The Difficulty of Post-Operative Surveillance of Calcitonin Negative Medullary Thyroid Cancer

Background: As a differentiated thyroid tumor, medullary thyroid cancer (MTC) typically maintains the secretory function of the c-cells with resultant increase in serum calcitonin level along with frequent elevations in serum chromogranin A (CgA) and carcinoembryonic antigen (CEA). Clinical Presentation: A 71-year-old female with history of multinodular goiter underwent a thyroid nodule biopsy after routine ultrasound surveillance revealed enlargement of two right lower lobe nodules compared with prior imaging. Fine needle aspiration (FNA) of one 3.1 x 1.9 x 2.7 cm right thyroid nodule revealed cellular material composed of spindle-shaped neoplastic cells, some of them with marked cytologic atypia, suspicious for a neuroendocrine tumor, specifically medullary thyroid carcinoma. A PET/CT scan was performed after injection of Gallium-68 dotatate radiotracer and revealed intense focal radiotracer activity in the approximately 2.5 x 2.1 cm right thyroid mid lower pole heterogeneous hypodense mass with tiny calcification inferiorly, consistent with the patient’s known tumor. There was no evidence of cervical octreotate avid metastatic lymphadenopathy and a chest x-ray showed no evidence of active pulmonary disease. The patient subsequently underwent a right partial thyroidectomy with isthmusectomy. Histopathology revealed a 2.8 x 1.9 x 1.9 cm neoplasm composed of spindle and polygonal cells growing in solid nests with neuroendocrine-type nuclei. Immunostains showed the tumor to be positive for AE1-AE3 cytokeratins, chromogranin, synaptophysin and CEA. It was focally positive for TTF-1 and calcitonin. Thyroglobulin and PAX-8 were negative. Using the AJCC 8(th) edition staging system, the tumor was staged a pT2Nx with margins uninvolved by carcinoma and no extrathyroidal extension or lymphatic invasion. Angioinvasion was present. Additional serum studies included a normal calcitonin value of <2.0 pg/ml (reference range 0-5.1 pg/ml), CEA 2.6 ng/ml (reference range <6.0 ng/ml), and a mildly elevated chromagranin A at 133 ng/ml (reference range 0-95 ng/ml). Plasma metanephrines, normetanephrines, vasoactive peptide, and glucagon levels were all unremarkable. Our patient’s surgical recovery was normal and two months later she remained asymptomatic without evidence of recurrence or metastasis. Discussion: The diagnosis and post-operative surveillance of medullary thyroid cancer is challenging; even more complicated is the rare case of calcitonin-negative MTC. The cause of calcitonin-negative MTC remains unclear. Further studies are needed for the discovery and development of novel biomarkers for post-operative surveillance and evaluation of clinical relapse.