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Thyroid Malignancies and Management

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INTRODUCTION

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CLASSIFICATION

A. Tumors of Follicular Cell Origin (Well-Differentiated)

1. Papillary Thyroid Carcinoma (PTC) - ~80%
2. Follicular Thyroid Carcinoma (FTC) - ~10%
3. Hurthle Cell Carcinoma (Oxyphilic type) - ~3%

B. Poorly Differentiated / Undifferentiated

1. Insular Carcinoma
2. Anaplastic (Undifferentiated) Carcinoma - ~2%

C. Tumors of Parafollicular C-Cell Origin

1. Medullary Thyroid Carcinoma (MTC) - ~3%

D. Non-Epithelial Tumors

1. Primary Thyroid Lymphoma (<1%)
2. Squamous Cell Carcinoma (<1%)
3. Metastatic Tumors (from kidney, lung, breast, melanoma)

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1. PAPILLARY THYROID CARCINOMA (PTC)

Epidemiology

• Most common thyroid malignancy (~80% of all cases)
• Occurs in all age groups; peak: women aged 40-50 years, men a decade later
• Female:Male = 3:1
• Incidence increased after Chernobyl (1986) and Fukushima (2011) nuclear disasters

Etiology / Risk Factors

• Ionizing radiation exposure - most well-established risk factor; malignancy appears 1-2 decades after exposure; doses of 20-29 Gy increase risk
• Associated syndromes: Familial adenomatous polyposis, Cowden syndrome, Gardner syndrome
• Majority arise spontaneously

Pathology

• Gross: Invasive with irregular outline; scirrhous or granular, gritty texture; multiloculated cystic change; psammoma calcifications impart a gritty texture (Figure 58.25, Scott-Brown's)
• Microscopic hallmark features:
  • "Orphan Annie eye" nuclei - large, pale nuclei with prominent nucleoli; ground glass appearance with margination of chromatin
  • Nuclear grooves ("coffee beans") - longitudinal grooves formed by redundant folded nuclear membrane
  • Intranuclear cytoplasmic pseudo-inclusions - eosinophilic inclusions formed by nuclear envelope enfolding
  • Psammoma bodies - concentric calcified lamellae
  • Papillae formation with fibrovascular cores
• Molecular alterations: MAPK pathway involved in 70% of cases
  • BRAF mutation - most common (~50%), associated with negative prognosis: higher extrathyroidal invasion, nodal/distant metastasis, higher recurrence
  • RET/PTC rearrangements, NTRK1, RAS mutations

Variants

• Classical/conventional PTC
• Follicular variant (FVPTC) - most common variant; encapsulated variant (EFVPTC/Lindsay tumor) now reclassified as NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) - no longer considered malignant
• Unfavorable/aggressive variants: Diffuse sclerosing, Tall-cell, Columnar cell variant

Spread

• Strongly lymphotropic - spreads via intrathyroidal lymphatics and to regional cervical lymph nodes
• At presentation: ~30% have clinically evident cervical nodal disease; ~3% distant metastasis
• Nodal metastases may undergo cystic formation and may be black in color
• Multifocality within the thyroid gland is characteristic
• Pediatric PTC: nodal metastasis in >60%; distant metastasis up to 20%

Diagnosis

• FNA (FNAC/FNA biopsy) - investigation of choice for thyroid nodules
• USG features of malignancy: size >4 cm, microcalcifications, irregular/infiltrative margins, hypoechogenicity, subcapsular localization, increased intranodular vascularity, enlarged regional lymph nodes
• Serum TSH (most important functional test)
• CT/MRI: for rapidly expanding tumors, mediastinal extension, bulky adenopathy - avoid iodinated contrast as it delays RAI therapy
• PET-CT: for treated PTC with elevated thyroglobulin and negative RAI scan (sensitivity 95%, specificity 81%)

Prognosis

• Excellent: 10-year survival >90%
• Age >40 years associated with increased recurrence and mortality
• Risk stratification: AGES mnemonic (Hay scheme): Age, Gender, Extent, Size
• AMES mnemonic (Cady scheme for PTC and FTC): Age, Metastasis, Extent, Size

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2. FOLLICULAR THYROID CARCINOMA (FTC)

Epidemiology

• Second most common (~10% of thyroid malignancies)
• More common in females; older age group (median: 6th decade) than PTC
• More common in iodine-deficient areas

Pathology

• Well-differentiated malignancy with follicular differentiation but lacks PTC nuclear features
• Diagnosis requires histology - capsular or vascular invasion confirms malignancy (cannot be diagnosed on FNAC alone)
• Categories: Minimally invasive vs. Widely invasive follicular carcinoma

Molecular Pathogenesis

• RAS mutations, PAX8-PPARγ gene rearrangements

Spread

• Hematogenous spread (unlike PTC) - distant metastasis (~16%) more common
• Nodal metastasis less common than PTC
• Typically unifocal; contralateral disease incidence approaches zero
• Distant mets to: lung, bone, liver

Prognosis

• Worse than PTC due to older age at presentation and higher distant metastasis rate
• Degree of invasiveness is the key prognostic factor

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3. HURTHLE CELL CARCINOMA

• Subtype of follicular carcinoma (oxyphilic type); ~3% of thyroid malignancies
• Derived from oxyphilic cells packed with mitochondria
• Diagnosis: Histologic capsular or vascular invasion (FNAC shows hypercellularity and eosinophilic cells)
• More aggressive: multifocal, bilateral, higher incidence of lymph node and distant metastasis - highest incidence of distant metastasis among well-differentiated thyroid carcinomas (WDTCs)
• Poor radioiodine uptake (~10% take up RAI) - less amenable to RAI therapy
• Overall survival significantly worse than FTC
• Management: Total/completion thyroidectomy; TSH suppression; thyroglobulin monitoring; periodic USG; 99mTc scan for persistent/metastatic disease

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4. MEDULLARY THYROID CARCINOMA (MTC)

Origin

• Arises from parafollicular C cells (neuroectodermal origin, concentrated in lateral superior poles)
• ~3% of all thyroid carcinomas

Clinical Features

• 70% sporadic - unifocal, patients 50-60 years, equal sex distribution
• 30% familial/hereditary - autosomal dominant, nearly 100% penetrance; multicentric and bilateral in 90%; preceded by multifocal C-cell hyperplasia
• Presents with neck mass ± cervical lymphadenopathy (≤20%)
• Local pain, dysphagia, dyspnea, dysphonia - indicate local invasion
• Distant metastases in 50% at diagnosis: mediastinum, liver, lung, bone

Hereditary Forms

Gene

• RET proto-oncogene mutation - all patients with MTC should be tested; genetic screening has replaced provocative pentagastrin-stimulation testing

Secretory Products

• Calcitonin (most important - used for diagnosis and surveillance)
• CEA, histaminidases, prostaglandins, serotonin

Pathology

• Gross: Solid, firm, gray cut surface; nonencapsulated but well-circumscribed
• Microscopy: Sheets of infiltrating neoplastic cells separated by collagen, amyloid (polymerized calcitonin - virtually pathognomonic), and dense irregular calcification

Pre-operative Workup

• Serum calcitonin + CEA
• RET proto-oncogene mutation testing
• Screen for pheochromocytoma before surgery (24-hour urinary catecholamines and metanephrines + abdominal MRI) - undiagnosed pheo can cause fatal intraoperative hypertensive crisis
• Serum calcium (for hyperparathyroidism)
• Family screening for all hereditary forms

Management

• Surgery is the only effective treatment
• Total thyroidectomy + central neck dissection for all MTC
• Palpable MTC: ipsilateral level II-V neck dissection; consider bilateral
• Postoperative surveillance: calcitonin, CEA levels

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5. ANAPLASTIC (UNDIFFERENTIATED) THYROID CARCINOMA

• Most aggressive thyroid malignancy; ~2% of thyroid cancers
• Typically patients >60 years; equal sex distribution
• May arise from dedifferentiation of pre-existing well-differentiated carcinoma
• Rapid growth with early invasion of trachea, esophagus, great vessels
• Presents with rapidly enlarging painful neck mass, dysphagia, dysphonia, dyspnea, stridor
• Distant metastases in >50% at presentation (lung most common)
• All anaplastic carcinomas are Stage IV (AJCC classification)
• Median survival: 6 months; <20% 1-year survival

Pathology

• Large pleomorphic cells, spindle cells, giant cells - highly mitotic
• Three microscopic patterns: spindle cell, giant cell, squamoid

Management

• No effective curative therapy
• Multimodal approach: surgery (debulking if feasible to relieve airway) + external beam radiotherapy + chemotherapy (doxorubicin-based or paclitaxel/docetaxel)
• Tracheostomy may be required for airway protection
• Lenvatinib + pembrolizumab or dabrafenib + trametinib (for BRAF V600E mutated cases) - targeted therapy options
• Goal is primarily palliative

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6. PRIMARY THYROID LYMPHOMA

• <1% of thyroid malignancies; Women:Men = 3:1; typically >50 years
• Strong association with Hashimoto's thyroiditis (chronic antigenic stimulation → lymphocyte transformation)
• Usually Non-Hodgkin B-cell type (most common: MALT lymphoma, DLBCL)
• Presents as rapidly enlarging, painless neck mass mimicking anaplastic carcinoma
• Symptoms: regional adenopathy, dysphagia, vocal cord paralysis
• Diagnosis: FNAC; core needle or open biopsy if needed; exclude generalized lymphoma
• Treatment: Chemotherapy (CHOP regimen) ± radiation; not primarily surgical
• Prognosis: 5-year survival ~50%; intrathyroid disease 85%; extrathyroid disease 40%

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SURGICAL MANAGEMENT OF THYROID MALIGNANCY

Extent of Surgery

Neck Dissection

• Level VI (central neck) dissection: for known lymphatic involvement, advanced-stage PTC
• Lateral neck dissection (levels II-IV ± V): for biopsy-proven lateral nodal disease; compartmental dissection - NOT "berry picking"
• MTC: ipsilateral levels II-V ± bilateral dissection for palpable MTC

Important Intraoperative Considerations

• Pre-op assessment of vocal cord mobility by indirect laryngoscopy/fiberoptic laryngoscopy (mandatory)
• RLN identification: inferolateral approach; nerve monitoring recommended
• External branch of SLN: protected by dissecting close to thyroid capsule; Joll's triangle - bounded by trachea, superior thyroid vessels, and pharyngeal constrictors
• Parathyroid glands: identify and preserve; reimplant if inadvertently removed
• RLN invasion: sacrifice only if preoperative vocal cord paralysis + intraoperative invasion; attempt primary repair, nerve graft, or ansa cervicalis transfer immediately
• Trachea/larynx: partial-thickness or full-thickness resection if fixed; primary anastomosis feasible for up to 4-5 ring resection

Substernal Goiter / Extended Disease

• Median sternotomy for: previous thyroid operations, no cervical thyroid tissue, invasive malignant tumors too large for cervical delivery

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POST-OPERATIVE MANAGEMENT

Radioactive Iodine (RAI / I-131) Therapy

• Indicated for: high-risk PTC, FTC, residual disease, distant metastases
• Requires total thyroidectomy first; avoid iodinated contrast CT pre-operatively
• Ablates residual thyroid tissue; improves surveillance sensitivity
• Hurthle cell and MTC rarely take up RAI

TSH Suppression Therapy

• Levothyroxine to suppress TSH (low/undetectable levels suppress TSH-dependent tumor growth)
• Goal TSH <0.1 mIU/L for high-risk patients; 0.1-0.5 mIU/L for low-risk

Surveillance

• Serum thyroglobulin (Tg) - tumor marker for PTC and FTC; should be undetectable after total thyroidectomy + RAI
• Serum calcitonin + CEA - for MTC
• Periodic neck USG - central and lateral compartments
• PET-CT: for elevated Tg with negative RAI scan ("flip-flop" phenomenon)

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PROGNOSTIC SCORING SYSTEMS

• AJCC staging uses age 55 as cutoff (updated from 45 in 8th edition): PTC/FTC in patients <55 years cannot be Stage III or IV

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SUMMARY TABLE: Key Differentiating Features

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COMPLICATIONS OF THYROID SURGERY

1. Hemorrhage - most urgent (hematoma causing airway compromise)
2. RLN injury (temporary/permanent) - hoarseness, voice changes
3. SLN (external branch) injury - loss of cricothyroid function; change in high-pitched voice
4. Hypoparathyroidism - hypocalcemia (most common complication of total thyroidectomy); temporary vs. permanent
5. Tracheomalacia - post-thyroidectomy airway collapse
6. Wound infection / seroma / chyle leak

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• K.J. Lee's Essential Otolaryngology, 11th Edition, Chapter 38
• Cummings Otolaryngology Head and Neck Surgery, 7th Edition, Chapters 122 & 28
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol 1 & 2
• Bailey and Love's Short Practice of Surgery, 28th Edition