PAPILLARY THYROID CARCINOMA (PTC)

Definition and Prevalence

• Papillary Thyroid Carcinoma (PTC): One of three thyroid epithelial–derived carcinomas (the others are follicular and anaplastic).
• Most common malignant thyroid tumor: ~75% of thyroid cancer cases.
• Peak Incidence: 4th and 5th decades of life (i.e., ages 30s to 50s).
• Gender Predominance: ~2.5:1 ratio in women vs. men.

Clinical Presentation

1. Thyroid Nodule
   • Often presents as a solitary thyroid nodule.
   • Increasingly detected incidentally on imaging (CT, ultrasound) done for other reasons.
2. Multifocality
   • PTC frequently has multiple foci within the thyroid.
   • When presenting via cervical lymph node biopsy showing “papillary lesion,” at least half of the intrathyroidal foci may be genetically distinct (independent clones).

Histopathology

1. Gross and Microscopic Features
   • Typically unencapsulated.
   • Characterized by papillary cords with delicate vascularized stroma lined by cuboidal/columnar cells.
   • Pure PTC usually lacks colloid/follicles.
   • Nuclear Features:
     • Large, oval nuclei with hypodense (Orphan Annie–eye) chromatin.
     • Cytoplasmic “pseudoinclusions” (redundant nuclear membrane).
   • Psammoma Bodies: Found in ~50% of PTC (calcified, scarred remains of tumor papillae).

1. Variants
   • Follicular Variant (~10%): Follicles plus classic PTC nuclear changes; overall prognosis similar to classic PTC.
   • Tall-Cell Variant (~1%): More aggressive; larger, more invasive.
   • Other Rare Variants (e.g., clear-cell, insular, columnar, trabecular, oxyphilic, diffuse sclerosing) → often more aggressive behavior.

Metastatic Patterns

• Regional Lymph Nodes (cervical, upper mediastinal) frequently involved.
• Distant Metastases are uncommon at initial diagnosis (~2%):
  • Lung is the most frequent distant site (often showing miliary pattern on imaging).
  • Bone less common (more likely in older patients).
  • Rare sites: Brain, liver, kidney, adrenal glands.

Prognosis and Risk Factors

1. Overall Behavior
   • One of the least aggressive human cancers; many patients do not die of PTC.
   • Still can be fatal in some cases, especially if high-risk features present.
2. High-Risk Features for Recurrence/Mortality
   • Age >45 years at diagnosis.
   • Tumor size >7 cm.
   • Soft-tissue invasion (e.g., trachea, esophagus).
   • Additional risk factors: Male gender, multicentric PTC, >10 lymph node metastases, age <7 years.

Treatment

1. Surgical Management
   • Total Thyroidectomy + Central Compartment Lymphadenectomy for PTC >1 cm or with known nodal metastases.
   • More extensive surgery if there is extrathyroidal invasion (trachea, esophagus).
   • Less Extensive Resection (lobectomy + isthmusectomy) may suffice for solitary PTC <1 cm.
2. Radioactive Iodine (131I)
   • Adjuvant therapy to ablate residual microscopic disease.
   • Not universally used; patient selection is individualized.
3. External-Beam Radiotherapy
   • Considered in unresectable disease not responsive to 131I.
4. Chemotherapy / Targeted Therapy
   • Systemic chemotherapy for aggressive, symptomatic, refractory disease.
   • Tyrosine Kinase Inhibitors and other molecular pathway–blocking drugs under investigation for refractory cases.
5. Thyroid Hormone Suppression
   • Levothyroxine therapy postoperatively to suppress TSH and reduce tumor stimulation.

FOLLICULAR THYROID CARCINOMA (FTC)

Definition and Incidence

• One of three thyroid epithelial–derived cancers (others: papillary carcinoma, anaplastic carcinoma).
• Second most common thyroid cancer after papillary thyroid carcinoma (PTC), accounting for ∼10% of all thyroid malignancies.

Demographics and Risk Factors

• Peak Incidence: 40–60 years of age.
• Female : Male ratio ~3:1.
• Geographic Iodine Deficiency: More common in iodine-deficient regions.

Clinical Presentation

1. Thyroid Nodule or Mass
   • May be small or large.
   • Typically solitary intrathyroidal focus (unlike PTC, which can be multifocal).
2. Fine-Needle Aspiration (FNA) Limitations
   • Cytology cannot distinguish FTC from a benign follicular adenoma.
   • Definitive diagnosis requires histologic evidence of tumor capsule or vascular invasion from en bloc surgical specimen.

Histopathology

1. Follicular Pattern
   • Organized follicles lined by high cuboidal epithelium, often containing colloid.
   • No papillary features (e.g., no psammoma bodies).
2. Capsular or Vascular Invasion
   • Hallmark for malignancy (distinguishes from benign adenoma).
3. Subtypes
   • Minimally Invasive FTC: Encapsulated, better prognosis.
   • Widely Invasive FTC: Invades blood vessels and adjacent thyroid tissue; worse prognosis.
4. Molecular Genetics
   • Often monoclonal; ~40% have RAS point mutations, associated with more aggressive behavior.

Metastasis and Spread

• Hematogenous Dissemination: Common; distant metastases in ~15% of patients at diagnosis.
• Most Frequent Sites: Bone, lung (less commonly liver, brain, urinary bladder, skin).
• Lymph Node Metastases: Much less common than in PTC.
• Skeletal Metastases: May histologically resemble normal thyroid tissue.

Prognosis

• Generally More Aggressive than papillary carcinoma.
• Poor prognosis factors:
  1. Larger Tumors
  2. Distant Metastasis
  3. Vascular Invasion
• Insular Carcinoma: A poorly differentiated FTC variant with a poor prognosis.
• Hürthle Cell Carcinoma: Oncocytic variant of FTC.

Treatment

1. Surgical Management
   • Total Thyroidectomy + Central Neck Lymph Node Dissection = standard of care.
   • Preoperative neck ultrasonography for lymph node mapping is essential.
2. Radioactive Iodine (131I)
   • FTC cells can take up 131I but less efficiently than normal follicular cells.
   • 131I used post-thyroidectomy to ablate remnant thyroid and microscopic metastatic disease.
3. Thyroid Hormone Suppression
   • Levothyroxine replacement post-surgery to suppress TSH, aiming to prevent TSH-driven tumor growth.
4. External-Beam Radiation Therapy
   • Used if residual primary or metastatic disease is unresectable.
5. Chemotherapy and Targeted Therapy
   • Systemic chemotherapy for disease refractory to other treatments.
   • Molecular pathway inhibitors (e.g., tyrosine kinase inhibitors) under investigation for refractory cases.

MEDULLARY THYROID CARCINOMA (MTC)

Definition and Incidence

• Neoplasm of Thyroid “C Cells”: Parafollicular cells derived from the embryonic neural crest.
• Accounts for ~3% of all thyroid malignancies.
• More accurately considered a neuroendocrine tumor rather than a conventional thyroid carcinoma.

Sporadic vs. Familial

1. Sporadic MTC
   • ~80% of cases.
   • Typically presents as a solitary thyroid nodule in patients aged 40–60 years; slight female preponderance.
   • At diagnosis, >50% have regional lymph node metastases.
2. Familial MTC
   • Associated with MEN 2A, MEN 2B, or Familial MTC (FMTC).
   • Inherited in an autosomal dominant fashion with RET proto-oncogene mutations.
   • Penetrance ~100% in MEN 2 syndromes.
   • MEN 2B form is more aggressive; prophylactic thyroidectomy is recommended in the first year of life.

Clinical Features and Metabolism

• Calcitonin Secretion: Elevated serum calcitonin can cause severe diarrhea.
• May secrete other hormones (e.g., ACTH → Cushing syndrome).
• Fine-Needle Aspiration (FNA) typically diagnostic in solitary thyroid nodule.

Histopathology

1. Solid Trabecular Pattern
   • Closely packed cells with variable nuclear size/hyperchromatism.
2. Immunostaining
   • Calcitonin, Galectin-3, Carcinoembryonic Antigen (CEA).

Genetic Testing

1. RET Proto-Oncogene
   • All patients with MTC should have genetic testing because ~7% of apparently sporadic cases harbor a RET mutation.
   • Identifies at-risk family members; allows early (prophylactic) thyroidectomy to prevent metastases.
2. Coexisting Endocrine Disorders
   • Rule out primary hyperparathyroidism and pheochromocytoma in MEN 2 patients.

Management

1. Surgical Treatment
   • Total Thyroidectomy is the treatment of choice.
   • Prognosis correlates with age at diagnosis; familial cases have better outcomes if operated on earlier.
2. Monitoring
   • Serum Calcitonin postoperatively to assess for surgical cure.
   • Persistent elevated calcitonin suggests residual or metastatic disease.
3. Advanced Disease
   • Metastases may involve neck nodes, mediastinum, lungs, liver, bone, kidneys.
   • Molecular pathway–blocking drugs (e.g., tyrosine kinase inhibitors) for unresectable or refractory disease.

HÜRTHLE CELL THYROID CARCINOMA (HCC)

Definition and Incidence

• Variant of Follicular Thyroid Carcinoma (FTC), also called the oncocytic variant of FTC.
• Accounts for 3%–4% of all thyroid malignancies.
• Distinctive Oncocytes (Hürthle or oxyphilic cells) constitute ≥75% of the tumor.

Demographics

• Age Range: Peak incidence at 40–70 years, median ~61 years.
• Gender: Approximately 2:1 female to male ratio.
• Typically presents as a painless solitary thyroid nodule, which may vary in size.

Pathology and Histology

1. Gross Appearance
   • Often mahogany-brown tumor(s) on gross examination.
2. Microscopic Features
   • Oncocytes: Eosinophilic, oxyphilic cells with abundant granular cytoplasm (packed with mitochondria).
   • Cells arranged in trabecular or plexiform patterns, separated by a dense capillary network.
   • Scant or No Colloid present.
   • Nuclei: Hyperchromatic, pleomorphic, prominent eosinophilic nucleoli.
   • Carcinoma Diagnosis depends on capsular invasion, vascular invasion, or metastasis.
3. Radioiodine Uptake
   • <10% of HCC lesions show significant radioiodine uptake.

Clinical Behavior and Metastasis

1. Comparative Aggression
   • More aggressive than standard follicular or papillary thyroid carcinoma.
2. Metastases
   • ~5% have distant metastases (lung or bone) at diagnosis.
   • ~25% have regional lymph node metastases.
3. Prognostic Factors
   • Distant Metastases at presentation → strong predictor of poor outcome.
   • Older Age, Larger Tumor Size, Male Gender, Extrathyroidal Invasion → worsen prognosis.
4. Recurrence Rate
   • ~35% overall recurrence post-surgery.

Treatment and Management

1. Surgical Approach
   • Total Thyroidectomy + Ipsilateral Central Neck Lymph Node Dissection (similar to FTC).
2. Adjuvant Therapy
   • Radioiodine typically not beneficial (low uptake).
   • External-Beam Radiotherapy may be considered for unresectable disease.
3. Systemic or Targeted Therapy
   • Molecular pathway–blocking drugs (e.g., tyrosine kinase inhibitors) may help in refractory cases.

ANAPLASTIC THYROID CARCINOMA (ATC)

Definition and Incidence

• Undifferentiated Thyroid Cancer: One of three epithelial-derived thyroid cancers (alongside papillary and follicular).
• Rare but Highly Malignant: ~2% of all thyroid malignancies.
• Demographics:
  • Typically occurs after age 50 (mean ~65 years).
  • ~Two-thirds of cases occur in women.

Clinical Presentation

1. Rapid Neck Mass Growth
   • Patients often recall a precise recent onset and describe rapid enlargement.
   • Usually painful/tender with local pressure symptoms (dyspnea, dysphagia, hoarseness, cough).
2. Systemic Symptoms
   • Weight loss, anorexia, fatigue, fever.
3. Physical Examination
   • Large tumor (often >5 cm), hard, frequently fixed to surrounding tissues.
   • Overlying skin may be warm or erythematous.
   • Cervical adenopathy often present.
   • Tracheal deviation, vocal cord paralysis (recurrent laryngeal nerve involvement).
   • Possible superior vena cava syndrome if tumor compresses thoracic inlet.

Pathogenesis and Precursor Lesions

• Association with Differentiated Thyroid Carcinoma:
  • ~20% have a history of PTC or FTC.
  • ~50% have a history of goiter.
• Likely “Dedifferentiation” from existing neoplasm (loss of tumor suppressor or new activating mutation).

Diagnosis

1. Biopsy
   • Fine-Needle Aspiration or surgical biopsy.
   • Histology: Solid, highly anaplastic growth with spindle cells and giant cells.
2. Imaging
   • CT of neck/chest aids in evaluating tumor extent, tracheal compression, planning therapy.

Metastasis and Local Invasion

• Local Invasion is rapid and lethal, infiltrating muscle, lymph nodes, trachea, esophagus, larynx, and major blood vessels.
• Cause of Death: Often tracheal compression/asphyxia.
• Distant Spread: Most commonly lungs, also bone, skin (chest wall), liver, heart, kidneys, adrenals.

Prognosis and Treatment

1. Surgery
   • Complete resection if tumor is apparently confined to the thyroid, but recurrence within months is common.
2. Adjuvant Therapy
   • External-beam radiotherapy may be considered after surgery.
   • Chemotherapy (e.g., paclitaxel) may provide brief partial responses.
3. Survival
   • Rarely exceeds 12 months from diagnosis.
   • Essentially 100% disease-specific mortality.