Discussion
Medullary thyroid cancers (MTC) originate from the parafollicular cells, also called the C- cells of the thyroid gland. MTC consists of approximately 1 to 2% of thyroid cancers in the United States, with the incidence of sporadic medullary thyroid cancer peaking in the fifth or sixth decade of life [6]. About 80 % of these cancers are sporadic, with the remaining 20% hereditary. Hereditary MTC can be isolated or part of the multiple endocrine neoplasms (MEN) syndromes [7]. MTC associated with MEN syndromes peaks around the second or third decade of life. C- cells of the thyroid gland secrete calcitonin; therefore, elevated serum calcitonin is a good indicator for MTC with high sensitivity and specificity [8]. Other markers which can aid in diagnosis include CEA and chromogranin A. There are rare cases of serum calcitonin-negative MTC. MTC often involves the upper portions of both thyroid lobes because the C- cells are predominantly found in the upper lobe of the thyroid gland [9].
Patients with MTC predominantly present with a thyroid nodule in the upper portion of the thyroid gland; about 70% will have cervical lymphadenopathy, and patients with T4 tumors and node-positive disease after surgery predict a higher chance of recurrence [10]. About 5 to 10% of patients will have metastatic disease at the time of presentation, commonly involving the liver, lung, bone, skin, and brain [11]. Rarely did patients present with diarrhea and flushing from very high calcitonin levels, and our patient presented only with isolated diarrhea.
Fine needle aspiration of the thyroid nodule is an accurate method for diagnosis, but sometimes the diagnosis can be challenging due to the morphological heterogeneity of this tumor [12], especially when the tissue sample is obtained outside the thyroid gland, like in our case. Although calcitonin levels have high sensitivity, routine calcitonin screening is controversial due to the risk of false positivity but can add value in patients with multinodular goiter [13]. Other markers, such as carcinoembryonic antigen (CEA) and chromogranin, should be cautiously evaluated as they may be elevated in other malignancies. Postoperative calcitonin and CEA doubling time provide a sensitive marker for disease progression.
Neck ultrasound or neck Computed Tomography (CT) is helpful in staging the disease. Gallium 68 Dotatate PET/CT can identify smaller lesions and helpful in patients with high calcitonin levels [14], like our patient, as we identified new bone lesions in the PET/CT. The pathological analysis is the gold standard for diagnosis and immunohistochemical expression of calcitonin, chromogranin, synaptophysin, CEA, and TTF1 [15]. The positivity in chromogranin and synaptophysin can lead to an alternative diagnosis, especially in diseases outside the thyroid, as seen in our patient. Approximately 50 to 60 % of MTCs harbor a somatic RET mutation, particularly the M918T mutation, and it’s associated with an aggressive clinical course [15]. In patients with germline RET mutation, it is recommended to screen for hyperparathyroidism and pheochromocytoma.
For locally advanced and metastatic MTC, chemotherapy and radiation have been largely ineffective. There is no role for radioactive iodine treatment or thyroid-stimulating hormone suppression. Tyrosine kinase inhibitors like vandetanib have some promising outcomes in progression-free survival compared to placebo [16]. Other multikinase TKIs which has shown responses include cabozantinib and lenvatinib [17, 18]. Selpercatinib is an ATP-competitive, highly selective, small-molecule RET kinase inhibitor studied in RET-mutated MTC. A phase 2 trial studied selpercatinib in patients previously treated with cabozantinib or vandetanib [19]. The results showed an objective response rate of 69%, with 9% having a complete response and 60% of patients with a partial response, which led to the FDA approval for this drug. Pralsetinib was studied in a phase 1/2 Arrow trial and eventually was FDA-approved in patients with RET mutant MTC patients. Efficacy for advanced or metastatic RET-mutant MTC was evaluated in 55 patients who received prior cabozantinib or vandetanib. The ORR was 60% in all patients and 66 % in patients with RET-mutant MTC who did not receive prior cabozantinib or vandetanib (29 patients). Phase 3 trials are ongoing for selpercatinib and pralsetinib in advanced medullary thyroid cancer patients.