Thyroid cancer is the most common form of endocrine malignancy and accounts for >3% of all annually diagnosed cancers worldwide.1 Medullary thyroid cancer (MTC) accounts for <5% of all thyroid cancers.2 MTC is 1 of the 5 main histological types of thyroid cancer and is the only type that develops from thyroid C-cells.1,2
Approximately 13% of patients with MTC who present with a palpable thyroid nodule have distant metastases and approximately 35% have cervical metastases.3 The main factors determining prognosis include age, tumor size, local and distant metastases, somatic RET M918T mutations, calcitonin, and carcinoembryonic antigen doubling times. MTC presents as either inherited (20%-25%) or sporadic (75%-80%) tumors, with hereditary MTC appearing as part of the multiple endocrine neoplasia 2 syndrome.3 Hereditary cancer is caused by germline mutations of the RET proto-oncogene while somatic RET mutations are commonly present in sporadic disease.
MTC presents clinically as a palpable thyroid nodule that may be solitary or appear in the context of a multinodular goiter.3 Sporadic MTC usually presents as a unilateral tumor,1,3 and hereditary MTC is typically associated with C-cell hyperplasia and multicentric and bilateral tumors.3 Some patients with MTC may present with systemic manifestations, including diarrhea, flushing, or painful bone metastases. Subsequent diagnosis is obtained through the typical diagnostic workup of thyroid nodules.3
The only curative treatment option for MTC is surgery, with the procedure of choice being total thyroidectomy with central lymph node dissection.3 More extensive surgery with lateral neck dissection may be considered depending on serum calcitonin levels and preoperative cervical ultrasound imaging. The appropriate treatment after surgery is determined by the presence and volume of residual disease as assessed through calcitonin measurement.3 There is currently no effective, curative therapeutic option for patients with locally advanced disease that is not amenable to surgery.3 Limited response rates have been documented regarding chemotherapy and external beam radiation.
Uninhibited tyrosine kinase receptor activation is a primary mechanism of cancer development, and the function of RET tyrosine kinase receptor in MTC pathogenesis is well documented.3 Vascular endothelial growth factor (VEGF) and hepatocyte growth factor, and their respective tyrosine kinase receptors play critical roles in pathogenesis, disease progression, and disease recurrence, and are overexpressed in MTC. In advanced RET-mutation–positive MTC, RET represents a significant therapeutic target.2 Vandetanib (Caprelsa) and cabozantinib (Cabometyx) are multikinase inhibitors approved for the treatment of advanced MTC.3 However, these drugs are relatively weak RET kinase inhibitors, and their clinical efficacy has been attributed more to their antiangiogenesis effects via VEGF receptor pathway inhibition.2 Emerging therapies, such as the small-molecule inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto), are potent RET-specific kinase inhibitors that have demonstrated positive outcomes in clinical trials among patients with advanced cancer driven by RET alterations. Selpercatinib was granted accelerated approval by the FDA for patients with advanced MTC.4
In summary, MTC is a relatively rare cancer with a good prognosis if detected early. While there are no curative therapeutic options for patients with advanced disease, our developing understanding of the RET pathway and the development of therapies targeting this pathway may improve outcomes for these patients.
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