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

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.