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Sarcoidosis - Robbins Revision Notes

Quick Recall Box

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Epidemiology

• Adults < 40 years predominantly affected
• Higher incidence in Danish/Swedish populations and African Americans (2-3x more than European descent)
• Unique feature: higher prevalence among nonsmokers - virtually unique to sarcoidosis among pulmonary diseases

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Pathogenesis

• Intraalveolar and interstitial accumulation of CD4+ Th1 cells
• Oligoclonal expansion of CD4+ Th1 T cells within the lung
• Increased Th1 cytokines: IL-2 (T-cell proliferation) and IFN-γ (macrophage activation)
• Increased IL-8, TNF, MIP-1α → recruit more T cells and monocytes → granuloma formation

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Morphology (MORPHOLOGY box - HIGH YIELD)

• Discrete compact collection of epithelioid macrophages
• Rimmed by an outer zone rich in CD4+ T cells
• Intermixed multinucleate giant cells (from fused macrophages)
• Thin layer of laminated fibroblasts peripherally → over time → hyalinized scar

1. Schaumann bodies - laminated concretions of calcium and proteins
2. Asteroid bodies - stellate inclusions within giant cells

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Organ Involvement

Lungs (90%)

• Granulomas in the interstitium (not air spaces)
• "Lymphangitic" distribution - around bronchioles, pulmonary venules, and pleura
• BAL: abundant CD4+ T cells
• 5-15% progress to diffuse interstitial fibrosis → honeycomb lung

Lymph Nodes (75-90%)

• Intrathoracic hilar and paratracheal enlargement
• 1/3 have peripheral lymphadenopathy
• Nodes are painless, firm, rubbery
• Key distinction from TB: "nonmatted" (non-adherent), no necrosis

Skin (~25%)

• Erythema nodosum - hallmark of acute sarcoidosis; bilateral raised, red, tender nodules on anterior legs; it's a panniculitis - classic sarcoid granulomas are actually uncommon in these lesions
• Discrete painless subcutaneous nodules - these DO contain typical noncaseating granulomas

Eyes (20-50%)

• Iritis or iridocyclitis (uveitis) - unilateral or bilateral
• Complications: corneal opacities, glaucoma, vision loss
• Posterior uveal tract: choroiditis, retinitis, optic nerve involvement
• Lacrimal gland involvement → sicca syndrome (dry eyes)

Parotid glands (<10%)

• Painful parotid enlargement, xerostomia (dry mouth)
• Mikulicz syndrome = combined uveoparotid involvement

Spleen

• Granulomas in ~75% microscopically
• Clinical splenomegaly in ~10%

Liver

• Granulomas (usually in portal triads) in ~75%
• Hepatomegaly or abnormal LFTs in ~1/3

Bone Marrow

• Granulomas in up to 40%; rarely causes severe manifestations

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Diagnosis

1. Clinical + radiologic findings consistent with sarcoidosis
2. Exclusion of other disorders (especially TB must be excluded)
3. Identification of noncaseating granulomas in involved tissues

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Clinical Course & Prognosis

• Many cases: asymptomatic, discovered incidentally on CXR (bilateral hilar adenopathy) or at autopsy
• Course is unpredictable - chronic progressive OR remissions (spontaneous or steroid-induced)
• Prognosis:
  • 65-70% recover with minimal/no residual manifestations
  • 20% develop permanent lung dysfunction or visual impairment
  • 10-15% succumb to progressive pulmonary fibrosis and cor pulmonale

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High-Yield Exam Traps

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Summary Mnemonic - SARCOID

• S - Schaumann/asteroid bodies (inclusions)
• A - Anergy to PPD/Candida skin tests (blood CD4 low)
• R - Restrictive lung disease (interstitial fibrosis)
• C - CD4+ Th1 cells drive it; Cor pulmonale (end-stage)
• O - Ocular (iritis/iridocyclitis), unknown etiology
• I - IL-2, IFN-γ (Th1 cytokines); Incidence in African Americans
• D - Diagnosis of exclusion; Diffuse hilar adenopathy on CXR

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Thyroid Neoplasms - Complete Robbins Revision Notes

Overview

• Solitary nodule (vs. multiple)
• Age < 30 years or male gender
• History of radiation exposure
• Cold nodule on radionuclide scan (does not take up radioactive iodine)
• Majority of solitary nodules are benign; carcinomas account for < 1% of solitary thyroid nodules

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1. Thyroid Adenoma (Follicular Adenoma)

Key Features

• Typically solitary, spherical lesion derived from follicular epithelium
• Most are nonfunctional; small proportion are toxic adenomas (produce thyroid hormone → thyrotoxicosis)
• Follicular adenomas are generally NOT forerunners of carcinoma, though shared genetics (RAS, PTEN) raise the possibility that some follicular carcinomas arise in preexisting adenomas

Genetics

Morphology

• Gross: Solitary, spherical, compresses adjacent thyroid
• Micro: Uniform follicles with colloid; cells uniform in size, shape, nuclear morphology; mitotic figures rare
• Key hallmark: Intact capsule encircling the ENTIRE tumor - this is what distinguishes adenoma from follicular carcinoma
• Occasional oxyphil (Hürthle cell) change - brightly eosinophilic granular cytoplasm

Radionuclide Scan

• Nonfunctional (cold nodule): Takes up less iodine than normal thyroid - up to 10% of cold nodules prove malignant
• Toxic adenoma (hot/warm nodule): Malignancy is uncommon in hot nodules

Prognosis

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2. Thyroid Carcinomas - Overview

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3. Papillary Thyroid Carcinoma (PTC)

Epidemiology

• Most common thyroid malignancy (~85% of cases in the US)
• Most often between 25-50 years of age
• Most thyroid carcinomas associated with prior ionizing radiation are papillary

Genetics (HIGH YIELD)

• BRAF V600E mutation - most common; associated with more aggressive behavior
• RET/PTC rearrangements - especially in radiation-induced PTC
• RAS mutations - seen in follicular variant of PTC

Morphology

• May be solitary or multifocal
• Some well-circumscribed, others infiltrate adjacent parenchyma (ill-defined margins)
• May contain fibrosis, calcification; often cystic

1. Branching papillae with fibrovascular stalk covered by cuboidal epithelial cells (single to multiple layers)
2. Orphan Annie eye nuclei (ground-glass nuclei) - finely dispersed chromatin giving optically clear/empty appearance
   • Plus: nuclear membrane irregularities → nuclear grooves (coffee-bean shapes) and pseudoinclusions (cytoplasm invaginating into nucleus)
3. Psammoma bodies - concentrically calcified structures within papillary cores or adjacent stroma
   • Almost NEVER found in follicular or medullary carcinomas
   • Strong indicator of PTC in FNA material
4. Lymphatic invasion commonly present; blood vessel involvement uncommon (contrast with follicular carcinoma)
5. Cervical lymph node metastases in up to 50% of cases

Clinical Features

• Usually presents as asymptomatic thyroid nodule; first manifestation may be enlarged cervical lymph node
• Nodules move freely with thyroid during swallowing
• Hoarseness, dysphagia, cough, dyspnea = advanced disease
• Cold mass on scintigraphy
• "Hot" nodules = almost never malignant (only do scintigraphy if TSH is low)

Prognosis

• Excellent - 10-year survival > 95%
• 5-20% have local/regional recurrences; 10-15% have distant metastases
• Prognosis worse with: age > 55, extrathyroidal extension, distant metastases

NIFTP (HIGH YIELD - new entity)

• Encapsulated follicular variant of PTC with NO invasion
• Reclassified from malignant to a low-risk neoplasm (no longer called carcinoma)
• Distinguished from invasive encapsulated follicular variant of PTC by absence of capsular/vascular invasion

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4. Follicular Thyroid Carcinoma (FTC)

Epidemiology

• 5-15% of primary thyroid cancers (US/iodine-sufficient areas)
• In iodine-deficient areas: rises to 25-40% of thyroid cancers
• Presents in older patients than PTC - peak incidence 40-60 years

Genetics

• RAS mutations (most common)
• PAX8-PPARG rearrangement (translocation) - characteristic of FTC

Morphology

• Usually solitary, circumscribed or widely infiltrative
• Sharply demarcated lesions can be indistinguishable from follicular adenomas grossly
• Gray to tan to pink; may be translucent (large colloid-filled follicles)
• Degenerative changes: central fibrosis, coarse calcification

• Uniform cells forming small follicles with colloid - resembles normal thyroid
• Nuclei LACK papillary carcinoma features; NO psammoma bodies
• Occasional oncocytic (Hürthle cell) variant - abundant granular eosinophilic cytoplasm
• Adenoma vs. Carcinoma: NO reliable cytologic difference on FNA - requires extensive histologic sampling of tumor capsule to identify:
  • Capsular invasion and/or
  • Vascular invasion (venous vessels within/just beyond capsule)

Spread Pattern (KEY CONTRAST WITH PTC)

• Hematogenous spread (not lymphatic) → distant metastases
• Lymph node involvement uncommon (opposite of PTC)
• Hematogenous mets most commonly to lung (and bone)

Prognosis

• Worse than PTC
• Minimally invasive FTC (capsular invasion only): excellent prognosis
• Widely invasive FTC: significantly worse

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5. Medullary Thyroid Carcinoma (MTC)

Origin

• Arises from parafollicular C cells (NOT follicular epithelium)
• C cells secrete calcitonin

Epidemiology & Association

• 5% of thyroid carcinomas
• Sporadic (70%): usually presents in 5th-6th decade, typically solitary
• Familial (30%): associated with RET proto-oncogene mutations
  • MEN-2A (Sipple syndrome): MTC + pheochromocytoma + parathyroid hyperplasia
  • MEN-2B: MTC + pheochromocytoma + mucosal neuromas + marfanoid habitus
  • Familial MTC (without MEN features)
  • Familial cases: often bilateral and multicentric

Morphology

• Polygonal to spindle-shaped cells in nests, trabeculae, or follicles
• Amyloid deposits in stroma (derived from calcitonin molecules) - distinctive feature
• C-cell hyperplasia precedes familial MTC (identified in prophylactic thyroidectomies)
• Bilateral/multicentric in familial cases

Clinical Features

• Sporadic: presents as neck mass ± compression effects (dysphagia, hoarseness)
• May secrete other peptide hormones → diarrhea (vasoactive intestinal peptide), flushing (calcitonin, serotonin)
• Screening: serum calcitonin levels or RET mutation testing for family members
• Members of MEN-2 kindreds with RET mutations → prophylactic thyroidectomy offered

Key Markers

• Serum calcitonin (elevated) - diagnostic marker and screening tool
• Amyloid in stroma (calcitonin-derived)

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6. Anaplastic (Undifferentiated) Thyroid Carcinoma

Key Features

• Represents <5% of thyroid tumors but is the most aggressive
• Usually occurs in patients >65 years of age
• May arise from dedifferentiation of pre-existing differentiated carcinoma (PTC or FTC) or de novo
• Near-100% mortality; most patients die within 1 year of diagnosis

Genetics

• TP53 mutations (most common) - often with co-existing RAS or BRAF mutations (suggesting progression from differentiated carcinoma)
• TERT promoter mutations

Morphology

• Highly pleomorphic, undifferentiated cells - may be:
  • Spindle cells
  • Giant cells
  • Mixed
• Extensive necrosis and mitotic figures
• Invades adjacent structures extensively

Clinical Features

• Rapidly enlarging, hard, fixed neck mass
• Often presents with airway obstruction, dysphagia, hoarseness at time of diagnosis
• Distant metastases common at presentation

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High-Yield Comparison Table

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Nodule Evaluation: Hot vs. Cold (HIGH YIELD)

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Key Exam Traps

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Mnemonic: PFMA (types in frequency order)

• Papillary - 85% - Psammoma, Papillae, Paediatric/young adults
• Follicular - 5-15% - Fibrovascular invasion needed, Far (haematogenous) spread
• Medullary - 5% - MEN-2, Marker calcitonin, aMyloid
• Anaplastic - <5% - Awful prognosis, Aged patients, Aggressive

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