Diagnostic challenges in calcitonin negative medullary thyroid carcinoma: a systematic review of 101 cases

Calcitonin-negative medullary thyroid carcinoma (CNMTC), a rare form of MTC characterized by classic histopathology with normal serum calcitonin levels, presents a diagnostic challenge. This systematic review aims to summarize the clinical and pathological features of CNMTC and evaluate the utility of alternative biochemical markers.

Eligibility criteria for this systematic review included patients with a confirmed histopathological diagnosis of medullary thyroid carcinoma (MTC), normal preoperative serum calcitonin levels, or negative immunohistochemical (IHC) stain for calcitonin. A comprehensive electronic search strategy was employed on PubMed, Scopus, and Embase databases from January 1^st, 1950, to March 9^th, 2023.

This systematic review consists of 32 studies with 101 patients (66% females, 33% males) with a mean age of 52.2 years. All patients had a preoperative serum calcitonin level below the upper reference limit. Out of 101 patients, only seven underwent the Pentagastrin Stimulation Test (PST), only two patients had elevated calcitonin levels after stimulation. A total of 59 patients were tested for carcinoembryonic antigen (CEA) levels, and the majority tested normal (n=51, 86.4%). A total of 57 patients (61.2%) were found to have positive IHC staining on operative specimens for calcitonin. No recurrence was reported in the majority of cases, only 10 patients (9.9%) experienced recurrence.

Despite the rarity of CNMTC, it is crucial to maintain a high level of suspicion when evaluating thyroid nodules. Total thyroidectomy with central neck dissection remains as the primary treatment. A multimarker approach may improve the sensitivity and specificity of CNMTC diagnosis and surveillance, particularly when calcitonin and CEA levels are inconclusive.