Differentiated thyroid carcinoma (ORPHA:146)
A rare, slow-growing, epithelial thyroid carcinoma typically presenting as an asymptomatic thyroid mass and is classed as either papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) or Hurthle cell thyroid cancer (HCTC).
Epidemiology
The annual incidence of differentiated thyroid cancer (DTC) is about 1/10,000, and the incidence appears to be increasing. The female to male ratio is about 3:1.
Clinical description
PTC, FTC, and HCTC have similar presentations, and constitute about 75, 20, and 5 percent of cases, respectively. About 10 percent of PTC are classified as tall cell variant, the most aggressive form of PTC. HCTC is generally considered slightly more aggressive than PTC and FTC. The age at diagnosis is usually over 30 years. Presentation is typically with an asymptomatic thyroid nodule. Rare but worrisome presentations include hoarseness due to vocal cord paralysis and obstruction of the airway or esophagus, and may suggest an aggressive variant of DTC or anaplastic thyroid carcinoma. DTC grows slowly, and distant metastases are rare at the time of presentation. The most common metastatic site is the cervical lymph nodes. Distant metastasis to lungs or bones is rare (about 5%). Pediatric cases are rare. They are more frequently present with lymph node involvement. Despite this apparently more aggressive presentation, the prognosis is excellent. Pathologically, PTC are usually composed of a mixture of papillae and follicles, frequently with relatively large nuclei containing folds and a clear center. About 50% contain calcium deposits. Different histological PTC subtypes have been described. FTC are characterized by microfollicles and presence of capsular and vascular invasion. HCTC, pathologically similar to FTC, are distinguished by mitochondria-rich, eosinophilic cytoplasm. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a recently described variant; it is currently unclear if it is a pre-malignant lesion or a DTC variant.
Etiology
DTC arise from the epithelial cells of the thyroid gland. Most DTCs are sporadic and without known cause. Ionizing radiation predisposes to PTC. Iodine deficiency is associated with an increased risk of FTC. The sporadic molecular pathogenesis of these three malignancies is partially understood. In PTC, the V600E BRAF mutation (7q34) as well as fusion genes involving RET (10q11.2) and NTRK1 (1q23.1) are common. Activating RAS mutations occur in both PTC and FTC as well as in benign thyroid lesions. The PAX8/PPARG fusion gene (2q13) is more frequently observed in FTC. About 5% of PTCs have a familial predisposition although the associated germline alterations are unknown. HCTC has a unique and complex genetic profile that includes somatic mutations (including DAXX, TERT, TP53, NRAS, NF1, CDKN1A, ARHGAP35 and complex I mtDNA) and widespread chromosomal loss.
Diagnostic methods
DTC usually presents on physical examination or ultrasound as an asymptomatic nodule within the thyroid gland. Serum concentrations of thyroid hormone are usually normal. Thyroid fine needle aspiration biopsy cytology is frequently used to distinguish between the benign and malignant nodules. Additional diagnostic techniques include ultrasound characteristics and genetic analyses of the fine needle biopsy material. Diagnosis is confirmed on pathology review following surgical resection.
Differential diagnosis
Differential diagnosis of thyroid nodules includes benign thyroid nodules (nodular goiter, thyroid cyst, follicular adenoma), other thyroid malignancies, as well as Hashimoto's thyroiditis and thyroid lymphoma.
Management and treatment
The treatment of DTC is prioritized. First, complete surgical resection is essential for cure. Second, thyroid hormone administration to suppress TSH to appropriate concentrations helps prevent recurrence. Third, since most DTCs maintain the ability to take up iodine, 131-iodine therapy is useful in eradicating residual microscopic disease. For those few patients refractory to conventional therapy, external radiation and multikinase inhibitors are effective. Long-term follow-up is essential due to the cumulative risk of recurrence (about 20% at 20 years).
Prognosis
Prognosis is generally good in most patients, but about 5% of cases are fatal. Good prognosis is associated with age below 55 years and tumors below 4 cm. Poor prognosis is associated with distant metastatic disease, progression to anaplastic thyroid cancer (occasional), and tumors with a TERT promoter mutation plus either an activating V600E BRAF mutation or activating RAS mutation.

                            Last update: 
                            June 2020


                            - Expert reviewer(s): 
                            Dr Carl MALCHOFF