Thyroid Cancer

Summary

Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Driver mutations involving the receptor tyrosine kinase pathway (such as RET and BRAF) and a family history of cancer or related syndromes increase the risk. Exposure to ionizing radiation and iodine deficiency are also considered risk factors. The major types can present as thyroid nodules or enlarged cervical lymph nodes. The diagnostic approach includes thyroid-stimulating hormone, ultrasonography, and biopsy. Treatment options are surgical removal of the thyroid gland , with the addition of radioactive iodine therapy and systemic therapy, depending on the type and extent of the thyroid malignancy.

Risk factors

• Ionizing radiation; (particularly during childhood): mostly associated with papillary carcinoma
• Iodine deficiency: higher frequency of follicular carcinoma
• Genetic factors
  • Medullary carcinoma: associated with MEN2 (RET gene mutations) or familial medullary carcinoma
  • Papillary carcinoma: associated with RET/PTC rearrangements and BRAF mutations
  • Follicular carcinoma: associated with RAS mutation
  • Undifferentiated/anaplastic carcinoma: associated with TP53 mutation

Overview

Papillary carcinoma

• Approximately 80% of cases
• Most common in young women
• Peak age: 30–50 years
• Present as asymptomatic nodules or metastasis to cervical lymph nodes
• Advanced disease: hoarseness, cough, dyspnea
• Associated with familial adenomatous polyposis , Cowden syndrome
• Least aggressive; very good prognosis if detected early
• Histopathologic features
  • Psammoma bodies (round calcified structure within papillae

Follicular carcinoma

• 10% of cases
• Women > men
• Peak age: 40–60 years
• Seen in areas of iodine deficiency
• Painless, slow-growing thyroid nodule
• Cold nodules on scintigraphy
• Commonly spreads hematogenously to lungs or bones
• Typically, regional lymph nodes are not involved.
• Associated with Cowden syndrome
• Good prognosis if detected early

Anaplastic carcinoma

• Approximately 1-2% of cases
• Most common in women
• Average age: 65 years
• ¼ of patients have past history of or coexisting differentiated carcinoma.
• Rapid growth → local compression
• Most have spread beyond the thyroid on presentation
• Spreads via lymphatics and bloodstream
• Poor prognosis

Medullary carcinoma

• < 10%of cases
• MEN2: Cases occur in young patients.
• Sporadic and familial cases peak at age 40–60 years.
• Can present as a neck or lymph node mass
• Also can manifest with:
  • Diarrhea , flushing (calcitonin and from tumor-secreted vasoactive intestinal peptide (VIP), prostaglandin and serotonin)
  • Cushing’s syndrome due to adrenocorticotropic hormone (ACTH)
• Other biomarker: carcinoembryonic antigen (CEA)
• Associated with MEN2 syndrome
• Familial type: more aggressive

Diagnosis

• Physical Examination: Presence of nodule.
• Blood Tests: Thyroid function tests.
• Ultrasound: To characterize the nodule.
• Fine-Needle Aspiration Biopsy (FNAB): Definitive diagnosis.
• Genetic Testing: For medullary carcinoma.

• Initial Approach
  • Physical examination: palpable thyroid nodule, cervical lymphadenopathy
  • TSH levels ➜ First test for thyroid nodule
    • Low TSH → suggests hyperfunctioning nodule → thyroid scintigraphy
    • Normal/High TSH → proceed with ultrasound
• Thyroid Ultrasound
  • Features suggesting malignancy:
    • Hypoechoic nodule
    • Microcalcifications (especially in papillary carcinoma)
    • Irregular margins
    • Taller than wide shape
    • Increased vascularity
• Fine Needle Aspiration (FNA) ➜ Definitive diagnosis
  • Indications:
    • Nodules > 1 cm with suspicious ultrasound features
    • Any size nodule with high-risk features or lymphadenopathy
    • Cold nodules on scintigraphy
  • Cannot distinguish follicular adenoma from carcinoma (needs surgical excision)
• Thyroid Scintigraphy (Radioiodine Uptake)
  • Indicated when TSH is low
  • Hot nodule = increased uptake → usually benign → no FNA needed
  • Cold nodule = decreased uptake → concern for malignancy → needs FNA
• Tumor Markers
  • Calcitonin: for medullary carcinoma (elevated in >95% of cases)
  • Thyroglobulin: used for monitoring after treatment of differentiated thyroid cancer
  • CEA: may be elevated in medullary carcinoma
• Additional Tests
  • Genetic testing: for suspected medullary carcinoma (RET mutations)
  • CT/MRI: for assessing local invasion or metastases

Benign thyroid nodules

Thyroid adenomas

• Follicular adenoma (most common)
• Hürthle cell adenoma (A subtype of follicular adenoma that is treated similarly to it)
• Toxic adenoma
• Papillary adenoma (least common)

Follicular adenoma

• It is a benign encapsulated tumor of the thyroid gland that is surrounded by a thin fibrous capsule.
• Follicular adenoma is the most common type of thyroid adenoma.
• 10–15% of follicular neoplasms are malignant.

Clinical features

• Often presents as a slow-growing solitary nodule
• Patients are typically euthyroid.
• In rare cases, patients can manifest with clinical features of hyperthyroidism (∼ 1% of follicular adenomas develop into toxic adenomas).

Diagnostics

• Follicular adenoma is a histopathological diagnosis. Cytology alone cannot distinguish between adenoma and carcinoma.
• Thyroid function tests: TSH is typically normal.
• Thyroid ultrasound: may show sonographic signs of malignancy or appear benign
• FNAC
  • Cannot distinguish between follicular adenoma and carcinoma
• Confirmatory test
  • Surgical excision (e.g., hemithyroidectomy ) with histologic analysis (A complete histopathological examination of the tumor is needed to rule out capsular and vascular invasion before establishing a diagnosis of follicular adenoma. Frozen-section analysis cannot always distinguish between follicular adenoma and carcinoma in all cases and its significance in the management of follicular adenomas is controversial.)