METASTATIC MEDULLARY THYROID CARCINOMA: DIAGNOSTIC DILEMMAS AND CHALLENGES IN MANAGEMENT

Abstract

Medullary thyroid carcinoma (MTC) is a neuroendocrine thyroid malignancy that develops sporadically or as part of syndromes and poses major diagnostic and therapeutic challenges. Early identification of syndromic associations and calcitonin-guided staging are critical for assessing disease extent and guiding management. We describe two patients with metastatic hereditary MTC. A 27 year old man with chronic diarrhea, marfanoid habitus, mucosal neuromas, medullated corneal nerve fibers and a germline RET p.Met918Thr mutation. MTC was locally advanced, with nodal disease, IVC thrombus and encasement of the carotid artery; it was deemed inoperable and treated with Cabozantinib. He had a stable adrenal lesion, was normotensive with normal urinary catecholamines, and family screening was negative. His course was complicated by appendiceal perforation with peritonitis requiring laparotomy and appendicectomy, followed by emergency debulking of the thyroid malignancy for airway compromise. He is planned to be initiated on Selpercatinib, a RET-specific Tyrosine kinase inhibitor(TKI). The second patient, a 50 year old man, was incidentally diagnosed with MTC following hemithyroidectomy done for multinodular goiter. He underwent completion thyroidectomy with excellent response for 9 years post-operatively, when he developed liver metastases. The germline RET exon 11 p.Cys634Tyr mutation was detected, without other neuroendocrine tumors. Due to intolerance to Cabozantinib and disease progression, he underwent hepatic metastasectomy, currently planned for Selpercatinib. Cascade testing identified affected relatives who underwent total thyroidectomy. Both patients had metastatic medullary thyroid carcinoma with distinct disease trajectories. RET p.Met918Thr mutation, likely de-novo, had a more aggressive course. RET exon 11 p.Cys634Tyr mutation experienced a prolonged disease-free interval of nine years following surgery before developing hepatic metastases. The diagnosis of MTC can be challenging when it presents with atypical symptoms. Early recognition of syndromic association and dynamic risk stratification guide therapeutic decisions. A multidisciplinary team approach integrating surgery, TKI therapy, and management of organ-specific metastases improves outcomes. Genetic testing and family screening enable timely intervention in at-risk family members.