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.

THYROID LESIONS - Complete Reference

SECTION 1: NORMAL THYROID - ANATOMY & PHYSIOLOGY

Anatomy

HPT Axis & Hormone Synthesis

• TRH (hypothalamus) → stimulates TSH from anterior pituitary thyrotrophs
• TSH binds thyroid follicular cell TSH receptor → Gs protein → ↑cAMP → promotes growth, T3/T4 synthesis and release
• Follicular epithelial cells convert thyroglobulin into T4 (thyroxine) and lesser amounts of T3
• Most circulating T4/T3 is bound to thyroxine-binding globulin (TBG), transthyretin, and albumin; only free fraction is active
• In periphery, T4 is deiodinated to T3, which binds thyroid hormone nuclear receptors with 10-fold greater affinity
• Net effect: increased basal metabolic rate; critical for brain development in fetus and neonate

SECTION 2: MASTER CLASSIFICATION OF THYROID LESIONS

THYROID LESIONS
│
├── A. NON-NEOPLASTIC
│   ├── 1. Goiter
│   │   ├── Diffuse (Endemic / Sporadic)
│   │   └── Multinodular Goiter (MNG)
│   │       └── Toxic MNG (Plummer Disease)
│   │
│   └── 2. Thyroiditis
│       ├── Hashimoto Thyroiditis (chronic lymphocytic)
│       ├── Graves Disease (autoimmune hyperthyroidism)
│       ├── Subacute Granulomatous (de Quervain)
│       ├── Painless / Subacute Lymphocytic (postpartum)
│       └── Riedel Thyroiditis (IgG4-related fibrosis)
│
├── B. BENIGN NEOPLASMS
│   └── 3. Follicular Adenoma
│       ├── Nonfunctioning ("cold" nodule)
│       ├── Toxic Adenoma ("hot" nodule / Plummer adenoma)
│       └── Oncocytic (Hürthle cell) Adenoma [WHO 2022 separate entity]
│
└── C. MALIGNANT NEOPLASMS
    │
    ├── FOLLICULAR CELL-DERIVED (95%)
    │   ├── 4. Papillary Thyroid Carcinoma (PTC) - >85%
    │   │   ├── Classical/conventional
    │   │   ├── Encapsulated follicular variant
    │   │   ├── Tall cell variant (aggressive)
    │   │   ├── Hobnail variant (aggressive)
    │   │   ├── Diffuse sclerosing variant
    │   │   ├── Columnar cell variant
    │   │   └── (>12 variants total)
    │   │
    │   ├── BORDERLINE / LOW-RISK ENTITIES
    │   │   ├── NIFTP (Non-Invasive Follicular Thyroid Neoplasm with
    │   │   │        Papillary-like nuclear features) - essentially benign
    │   │   ├── HTT (Hyalinizing Trabecular Tumor)
    │   │   └── UMP (Uncertain Malignant Potential)
    │   │
    │   ├── 5. Follicular Thyroid Carcinoma (FTC) - 5-15%
    │   │   ├── Minimally invasive
    │   │   └── Widely invasive
    │   │
    │   ├── 6. Oncocytic Carcinoma of Thyroid (OCA) - ~5% of DTC
    │   │       [WHO 2022 replaces "Hürthle cell carcinoma"]
    │   │
    │   ├── 7. Poorly Differentiated Thyroid Carcinoma (PDTC)
    │   │       [insular carcinoma] - between DTC and anaplastic
    │   │
    │   └── 8. Anaplastic (Undifferentiated) Carcinoma - <5%
    │
    ├── C-CELL DERIVED (5%)
    │   └── 9. Medullary Thyroid Carcinoma (MTC)
    │       ├── Sporadic (70%)
    │       └── Familial (30%)
    │           ├── MEN-2A (MTC + pheo + HPT)
    │           ├── MEN-2B (MTC + pheo + mucosal neuromas)
    │           └── Familial MTC (no other endocrinopathy)
    │
    └── RARE / SECONDARY
        ├── Primary Thyroid Lymphoma (usually DLBCL, in Hashimoto background)
        └── Metastases to thyroid (renal cell, lung, breast, melanoma)

SECTION 3: NON-NEOPLASTIC LESIONS IN DETAIL

3A. GOITER

Diffuse Goiter

• Follicles lined by crowded columnar cells (hyperplastic phase)
• Involution produces flattened cuboidal cells and colloid-rich gland (colloid goiter)
• Cut surface: brown, glassy, translucent

Multinodular Goiter (MNG)

• Dominant: neck mass and compressive symptoms (dysphagia, stridor, SVC obstruction with retrosternal extension)
• Usually euthyroid
• Toxic MNG (Plummer disease): autonomous hyperthyroidism develops in long-standing MNG; multiple warm/hot nodules on scintigraphy
• Nodules within MNG carry a ~5% risk of malignancy (similar to solitary nodules)

3B. THYROIDITIS

Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)

• Autoantibodies: anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin in the vast majority
• Genetic predisposition: polymorphisms in CTLA4, PTPN22, IL2RA (T-cell regulatory genes)
• CD8+ cytotoxic T cells directly kill follicular cells
• CD4+ Th1 cells produce IFN-γ → macrophage activation → follicular damage

• Thyroid diffusely enlarged, well-demarcated, pale yellow-tan, firm
• Extensive mononuclear infiltrate: lymphocytes, plasma cells, lymphoid follicles with germinal centers
• Atrophic thyroid follicles with eosinophilic oncocytes (formerly Hürthle cells) - metaplastic response

Graves Disease

1. Thyrotoxicosis
2. Ophthalmopathy (exophthalmos - from retroorbital glycosaminoglycan deposition + lymphocytic infiltration)
3. Dermopathy (pretibial myxedema - scaly, indurated skin over shins)

Subacute Granulomatous Thyroiditis (de Quervain Thyroiditis)

• Acute onset: painful neck, particularly with swallowing; fever; malaise; ESR and WBC elevated
• Triphasic thyroid function:
  1. Transient thyrotoxicosis (follicle destruction → preformed hormone release)
  2. Hypothyroid phase (depleted stores)
  3. Return to euthyroidism within 6-8 weeks
• Self-limited; NSAIDs/steroids for pain

Painless (Subacute Lymphocytic) Thyroiditis

• Autoimmune variant of Hashimoto thyroiditis
• Affects middle-aged women; subset occurs postpartum (postpartum thyroiditis)
• Circulating antithyroid antibodies in majority
• Painless thyroid mass or transient thyrotoxicosis → euthyroidism; minority progress to hypothyroidism
• Histology: lymphocytic infiltration + hyperplastic germinal centers

Riedel Thyroiditis

• Manifestation of IgG4-related disease
• Dense lymphoplasmacytic infiltrates and extensive fibrosis involving thyroid and contiguous neck structures (may encase parathyroids, recurrent laryngeal nerve)
• Clinically: rock-hard, fixed thyroid mass - mimics malignancy
• Associated with IgG4-related fibrosis elsewhere (retroperitoneum, etc.)
• ~1/3 of patients are hypothyroid
• Treatment: steroids (IgG4-RD protocol), surgery for compressive symptoms

SECTION 4: FOLLICULAR ADENOMA (Benign Neoplasm)

Molecular Pathogenesis

Morphology

• Solitary, well-demarcated, compresses adjacent parenchyma
• Uniform follicles with colloid, minimal mitoses
• Intact circumferential capsule (mandatory criterion)
• Cells may show Hürthle (oncocytic) cell change

Functional Classification

Clinical

• Painless mass; found on routine exam or imaging
• FNA + ultrasound mandatory pre-operatively
• Surgical excision required to evaluate capsular integrity (cannot exclude carcinoma by FNA alone in follicular lesions)
• Excellent prognosis; no recurrence after excision

SECTION 5: BORDERLINE / LOW-RISK ENTITIES (WHO 2022)

NIFTP (Non-Invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features)

• Previously called "encapsulated follicular variant of PTC"
• Has nuclear features of PTC (ground-glass nuclei, grooves) but no capsular or vascular invasion
• Almost always follows a benign course
• Thyroid lobectomy is adequate treatment; no RAI needed
• Reclassified from cancer to borderline/precancerous entity to prevent overtreatment

HTT (Hyalinizing Trabecular Tumor)

• Trabecular growth pattern with hyalinized stroma
• Almost always benign; lobectomy adequate

UMP (Uncertain Malignant Potential)

• Features intermediate between adenoma and carcinoma
• Metastatic potential uncertain; requires closer follow-up

SECTION 6: MALIGNANT THYROID NEOPLASMS IN DETAIL

Molecular Oncogenesis Overview (WHO 2022 / Cancer Genome Atlas)

• Activated by growth factors → RTK → RAS → RAF → MEK → ERK
• Promotes proliferation, dedifferentiation, and tumor growth
• Key alterations: BRAF V600E (PTC), RET/PTC fusions, NTRK fusions, RAS mutations

• Key alterations: RAS mutations, PIK3CA gain-of-function, PTEN loss-of-function, PAX8-PPARG fusion

6A. PAPILLARY THYROID CARCINOMA (PTC)

• BRAF V600E - 40-65% (most common single mutation; correlates with reduced differentiation markers, higher risk of extrathyroidal extension)
• RAS mutations - 10-30%
• RET/PTC gene fusions - 10-20% (>20 fusion partners; PTC1/CCDC6 most common)
• NTRK1 or NTRK3 fusions - subset, especially childhood tumors

Morphology

• Lymphatic spread to cervical lymph nodes in up to 50% of cases
• Hematogenous spread (lung) in a minority

• Usually presents as asymptomatic cold thyroid nodule or cervical lymph node metastasis
• Moves freely with thyroid on swallowing
• Hoarseness/dysphagia/dyspnea = advanced disease
• FNA with molecular testing is diagnostic preoperatively
• 10-year survival >95% - most indolent thyroid malignancy
• Isolated cervical lymph node metastases do not significantly worsen prognosis
• Poor prognosis factors: age >40, extrathyroidal extension, distant metastases, BRAF mutation in aggressive variants

• Low-risk DTC (<1 cm): lobectomy or active surveillance
• Intermediate-risk (1-4 cm, no ETE or nodes): lobectomy acceptable alternative to total thyroidectomy
• High-risk (≥4 cm, nodal or distant metastases, ETE, familial): total thyroidectomy + lymph node dissection
• Adjuvant radioactive iodine (RAI/I-131) for higher-risk cases
• TSH suppression with levothyroxine
• Targeted therapy: lenvatinib, sorafenib for RAI-refractory advanced disease; BRAF inhibitors (dabrafenib) for BRAF V600E

6B. FOLLICULAR THYROID CARCINOMA (FTC)

• PAX8-PPARG fusion [t(2;3)(q13;p25)] - up to 50%
• RAS mutations - most common point mutations (shared with follicular adenomas)
• PIK3CA gain-of-function - ~10%
• PTEN loss-of-function - ~10%
• TERT promoter mutations (widely invasive/aggressive subset)
• Iodine deficiency increases FTC incidence; iodine-sufficient areas show stable/declining rates

• Clinical exam
• Ultrasound features
• FNA cytology (FNA reports "follicular neoplasm" = indeterminate, Bethesda IV)

• Single nodule; may be well-circumscribed or widely infiltrative
• Microscopy: uniform cells in small follicles resembling normal thyroid
• Key diagnostic finding: mushroom-like protrusion of tumor through fibrous capsule (capsular invasion) and/or tumor cells inside vascular spaces lined by endothelium (vascular invasion)

• Hematogenous (lungs, bone, liver) - contrasts sharply with PTC's lymphatic spread
• Regional lymph node metastases <10%

• Previously called Hürthle cell carcinoma (now discouraged - historical misnomer)
• At least 75% oncocytic (eosinophilic granular cytoplasm) cells
• ~5% of differentiated thyroid cancers
• Peak age: 6th-7th decades
• Can metastasize both lymphatically AND hematogenously
• Distant metastases in up to 20% at initial diagnosis
• 5-year overall survival ~85%, but only 24% with distant metastases
• Does NOT reliably take up radioiodine (functional mitochondrial abnormality)

• Presents as cold solitary thyroid nodule
• Surgical excision + pathologic examination required for definitive diagnosis

6C. POORLY DIFFERENTIATED THYROID CARCINOMA (PDTC)

• Also called insular carcinoma (from insulae = islands of tumor cells)
• Intermediate behavior between well-differentiated carcinomas and anaplastic carcinoma
• Molecular alterations: PDTC mutations (RAS, BRAF) + additional hits (TERT promoter, TP53)
• Histology: solid/trabecular/insular growth; mitoses; necrosis
• More aggressive than PTC or FTC; poorer prognosis
• May retain some RAI uptake

6D. ANAPLASTIC (UNDIFFERENTIATED) THYROID CARCINOMA (ATC)

• TP53 loss-of-function (most important unique driver - enables dedifferentiation)
• TERT promoter mutations - central role in aggressive behavior
• Also carries mutations from precursor well-differentiated carcinomas: RAS, BRAF, PIK3CA
• Can arise de novo or by dedifferentiation from existing papillary/follicular carcinoma (more common)

• Bulky masses growing rapidly beyond the thyroid capsule into adjacent neck structures
• Highly anaplastic cells: large pleomorphic, or spindle-shaped, or mixed
• Foci of papillary/follicular differentiation may be present (pointing to origin from prior cancer)
• Necrosis common

• Rapid neck mass growth - days to weeks
• Local compression/invasion: hoarseness, dysphagia, stridor
• Distant metastases common at presentation
• Death usually within 1 year (often <6 months) from local disease
• Does not respond to RAI or TSH suppression

• Surgery + external beam radiation + chemotherapy (multimodality)
• Dabrafenib + trametinib (BRAF + MEK inhibition) for BRAF V600E-mutated ATC - most impactful modern therapy
• Pembrolizumab and other immunotherapies under investigation

6E. MEDULLARY THYROID CARCINOMA (MTC)

• Located mainly in the lateral portions of the superior thyroid poles
• Secrete calcitonin, CEA, serotonin, somatostatin, VIP, histaminidases, prostaglandins
• Calcitonin lowers serum calcium (opposes PTH) - but hypocalcemia is NOT prominent in MTC

• Solid, firm, gray, nonencapsulated but well-circumscribed
• Polygonal to spindle-shaped cells in nests, trabeculae, glandlike structures
• Amyloid deposits in stroma (derived from altered calcitonin molecules) - pathognomonic feature; confirmed by Congo red staining
• Electron microscopy: membrane-bound dense secretory granules
• Sporadic: solitary; familial: bilateral, multicentric

• Neck mass ± palpable cervical lymphadenopathy
• Local invasion: dysphagia, dyspnea, dysphonia
• Diarrhea/flushing from VIP/serotonin secretion (paraneoplastic)
• Cushing syndrome from ACTH production (rare)
• Distant metastases in 50% at diagnosis (mediastinum, liver, lung, bone)

1. Serum calcitonin + CEA
2. RET mutation testing (germline in all patients)
3. Screen for pheochromocytoma: 24-hr urine catecholamines + metanephrines + abdominal MRI (must be done BEFORE thyroidectomy - undiagnosed pheo causes intraoperative hypertensive crisis and death)
4. Screen for hyperparathyroidism (serum calcium)
5. Family screening if germline RET mutation found

• Total thyroidectomy (high multicentricity and aggressive course)
• Bilateral central neck dissection (levels VI-VII) for all patients
• Lateral neck dissection based on calcitonin levels (ipsilateral if >20 pg/mL; bilateral if >200 pg/mL)
• Children with MEN-2A: prophylactic total thyroidectomy before age 5
• Children with MEN-2B: prophylactic thyroidectomy before age 1
• Targeted therapy for advanced disease: vandetanib (RET/VEGFR/EGFR inhibitor) or cabozantinib (RET/MET/VEGFR inhibitor) - both FDA approved
• Newer selective RET inhibitors: selpercatinib (LOXO-292), pralsetinib - superior selectivity with fewer off-target effects

SECTION 7: EVALUATION OF THYROID NODULES

Epidemiology of Thyroid Nodules

• Palpable nodules: ~5% of women, ~1% of men (iodine-replete areas)
• Ultrasound-detectable nodules: 19-68% of the general population ("incidentalomas")
• Most nodules are benign and require no extensive workup or surgery
• Primary indications for surgery: (1) concern for malignancy, (2) hyperfunction, (3) compressive symptoms

Red Flags for Malignancy (History/Physical)

• Age <20 or >70 years
• Male sex
• Hoarseness, dysphagia (local invasion)
• Firm, fixed (immobile) nodule
• Nodule size >3-4 cm
• Cervical lymphadenopathy
• History of head/neck irradiation
• First-degree family history of thyroid cancer or MEN syndrome

Diagnostic Algorithm

Ultrasound Risk Stratification

Features Suggesting Malignancy (in decreasing specificity)

1. Microcalcifications (psammoma bodies - PTC)
2. Hypoechogenicity / marked hypoechogenicity
3. Irregular, infiltrative margins
4. Taller-than-wide shape (on transverse view)
5. Extrathyroidal extension
6. Intranodular vascularity (more correlated with FTC)

Features Suggesting Benign Nodule

• Purely cystic (nearly 0% malignancy risk)
• Spongiform pattern (>50% microcystic = dramatic risk reduction)
• Isoechoic/hyperechoic with smooth margins and thin peripheral halo
• Comet-tail artifact (colloid crystals)
• Hot on radionuclide scan

ATA Risk Categories and FNA Thresholds

The Bethesda System for Reporting Thyroid FNA Cytopathology

Molecular Testing (Bethesda III/IV)

SECTION 8: STAGING (AJCC 8th Edition)

Age <55 years

Age ≥55 years

SECTION 9: RESPONSE-TO-THERAPY CLASSIFICATION (ATA)

SECTION 10: COMPARATIVE SUMMARY TABLE

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