Thyroid Lesions - Classification and Full Details

MASTER CLASSIFICATION OF THYROID LESIONS

THYROID LESIONS
├── A. NON-NEOPLASTIC
│   ├── Goiter (Diffuse / Multinodular)
│   └── Thyroiditis
│       ├── Hashimoto
│       ├── Subacute Granulomatous (de Quervain)
│       ├── Painless (Subacute Lymphocytic)
│       └── Riedel
├── B. BENIGN NEOPLASMS
│   └── Follicular Adenoma
│       ├── Nonfunctioning (cold nodule)
│       └── Toxic Adenoma (hot nodule)
└── C. MALIGNANT NEOPLASMS (Thyroid Carcinoma)
    ├── Papillary Thyroid Carcinoma (PTC) - >85%
    ├── Follicular Thyroid Carcinoma (FTC) - 5-15%
    ├── Anaplastic (Undifferentiated) Carcinoma - <5%
    └── Medullary Thyroid Carcinoma (MTC) - ~5%

PART I: NON-NEOPLASTIC LESIONS

1. Goiter

• Follicles lined by crowded columnar cells (hyperplastic phase) or flattened cuboidal cells (involution/colloid phase)
• Cut surface: brown, gelatinous, translucent

2. Thyroiditis

PART II: BENIGN NEOPLASMS

Follicular Adenoma

• Toxic adenoma: Gain-of-function mutations in the TSH receptor (TSHR) or the Gs-alpha subunit (GNAS) → constitutive TSH signaling → autonomous thyroid hormone secretion → hyperthyroidism
• Nonfunctioning adenoma: Mutations in RAS (<20%) and PTEN (shared with follicular carcinoma)

• Solitary, compresses adjacent thyroid
• Uniform follicles containing colloid, minimal mitoses
• Cells may show Hurthle (oxyphil) cell change
• Intact, complete capsule - mandatory criterion

• Most present as painless nodules
• Nonfunctioning: cold nodule on radionuclide scan (up to 10% of cold nodules are malignant)
• Toxic adenoma: warm/hot nodule, features of thyrotoxicosis
• FNA + ultrasound essential pre-operatively
• Surgically excised to evaluate capsular integrity
• Excellent prognosis; do not recur

PART III: MALIGNANT NEOPLASMS (Thyroid Carcinomas)

Frequency Overview

1. Papillary Thyroid Carcinoma (PTC)

• BRAF point mutation: 40-65% (most common single alteration)
• RAS mutations: 10-30%
• RET/NTRK gene fusions (translocations): 10-20%
• These are mutually exclusive - each one constitutively activates MAPK signaling
• Ionizing radiation (especially in first 2 decades of life) is a major risk factor; incidence surged among children after Chernobyl (1986)

• Solitary or multifocal; may be encapsulated or infiltrative
• Diagnostic nuclear hallmarks (sufficient even without papillary architecture):
  • Branching papillae with fibrovascular stalks lined by cuboidal cells
  • Ground-glass (Orphan Annie eye) nuclei - optically clear/empty due to finely dispersed chromatin
  • Intranuclear pseudo-inclusions - cytoplasmic invaginations
  • Intranuclear grooves
  • Psammoma bodies - concentrically calcified structures in papillary cores (rarely in follicular or medullary carcinomas)
• Lymphatic invasion common; blood vessel invasion uncommon in smaller lesions
• Cervical lymph node metastasis in up to 50% of cases

• Encapsulated follicular variant (common; carries PAX8-PPARG fusion in ~1/3)
• Tall cell, columnar cell, diffuse sclerosing, oncocytic, hobnail, and others

• Usually a painless neck mass (within thyroid or as cervical node metastasis)
• Nonfunctional; FNA is diagnostic pre-operatively
• 10-year survival >95% - indolent course
• Isolated cervical node metastases do not significantly worsen prognosis
• Hematogenous metastasis to lungs in a minority
• Prognosis influenced by: age >40, extrathyroidal extension, distant metastases

2. Follicular Thyroid Carcinoma (FTC)

• RAS mutations (shared with adenomas and anaplastic carcinoma)
• PIK3CA gain-of-function (encodes PI3K)
• PTEN loss-of-function (negative regulator of PI3K)
• PAX8-PPARG fusion [t(2;3)(q13;p25)] - found in up to 50%; PAX8 regulates thyroid development, PPARG governs terminal differentiation
• Iodine deficiency increases FTC risk; iodine-sufficient areas show stable/declining incidence

• Single nodule; may be well-circumscribed or widely infiltrative
• Grossly indistinguishable from follicular adenoma
• On microscopy: uniform cells forming small colloid-containing follicles
• Diagnosis of carcinoma requires demonstration of capsular and/or vascular invasion (requires extensive sampling of the tumor-capsule interface)

• Minimally invasive FTC: Focal capsular ± vascular invasion; <10% die within 10 years
• Widely invasive FTC: Extensive invasion; ~50% die within 10 years

• Presents as solitary cold nodule
• Hematogenous spread (lungs, bone, liver) is characteristic - in contrast to PTC's lymphatic spread
• Regional lymph node metastasis is uncommon
• Rarely hyperfunctional

• A variant with brightly eosinophilic granular cytoplasm (oxyphil change)
• Worst survival among well-differentiated thyroid cancers
• Highest incidence of distant metastases among well-differentiated tumors

3. Anaplastic (Undifferentiated) Thyroid Carcinoma

• Shares mutations with well-differentiated carcinomas (RAS, PIK3CA)
• Additional mutations unique to anaplastic carcinoma:
  • TP53 loss-of-function (most important driver of dedifferentiation)
• Typically arises by progression/dedifferentiation from existing papillary or follicular carcinoma

• Bulky masses growing rapidly beyond the thyroid capsule into adjacent neck structures
• Microscopically: highly anaplastic cells - large and pleomorphic, or spindle-shaped, or a mixture
• Foci of papillary/follicular differentiation may be present (pointing to origin)

• Rapid growth, invading vital neck structures
• Distant metastases common
• Death in most cases within 1 year due to aggressive local extension
• Unresponsive to most conventional therapies; BRAF-targeted therapy (dabrafenib + trametinib) used for BRAF V600E-mutated tumors

4. Medullary Thyroid Carcinoma (MTC)

• C cells are of neuroectodermal origin, located mainly in the lateral superior thyroid poles
• Secrete calcitonin (diagnostic and surveillance marker), CEA, serotonin, somatostatin, VIP, histaminidases, prostaglandins

• Sporadic (70%): Unifocal; acquired RET mutations in ~50%; peak age 50-60 years; M = F
• Familial (30%): Germline RET mutations; autosomal dominant, ~100% penetrance; multicentric and bilateral in 90%
  • Familial MTC alone (no associated endocrinopathy)
  • MEN-2A: MTC + pheochromocytoma + primary hyperparathyroidism
  • MEN-2B: MTC + pheochromocytoma + mucosal neuromas + Marfanoid habitus (most aggressive; MTC can appear in first year of life)

• Solid, firm, gray, nonencapsulated but well-circumscribed
• Polygonal to spindle-shaped cells in nests, trabeculae, or glandlike structures
• Amyloid deposits in stroma (derived from altered calcitonin molecules) - a distinctive feature
• Familial MTC: multicentric C-cell hyperplasia in surrounding parenchyma (precursor lesion)

• Neck mass ± cervical lymphadenopathy (palpable nodes in ≤20%)
• Local invasion symptoms: dysphagia, dyspnea, dysphonia
• Diarrhea/flushing from VIP or serotonin secretion
• Distant metastases in 50% at diagnosis (mediastinum, liver, lung, bone)
• Does NOT respond to radioiodine or TSH suppression (C cell origin)

• Serum calcitonin + CEA
• RET mutation testing in all patients
• Screen for pheochromocytoma (24-hr urinary catecholamines/metanephrines + abdominal MRI)
• Screen for hyperparathyroidism (serum calcium)

• Total thyroidectomy + bilateral central neck dissection (level VI, VII)
• Lateral neck dissection for palpable nodes or elevated calcitonin (ipsilateral if >20 pg/mL, bilateral if >200 pg/mL)
• Targeted therapy for advanced disease: vandetanib or cabozantinib (RET inhibitors); newer RET-selective inhibitors (selpercatinib, pralsetinib) under study

COMPARATIVE SUMMARY TABLE

BETHESDA SYSTEM (FNA Cytology Classification)

ULTRASOUND RISK CLASSIFICATION (TI-RADS / ATA)

• Hypoechogenicity / marked hypoechogenicity
• Microcalcifications (psammoma bodies)
• Irregular margins / infiltrative borders
• Taller-than-wide shape on transverse view
• Extrathyroidal extension

• Purely cystic lesion
• Spongiform appearance (honeycomb pattern)
• Isoechoic/hyperechoic with smooth margins
• Comet-tail artifact (colloid crystals)
• Hot on radionuclide scan

Recent literature note: A 2024 review (PMID: 38672067) discusses updates to the WHO 2022 classification of thyroid tumors, including recognition of low-risk encapsulated follicular variant PTC as "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) - a borderline entity with essentially benign behavior that should be distinguished from invasive carcinoma.

What Was Covered

1. Normal thyroid anatomy and physiology - HPT axis, hormone synthesis, TSH signaling (with diagram)
2. Complete classification tree - All lesions from non-neoplastic to malignant, including the 2022 WHO updates
3. Non-neoplastic lesions in full detail:
   • Diffuse and multinodular goiter (endemic vs sporadic)
   • Hashimoto thyroiditis (with pathogenesis diagram and histology image)
   • Graves disease (triad, TSI mechanism, treatment)
   • de Quervain, painless/postpartum, and Riedel thyroiditis
4. Follicular adenoma - toxic vs nonfunctioning, molecular genetics, hot/cold nodule distinction
5. WHO 2022 borderline entities - NIFTP, HTT, UMP
6. All 6 malignant subtypes with morphology images, molecular alterations, spread patterns, prognosis, and targeted therapies - PTC (with Orphan Annie eye nuclei image), FTC (capsular invasion), OCA (new WHO 2022 term), PDTC, ATC (anaplastic), MTC (amyloid, RET/MEN-2)
7. Thyroid nodule evaluation - red flags, ATA risk stratification, FNA thresholds (with algorithm flowchart)
8. Bethesda System (Bethesda I-VI) with malignancy risks
9. AJCC 8th edition staging for DTC
10. Complete comparative summary table across all 6 malignant types