromocytoma
• § Mets

ADRENAL MEDULLARY TUMORS

Functional classification (WHO)

• § Functional
  • Ø Hyperfunction
  • Ø HTN
  • Ø Watery diarrhea, hypoK, achlorhydria syndrome
  • Ø Cushing
  • Ø Others including acromegaly
  • § Non functional disturbance
  • § Unknown

Genetics

• § MEN2a
• § MEN2b
• § VHL
• § NF1
• § SDHD, SDHB, SDHC

BENIGN PHEOCHROMOCYTOMA

Name the familial syndromes assoc/ ~

• § MEN2a
• § MEN2b
• § VHL[174]
• § NF1
• § Sturge-Weber

Clinical

• § HTN, headache, diaphoresis
• § Mostly benign (remember 10% rule[175])
• § Free catecholamines (A, NA, DA) and metabolites (VMA[176], metanephrines) in urine[177]

Gross

• § Variable size
• § WC, no fibrous capsule
• § Not as yellow as ACA/ACC, rather brain-colored (gray-white)
• § Chromaffin reaction in potassium dichromate due to oxidation of catecholamines[178]

Micro

• § Zellballen[179] (small nests of polygonal cells) “often a bit spindly”+rich vascular network
• § Polygonal cells with granular blue cytoplasm
• § Salt-and-pepper chromatin
• § +/-PAS+ cytoplasmic globules
• § +/-atypia
• § No mitoses
• § Can get capsular invasion with benign, so need mets to call malignant
• § +/-melanin

IHC

• § CG+
• § SYN+
• § S100+ sustentacular cells
• § Calretinin?
• § MelanA?

EM

• § Dense core membrane bound neurosecretory granules[180]

DD

• § ACA/ACC: no basophilic granular cytoplasm, not zellballen, CG-, melanA+, calretinin+
• § Malignant pheochromocytoma
• § Metastatic NE carcinoma
• § ASPS

MALIGNANT PHEOCHROMOCYTOMA

Clinical

• § MIBG scan can trace it

Micro

• § Invasion (capsule, BV, fat)
• § Expansile nests or diffuse growth
• § Necrosis
• § Hypercellularity
• § Cellular monotony or profound pleomorphism, hyperchromasia, macronucleoli[181]
• § Tumor spindling
• § Increased mitoses, atypical forms
• § Metastatic foci

COMPOSITE PHEOCHROMOCYTOMA/PARAGANGLIOMA

NEUROBLASTOMA

Clinical

• § No1 tumour <1yo[182]
• § In adrenal medulla[183]
• § From neural-crest derived neuroblasts
• § Adrenals, parasympathetic chain (most common second location is paravertebral)
• § Increased catecholamine metabolites (VMA, HVA)

Outcome

• § May spontaneously regress or mature[184]

Gross

• § Sharply demarcated mass with fibrous pseudocapsule, brain-like soft cut surface
• § Hemorrhage, necrosis, cyst formation (more prevalent in poorly differentiated)
• § Calcification with increasing size

Micro

• § Soft, brain-like tissue
• § Solid sheets of small round blue cells
• § H-W rosettesà neurofibrillary center[185]
• § Neuropil
  • Ø Ganglioneuroma (abundant schwannian stroma and ganglion cells)
  • Ø Maturing ganglion cells

 

Subgroupings

• § Undifferentiated: small round blue cells
• § PD: scant neuropil, <5% ganglion cells[186]
• § Differentiating: abundant neuropil, 5-50% ganglion cells
• § Ganglioneuroblastoma: >50% ganglion-like cells but still with primitive cells present

3 major categories from immatureà mature

• § Neuroblastoma
• § Ganglioneuroblastoma
• § Ganglioneuroma

IHC

• § S100, variable NSE, chrA, syn

Poor prognosis

• § –↑ mitosis, karyorrhexis
• § MYCN amplification*
• § Diploid or tetraploid
• § 1p loss
• § ↓ TRK-A,C expression

DD

• § RMS
• § Lymphoma
• § EWS/PNET
• § Wilms
• § OS
• § MPNST
• § DSRCT

OTHER ADRENAL TUMORS

ADENOMATOID TUMOR

SEX-CORD STROMAL TUMOR

SOFT AND GERM CELL TUMORS

MYELOLIPOMA

Clinical

• § Incidental finding
• § Also in liver, mediastinum and GI

Micro

• § Marrow[187] and fat

HEMANGIOMA

LEIOMYOMA

TERATOMA

SCHWANNOMA

GANGLIONEUROMA

Micro

• § Mature schwannian stroma
• § Interspersed ganglion cells[188]
• § +/-immature ganglion cells (do not change prognosis)
• § Thorough sampling to rule out neuroblastic foci!

Clinical

• § Benign neuroblastic tumor composed of mature ganglion cells and schwannian stroma
• § Mostly in posterior mediastinum and adrenals

Gross

• § WC, rubbery, firm, gray white

IHC

• § NF+, SYN+, CG+, NSE+: in ganglion cells[189] and axons
• § S100+: schwannian stroma[190]
• § VIM+
• § CK-
• § No4 metastatic site
• § Bilateral in ½
• § >90% carcinomas
• § Functional adrenal insufficiency if >90% of parenchymal destruction
• § Usually bilateral
• § Lung, breast, melanoma, kidney
• § 50-60
• § Tumors from parasympathetic or sympathetic nerves
• § 10% bilateral, multiple, familial, pediatric and malignant
• § I-MIBG localizes tumor
• § Surgery with preoperative adrenergic blockage

ANGIOSARCOMA

METS

OTHER MASSES

OVARIAN THECAL METAPLASIA

METS

EXTRA-ADRENAL PARAGANGLIOMA

PARAGANGLIOMA

Gross

• § Pseudocapsule

Micro

• § Nests/Zellballen
• § Polygonal cells with granular basophilic to eosinophilic cytoplasm[191]
• § Dark nuclei with possible atypia
• § FV septa
• § +/- melanin
• § Eosinophilic cytoplasmic globules

IHC

• § Chief: NE markers+, CD56+
• § Sustentacular: S100+

MALIGNANT PARAGANGLIOMA

Gross

• § Large with hemonecrosis

Micro

• § Widely invasive (capsule, BV, surrounding tissue)
• § Confluent necrosis
• § Large nests or diffuse growth
• § Profound pleomorphism
• § Increased mitoses and atypical forms

IHC

• § Decreased S100 in sustentacular cells
• § Increased Ki67
• § O2 sensing chemoreceptor at carotid bifurcation[192]

CAROTID BODY

JUGULOTYMPANIC (middle ear)

VAGAL

LARYNGEAL

AORTICO-PULMONARY

GANGLIOCYTIC

CAUDA EQUINA

ORBITAL NASOPHARYNGEAL

EXTRA-ADRENAL SYMPATHETIC PARAGANGLIOMA

SUP AND INF PARAAORTIC PARAGANGLIOMA

URINARY BLADDER

INTRATHORACIC AND CERVICAL PARAVERTEBRAL

PANCREAS

NORMAL

Effects of insulin[193]

• § Anabolic hormone
  • Ø Glucose and amino acid uptake by peripheral tissues (skeletal muscle, cardiac muscle and fat)
  • Ø Glycogen formation in liver and skeletal muscles
  • Ø Glucose conversion to TG
  • Ø Protein synthesis
• § Mitogenic effects[194]
  • Ø Initiating DNA synthesis
  • Ø Stimulation of cell growth and differentiation

What happens to β cells in hyperglycemia

• § Hyperglycemiaà glucose uptake into pancreatic β cells via insulin-independent GLUT2à ATP generated from intracytoplasmic glucoseà inhibits ATP-sensitive K+ channel on β-cell membraneà membrane depolarization with influx of Caà immediate phase of preformed insulin release
• § Persistent secretory stimulusà delayed and protracted response (active synthesis of insulin)

DM

4 end organs

• § BV, kidneys, eyes, nerves

How to diagnose clinically?

• § Glucose production by liver, glucose uptake by peripheral tissues, insulin and glucagon
• § Diagnosis
  • Ø Random glucose ≥200mg/dL with classical ssx
  • Ø Fasting glucose ≥126mg/dL
  • Ø Abnormal oral glucose tolerance test (≥200mg/dL 2h after load)

Complications

• § Macrovascular: atherosclerosis, MI, stroke, gangrene
• § Microvascular:

WD ENDOCRINE TUMOR

• § Pancreatic endocrine neoplasms (PEN)=islet cell tumors
• § Definition of invasion for islet cell tumorsà must be outside of pancreatic parenchyma (not just tumor capsule)
• § DM symptoms, migratory necrotizing skin erythema, anemia
• § High serum glucagon
• § High serum somatostatin
• § DM symptoms, cholelithiasis, steatorrhea, hypochlorhydria
• § ZES triad: recalcitrant PUD[195], gastric hypersecretion, gastrinoma. Also diarrhea
• § 60% malignant
• § Very difficult to resect
• § Duodenum and peripancreatic soft tissue (gastrinoma triangle)
• § MEN1: multifocal

FUNCTIONING

INSULINOMA

GLUCAGONOMA

SOMATOSTATINOMA (δ-cells)

GASTRINOMA (ZES)

EM

• § Resembles gastric G cells
• § WDHA=watery diarrhea, hypoK, achlorhydria
• § Pancreatic carcinoid: serotonin
• § Pancreatic polypeptide-secreting islet cell tumor: asymptomatic

VIPOMA (vasoactive intestinal polypeptide)

OTHERS

NON-FUNCTIONING

MICROADENOMA (<0.5cm)

OTHERS

WD ENDOCRINE CARCINOMAS

FUNCTIONING

INSULINOMA

• § No1 islet cell tumor
• § Often solitary
• § Usually small (<2cm), encapsulated, firm, yellow
• § Cords and nests of WD β-cells

EM

• § Β-cell granules[196]
• § MEN I: 4P’s and an A
• § parathyroid hyperplasia
• § pituitiary adenoma
• § pancreatic HP adenoma/carcinoma
• § parafollicular cell HP (thyroid)
• § adrenal cortical adenoma
• § gene: MEN1
• § MENIIa:
• § pheochromocytoma and medullary ca
• § + parathryoid HP
• § gene: RET
• § MENIIb:
• § pheochromocytoma and medullary ca
• § + mucocutaneous lesions, Marfanoid habitus
• § gene: RET
• § MENIIc: (Familial Medullary Carcinoma)

GLUCOGONOMA

SOMATOSTATINOMA

GASTRINOMA

VIPOMA

CARCINOID

POORLY-DIFFERENTIATED ENDOCRINOME CARCINOMA-SMALL CELL CARCINOMA

MIXED

NON-FUNCTIONING

HEREDITARY

MEN SYNDROME

1. MEN1

 

2. MEN2

3. HYPERPARATHYROIDISM-JAW TUMOR SYNDROME

4. VHL

• § 1: retinal angioma, hemangioblastoma, RCC
• § 2A: retinal angioma, hemangioblastoma, pheochromocytomas
• § 2B: hemangioblastoma, pheochromocytomas, RCC
• § 2C: pheochromocytoma
• § Congenital absence of parathyroid
• § Agenesis/hypoplasia of thymus
• § “CATCH-22” (velocardiofacial)
  • Ø Cleft palate
  • Ø Appearance
  • Ø Thymus/immunodeficiency[197]
  • Ø Calcium salt low
  • Ø Heart defect

5. FAMILIAL PARAGANGLIOMA-PHEOCHROMOCYTOMA SYNDROME CAUSED BY SDHB, SDHC AND SDHD MUTATIONS

6. NF1

7. CARNEY COMPLEX

8. MCCUNE-ALBRIGHT SYNDROME

9. FAMILIAL NON-MEDULLARY THYROID CANCER

10. DIGEORGE SYNDROME***

ACA VS ACC[198]

Van Slooten system[199]

• § Extensive regressive changes (necrosis, hemorrhage, fibrosis, calcification)à 5.7
• § Loss of normal structureà 1.6
• § Moderate-marked nuclear atypiaà 2.1
• § Moderate-marked hyperchromasiaà 2.6
• § Abormal nucleolià 4.1
• § Mitoses ≥2/10à 9.0
• § Vascular or capsular invasionà 3.3

Hough system[200]

• § Histologic
  • Ø Diffuse growthà 0.92
  • Ø Vascular invasionà 0.92
  • Ø Necrosisà 0.69
  • Ø Broad fibrous bandà 1.00
  • Ø Capsular invasionà 0.37
  • Ø Mitoses 1/10à 0.60
  • Ø Moderate-marked pleomorphismà 0.39
• § Nonhistologic
  • Ø >100gà 0.60
  • Ø Urinary 17-ketosteroidsà 0.50
  • Ø Response to ACTHà 0.42
  • Ø Cushing with virilism, virilism alone or no clinical manifestationsà 0.42
  • Ø Weight lossà 2.00

Weiss

• § Venous invasion
• § Moderate-marked pleomorphism
• § Necrosis
• § Mitoses
• § Diffuse growth
• § Capsular invasion
• § Atypical mitoses
• § Sinusoidal invasion
• § Clear cells <25%
• § <5cm
• § <50g
• § <5/50HPF
• § Solid, yellow cut surface
• § Rare hemorrhage and necrosis
• § Capsule not infiltrated by tumour in adenoma
• § Rare mitoses
• § Strong LMK and weak VIM (opposite in ACC)

ACA VS ACC (hint: rule of 5) (Gannon)[201]***

ACC VS PHEOCHROMOCYTOMA VS RCC VS HCC***

ACC	Pheochromocytoma	RCC	HCC
CK+/-[202]	-[203]	CK+	CK+
VIM+	+/-	+	+/-
+/-	NF+	-	-
+/-	S100+	+/-	+/-
-	-	EMA+	+/-
-	-	-	CEA+
-	CG+	-	-
+/-	SYN+	-	-
-	-	-	AFP+
MEL-A+	-	-	-
CAL+	-	-/+	-
INH+	-	-/+	-/+

ADRENAL CYSTS[204]***

• § Vascular cyst: endothelial cyst
• § Parasitic cyst: echinococcal
• § Pseudocyst
• § Epithelial cyst: lymphangioma,…
• § Cystic degeneration in a primary or metastatic tumor
• § T1: ≤5cm, no local invasion
• § T2: >5cm, no local invasion
• § T3: any size, local invasion but not into organs
• § T4: organ invasion
• § N1: positive regional LN
• § M1: distant mets

STAGING ADRENAL CORTICAL CARCINOMA

IHC PANEL FOR ACC VS PHEOCHROMOCYTOMA

• § CG[205]
• § INH
• § S100
• § MelanA

HOW TO ESTIMATE MALIGNANT POTENTIAL OF PHEOCHROMOCYTOMAS (PASS SCORE)[206]

• § Large nests or diffuse growth[207]à 2
• § Central or confluent necrosisà 2
• § Hypercellularityà 2
• § Cellular monotonyà 2
• § Tumor cell spindling[208]à 2
• § Mitoses ≥4/10à 2
• § Atypical mitosesà 2
• § Fat invasionà 2
• § Vascular invasionà 1
• § Capsular invasionà 1
• § Profound pleomorphismà 1
• § Nuclear hyperchromasiaà 1

CK7-/CK20- TUMORS

• § Adrenal cortical carcinoma (remember this)
• § Prostate
• § RCC
• § HCC

CK7+/CK20+ TUMORS

INHIBIN+/CALRETININ+ TUMORS

• § Sex cord-stromal tumors?
• § Adrenal cortical adenoma/carcinoma
• § 1: localized tumor, completely excised, with or without microscopic residual disease and negative LN
• § 2A: localized tumor, incompletely excised, negative LN
• § 2B: same as 2A but with positive ipsilateral LN, negative controlateral LN
• § 3: unresectable tumor, crossing midline with or without LN, midline tumor with bilateral LN involvement
• § 4: dissemination to distant LN, bone, marrow, liver, skin or other
• § 4S: localized primary tumor, dissemination limited to skin, liver, +/-marrow, <1 year of age

STAGING FOR NEUROBLASTOMA

PROGNOSIS FOR NEUROBLASTOMA***

Favorable	Unfavorable
Stage 1, 2, 4S	3, 4
<1yo	>1yo
Low ferritin, LDH	High
Low NSE	High
Favorable histology	Unfavorable
Normal	Amplified n-MYC (>10 copies)
Hyperdiploid	Diploid
Normal	Deletion of 1p
High TRK-A	Normal or low

THYROIDECTOMY

“Make sure the name and unique number match on the requisition and bucket.”

2. “WOMEN FPI SEPS D”

3.  Sample the following areas (going through the TNM stages):

• § Cut longitudinal sections
• § Take sections from tumour + capsule “looking for invasion” + extrathryroidal tissue “looking for extrathyroidal spread into muscle or soft tissue”
• § Look for parathryroid glands, weigh and submit
• § T1: ≤2cm
• § T2: 2-4cm
• § T3: >4 cm or extension to muscle/soft tissue
• Ø T4[210]: extension beyond muscle/soft tissue
  • Ø T4a: into subcutis, larynx, trachea, esophagus, recurrent laryngeal nerve
  • Ø T4b: into prevertebral fascia, mediastinal BV, encases carotids
• § N0:
• § N1: regional LN
  • Ø N1a:
  • Ø N1b:
• § M0:
• § M1: distant mets

STAGING THYROID[209]

SYNOPTIC REPORT THYROIDECTOMY

PS, HHoTTeLL  MaNiC

+

• § Encapsulation
• § Capsular invasion
• § Extrathyroid extension
• § C-cell HP
• § Parathyroid glands

CAUSES OF HYPERHYROIDISM[211] (Rosai)

Primary

• § Graves disease with diffuse HP (85%)
• § Toxic FA
• § Toxic MNG
• § Various thyroidits with hormone leakage: subacute lymphocytic thyroiditis, early Hashimoto, early subacute granulomatous thyroiditis

Secondary

• § Trophoblastic tumor
• § Struma ovarii
• § Iatrogenic (amiodarone)
• § T4 intake
• § Pituitary thyrotroph cell adenoma

SYMPTOMS OF HYPERTHYROIDISM

• § Cardiac[212]: increased output, increased contractility, increased peripheral O2 requiredà tachycardia, palpitations, cardiomegaly, arrhythmia (Afib)
• § Ocular: staring gaze, lid lag, ophthalmopathy (Graves)
• § Neuromuscular: tremor, hyperactivity, emotional lability, anxiety, inability to concentrate, insomnia
• § Skin: warm, moist, flushed, infiltrative dermopathy (Graves)
• § GI: malabsorption from hypermotility, diarrhea
• § Apathetic hyperthyroidism: elderly with less obvious typical ssx of hyperT4

CAUSES OF HYPOTHYROIDISM (parenchymal loss, inability to synthesis, higher function)

Primary

• § Radioablation
• § Surgical ablation
• § Various thyroiditis: Hashimoto’s, Riedel’s thyroiditis
• § Dyshormonogenetic goiter (inborn metabolic error)
• § Drugs (goitrogens)
• § Infiltrative lesions
• § Iodine deficiency

Secondary

• § Hypothalamic lesions (↓TRH)
• § Pituitary lesions (↓TSH)

SYMPTOMS OF HYPOTHYROIDISM

• § Cretinism: during perinatal period of infancy
• § Myxedema: older children and adults

NECK CYSTS WITH SQUAMOUS DEBRIS***

• § Thyroglossal duct cyst
• § Epidermoid cyst
• § Degenerated cystic adenomatoid nodule?
• § Branchial cleft cyst
• § SCC

NECK CYSTS WITH LYMPHOCYTIC INFILTRATE

• § Branchial cleft cyst
• § Nodal metastasis of cystic PTC
• § Lymphangioma

NORMAL ECTOPIC TISSUES IN THYMUS

• § Thymus
• § Parathyroid
• § Salivary gland

MULTINUCLEATED GIANT CELLS IN THYROID (Goldblum)

• § Granulomatous thyroiditis
• § Goiter nodule
• § Lymphocytic thyroiditis
• § Palpation thyroiditis
• § PTC
• § Ruptured thyroid follicle
• § Postoperative

SOLITARY THYROID NODULE[213][214]***

• § Early MNG (2/3)
• § Adenoma (1/3)
• § Carcinoma (5%)
• § Simple cyst
• § Thyroiditis

RF FOR MALIGNANCY IN THYROID NODULE

• § Young
• § Male
• § Solitary
• § Cold
• § Radiation

RANK THYROID TUMORS BY PROGNOSIS, INCIDENCE, AGE, GENDER PREDILECTION, MODE OF SPREAD

HYPERPLASTIC DISORDERS OF THYROID

• § Graves
• § MNG
• § Dyshormonogenetic goiter

DIFFUSE VS NODULAR GOITERS/HP[215]

• § Diffuse: Graves, early Hashimoto, early MNG[216], amyloid thyroid
• § Nodular: MNG, dyshormonogenetic goiter, late Hashimoto, longstanding Graves

SYMMETRIC VS ASYMMETRIC THYROIDS

• § Symmetric:
• § Asymmetric: Riedel, dyshormonogenetic goiter

PROGNOSIS FOR PTC (Robbins)

• § Age: >40 bad
• § Extrathyroidal extension
• § Distant metastasis

PROGNOSIS FOR FTC

• § Extension of extrathyroidal extension (minimally invasive, angioinvasive, widely invasive) at presentation[217]

PROGNOSIS FOR MTC (Robbins)***

• § FMTC more indolent
• § Sporadic and MEN2a/2b more aggressive[218]

CAUSES OF CUSHING’S SYNDROME? (“ACTH PALS”)

• § Pituitary tumour
• § Adrenal cortical tumour or HP
• § Lung (small cell, carcinoid) or Pancreas: high grade neuroendocrine ca
• § Steroid administration

HYPERALDOSTERONISM

• § Adrenal adenomaà Conn syndrome
• § Adrenocortical HP
• § Hybrid glomerulosa cells responsive to ACTH

STEPS OF THYROID HORMONE SYNTHESIS*

• § Iodine transport
• § Organification
• § Dehalogenation
• § Iodotyrosine coupling

ADRENAL HYPERPLASIA[219]

• § Diffuse: thickened and yellow
• § Nodular: multiple yellow nodules

VARIANTS OF FOLLICULAR ADENOMAS

• § Hürthle cell (oncocytic)
• § Colloid?
• § Fetal
• § Clear cell
• § Signet-ring cell
• § Trabecular
• § Atypical
• § Papillary???

PROGNOSIS FOR THYROID CARCINOMA

• § Tumor size
• § Nuclear pleomorphism
• § Necrosis
• § Mitoses
• § Vascular invasion
• § Extraglandular tumor extension

TREATMENT FOR THYROID NEOPLASMS

• § Lobectomy +thyroid hormone to suppress TSHà FTC, PTC, FA
• § Thyroidectomy: PTC, invasive FTC, PDTC, MTC
• § Radial neck dissection: MTC

INDICATIONS FOR FNA

• § Evaluation of a cold nodule

INDICATIONS FOR NECK DISSECTION (Goldblum)

• § Evaluate LN status
• § Resect clinically obvious neck disease

INDICATIONS FOR FS IN ENDOCRINE PATHOLOGY (Goldblum)

• § Specimen adequacy for special studies (culture, IHC, molecular studies, EM, flow cytometry)
• § Different definitive treatment based on diagnosis (extent of disease)
• § Unsuccessful previous attempts at diagnosis
• § Surgical margins (rare in endocrine pathology)

IHC FOR THYROID, C-CELLS AND PARATHYROID

Thyroid	C-cells	Parathyroid
TG+	-	-
TTF1+	TTF1+	-
-	NE markers+	NE markers+
-	Calcitonin+	-
-	-	PTH+
CK+	?	CK+

THYROID CYSTS

• § Simple colloid cyst[220]
• § Lymphoepithelial cyst

AMYLOID IN THYROID

• § Amyloid goiter
• § MTC

PITUITARY AND SELLAR REGION LESIONS (Steinberg)

• § Benign
  • Ø Pituitary adenoma
  • Ø Meningioma
  • Ø Craniopharyngioma[221]
  • Ø Granular cell tumor
  • Ø Gangliocytoma
  • Ø Paraganglioma
  • Ø Schwannoma
  • Ø Glomangioma
  • Ø Spindle cell oncocytoma
  • Ø Hemangioma
  • Ø Hemangioblastoma
  • Ø Myxoma
  • Ø Fibrous dysplasia of bone
  • Ø GCTB
  • § Inflammatory
    • Ø Mucocele
    • Ø Lymphocytic hypophysitis
    • Ø Sarcoidosis
    • Ø Giant cell granuloma
    • Ø Histiocytosis X
    • § Vascular
      • Ø Pituitary infarction
      • Ø Pituitary apoplexy
      • Ø Aneurysm
      • § Cysts***
        • Ø Rathke cleft cyst
        • Ø Epidermoid cyst
        • Ø Dermoid cysts
        • § Malignant
          • Ø Chordoma
          • Ø GCT
          • Ø HPC
          • Ø Metastatic
          • Ø Plasmacytoma
          • § Infectious
            • Ø Cysticercosis
            • Ø Hydatid cyst

MEN CLASSIFICATION

• § MEN1: pituitary adenoma, parathyroid HP/adenoma, pancreatic islet HP/adenoma/carcinomaà MEN1 (menin)
• § MEN2a: parathyroid HP, pheochromocytoma, C-cell HP/MTCà RET[222]
• § MEN2b: pheochromocytoma, C-cell HP/MTC, mucocutaneous ganglioneuromas, Marfanoid habitusà RET

REPORTING PARAGANGLIOMA

• § Size
• § Solitary or multiple
• § Invasion into surrounding tissue
• § Necrosis

FEATURES OF INCREASED RISK IN PARAGANGLIOMA (Lester)[223]

• § Extra-adrenal location
• § Coarse nodular or multiple nodules on gross examination
• § Confluent tumor necrosis
• § Absence of hyaline globules

VASCULAR INVASION FOR FTC (Lester)

• § BV must be within or outside capsule
• § BV must be large caliber with identifiable wall with endothelial lining
• § Intravascular tumor must be covered by endothelium or attached to wall and associated with thrombus

CAPSULAR INVASION FOR FTC (Lester)

• § Bulging out but still covered by fibrous capsule
• § Through-and-through regardless mushroom-shaped or not[224]
• § Satellite nodule outside capsule

FEATURES OF INCREASED RISK IN PHEOCHROMOCYTOMA[225] (Lester)

• § Male
• § Large size
• § Coarse nodularity
• § Necrosis
• § Predominantly small tumor cell size
• § Absence of cytoplasmic hyaline globules
• § Absence of neuropeptides+/-S100+ sustentacular cells by IHC

OTHER CAUSES OF HYPERPRL

• § Pregnancy
• § Lactotroph HP[226]

CLASSIFICATION OF DIBETES MELLITUS

• § Type 1: β-cell destruction (immune or idiopathic)
• § Type 2: insulin resistance
• § Genetic[227] defects of β-cells
  • Ø MODY (maturity-onset diabetes of young)[228]
  • Ø Mitochondrial DNA mutations[229]
• § Genetic defects in insulin processing
• § Exocrine pancreatic defects
  • Ø Chronic pancreatitis
  • Ø Pancreatectomy
  • Ø Neoplasia
  • Ø CF
  • Ø Hemochromatosis
• § Endocrinopathies
  • Ø Acromegaly
  • Ø Cushing syndrome
  • Ø HyperT4
  • Ø Pheochromcytoma
  • Ø Glucagonoma
• § Infections
• § Drugs
  • Ø CTSD
  • Ø T4
  • Ø Thiazides
• § Syndromes associated with DM
  • Ø Down
  • Ø Klinefelter
  • Ø Turner
• § Gestational

PATHOPHYSIOLOGY OF DM***

• § Nonenzymatic glycosylation
  • Ø Glycosylation of proteins (Hb, collagen, others)à irreversible advanced glycosylation end (AGE) productsà accumulation of AGE products in BV wallsà traps plasma lipoproteins, decreased normal proteolysis
• § Intracellular hyperglycemia with disturbances in polyol pathways
  • Ø Increased intracytoplasmic sorbitol and fructose to maintain inward glucose drive[230]à water influxà cell edema and cell death
• § Activation of protein kinase C (PKC)
  • Ø Intracellular hyperglycemiaà increased DAG[231] synthesis from glycolytic intermediatesà activates PKCà increased VEGF, ECM and BM deposits, increased PAI-1[232]

UNEQUIVOCAL CRITERIA OF MALIGNANCY IN PANCREATIC ENDOCRINE NEOPLASMS***

• § Metastasis to regional LN or distant organs
• § Vascular invasion
• § Gross invasion of adjacent viscera (capsular invasion does not count!)

INCREASED RISK OF MALIGNANCY IN PANCREATIC ENDOCRINE NEOPLASMS***

• § Invasion beyond tumor capsule into pancreatic parenchyma
• § High mitoses
• § Tumor necrosis
• § Significant atypia
• § Functional status of some tumors (insulinomas 90% benign vs gastrinoma or nonfunctioning tumors often malignant)

CAUSES OF HYPERINSULINISM

• § Insulinoma
• § Diffuse HP of islets in neonates born to diabetic mom
• § Beckwith-Wiedemann syndrome

THYROTOXICOSIS

• § T4 intake
• § Graves
• § Toxic adenoma
• § MNG (toxic)

PAINFUL VS PAINLESS THYROID

Painful

• § Acute thyroiditis (infectious mostly)
• § Subacute granulomatous thyroiditis[233]

Painless

• § Hashimoto
• § Riedel thyroiditis

ATYPICAL ADENOMA IN THYROID

• § Hypercellular
• § Spindle
• § Atypical

TREATMENT FOR THYROID TUMORS

• § MTCà neck dissection required?
• § FTCà ?
• § PTCà LN dissection if clinically+

NON-EPITHELIAL TUMORS IN THYROID

HOW CANCER CAUSES CALCEMIA

• § PTH related substance
• § Bone lysis from RANKL receptor?

MOST RELIABLE WAY TO CONFIRM ADENOMA?

• § Intraoperative calcium level after removal

ATYPICAL PARATHYROID ADENOMA

• § Atypia?

HOW TO DIFFERENTIATE MELANOMA FROM ACC?

• § HMB45+ in melanoma but not ACC

DIFFERENT TYPES OF CONGENITAL ADRENAL HYPERPLASIA

• § S

USE RCC FOR CLEAR CELL AND PAPILLARY RCC

 

COMPARE CRETINISM AND MYXEDEMA

Cretinism	Myxedema
Perinatal or infancy[234]	Older kids and adults
Neuroskeletal: severe MR, umbilical hernia, coarse facial features[235]	Slow activity and mentation, cold intolerance, obesity, dry skin/hair, constipation, fatigue, cardiomegaly, pericardial effusion, hair loss, accumulation of MPS in dermis (myxedema)

CLINICAL CRITERIA FOR MALIGNANT THYROID NODULE

• § Solitary
• § Younger (<40)
• § Males
• § History of radiation
• § Cold
• § Suspicious FNA

RF FOR THYROID TUMORS

• § Radiation for PTC
• § Iodine deficiency[236] for FTC (Robbins)
• § Genetics

GENETICS FOR THYROID CANCERS

• § FTC[237]
  • Ø RAS[238]
  • Ø T(2;3) PAX8-PPARγ[239]
• § PTC[240]
  • Ø RET/PTC[241] or RET/NTRK1[242]
  • Ø BRAF[243]
• § MTC
  • Ø RET[244] mutations either germline (MEN2a/2b) or sporadic
• § Anaplastic
  • Ø P53 mutation[245]

EFFECTS OF PTH

• § Increased Ca from activating OC
• § Increases renal tubular reabsorption of Ca
• § Increases vitD hydroxylation in kidney (1,25)
• § Increases urinary PO4 excretion
• § Increases GI Ca absorption
• § Malignancy is no1 for symptomatic, primary hyperPTH is no1 for asymptomatic
• § Osteolytic metastasis from local release of cytokines[246]
• § PTH-related protein (PTHrP)[247]
• § Sporadic >>> familial
  • Ø MEN1: adenoma, HP, carcinoma
  • Ø MEN2a: only HP
  • Ø FHH[248] (familial hypocalciuric hypercalcemia): mutations at CASR[249]à decreased receptor sensitivity to extracellular Ca
• § PRAD1[251]: encodes cyclinD1, which is overexpressed in 40% of parathyroid adenomas
• § MEN1: LOH in 20-30%

NO1 CAUSE FOR SYMPTOMATIC HYPERCA VS ASYMPTOMATIC HYPERCA?* (ROBBINS)

MECHANISM OF HYPERCALCEMIA IN MALIGNANCIES

3 FAMILIAL CAUSES OF PRIMARY HYPERPTH AND GENETICS

GENETICS OF SPORADIC PARATHYROID ADENOMAS[250]

PARATHYROID ADENOMA VS PARATHYROID HP***

Parathyroid adenoma	Parathyroid HP
Always solitary[252]	All glands although asymmetric[253] involvement
500mg-5000g	Combined weight rarely exceeds 1000mg
Delicate capsule	No
Other glands normal or atrophic	All glands involved, diffuse or nodular
One cell population[254]+/-foci of oxyphil cells	Most commonly chief cell HP
Compressed surrounding normal tissue	No
Fatless	Fatless

EFFECTS OF HYPERPTH ON DIFFERENT ORGANS*** (bones, stones, groans, moans)

Bones

• § Osteoporosis
• § Fractures
• § Ostetis fibrosis cystica[255][256][257]
• § Brown tumour of hyperPTH

Stones

• § Nephrolithiasis
• § Metastatic calcification in lungs, heart (AV and MV calcifications), vessels (calciphylaxis[258]), stomach, kidney (nephrocalcinosis)

Groans

• § PUD
• § Cholelithiasis
• § Pancreatitis
• § Constipation

Moans

• § Depression
• § Seizures
• § Weakness
• § Fatigue
• § Surgery
• § Congenital absence (DiGeorge)
• § Familial hypoPTH[259] (aka AI polyendocrinopathy syndrome type 1[260] or APS1)

CAUSES OF HYPOPARATHYROIDISM (Robbins)

EFFECTS OF HYPOCALCEMIA (Robbins)

• § Tetany, muscle cramps, carpopedal spasms, laryngeal stridor, convulsions
• § Mental status change: irritability, psychosis
• § Intracranial: parkinsonian-like movement disorders, increased ICP with papilledema
• § Ocular: calcification of lensà cataracts
• § Cardiac conduction: long QT

DIABETIC EFFETS ON EACH ORGAN

Pancreas

• § DM1: decreased number and size of islets, insulitis[261]
• § DM2: β-cell degranulation, fibrosis of islets, deposition of amyloid[262]

Macrovascular

• § Atherosclerosis of aorta and large-medium sized BV

Microvascular

• § Hyaline arteriolosclerosis from HTN
• § Diffuse thickening of BM[263][264]

Kidney[265]

• § Glomeruli: mesangial sclerosis, nodular and diffuse GS, exudative lesions
• § BV: arteriolosclerosis from HTN (benign nephrosclerosis)
• § Infection: papillary necrosis, pyelonephritis

Eyes

• § Non-proliferative: intraretinal and preretinal hemorrhages, exudates, edema, thickening of retinal capillaries, microaneurysms
• § Proliferative: neovascularization and fibrosis of retina

Nerves

• § Symmetric peripheral neuropathy, both motor and sensory
• § Autonomic neuropathy
• § Diabetic mononeuropathy: from microangiopathy

General

• § Susceptibility to infections: skin infections, TB, pneumonia, pyelonephritis

 

 

 

COMMON NE HORMONE-PRODUCING TUMORS (Steinberg)

Calcitonin	C-cell/MTC	Laryngeal NE Pancreatic NE
ACTH	Pituitary/pituitary adenoma	Pancreatic NE Lung NE Pheochromocytoma
CRH	Hypothalamic neurons	Pancreatic NE
GH	Pituitary/pituitary adenoma	Pancreatic NE
GHRH	Hypothalamic neurons	Pancreatic NE
Pancreatic polypeptides	Pancreatic islets/pancreatic NE	Intestinal NE
Somatostatin	Pancreatic islets/pancreatic NE/duodenum/stomach	Intestinal NE

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