Role of the calcium stimulation test in diagnosing medullary thyroid cancer: is it adequate to achieve a diagnosis in both sexes? An individual patient data meta-analysis

Background: Early diagnosis of medullary thyroid cancer (MTC) when basal calcitonin (CT) levels are <100 pg/mL remains a clinical challenge. The calcium stimulation test is a unique tool for stimulating CT. However, standardized and sex-specific cutoff values are lacking.Therefore, this study aimed to investigate whether the calcium stimulation test for CT is adequate for diagnosing MTC in both sexes and to identify sex-specific cutoff values. Methods: This was an individual patient data (IPD) meta-analysis. A literature search was performed using Scopus, PubMed, and Web of Science until September, 2024, to identify articles on the calcium stimulation test for diagnosing MTC. Results: A total of five studies involving 243 patients (148 females and 95 males) who underwent total thyroidectomy were included in this study. Before surgery, all patients underwent the calcium stimulation test with calcium gluconate (25 mg/kg) for CT assessed by chemiluminescence assay. In females, a global threshold of 162 pg/mL was identified, with a pooled sensitivity of 0.90 (95% confidence interval (95% CI): 0.79–0.97) and specificity of 0.66 (95% CI: 0.56–0.75). The pooled area under the curve (AUC) was 0.87 (95% CI: 0.76–0.97). In males, a global threshold of 562 pg/mL was identified, with a pooled sensitivity of 0.79 (95% CI: 0.60–0.92) and specificity of 0.89 (95% CI: 0.79–0.96). The pooled AUC was 0.94 (95% CI: 0.90–0.99). Conclusions: The calcium stimulation test for CT for the diagnosis of MTC showed better performance in males than in females, with a suggested cutoff value of 562 pg/mL in males. Significance statement The management of indeterminate calcitonin (CT) values is still challenging in the early diagnosis of MTC, lacking general recommendations, which can help clinicians in these cases. This is the first IPD meta-analysis that underscores the sex-based disparity in the diagnostic accuracy of the calcium stimulation test for CT in suspected MTC cases, showing better performance in diagnosing MTC in male versus female patients, with a cutoff value of 562 pg/mL in male subjects. In the context of the limited literature, this paper provides added value for the clinical endocrine practitioner, suggesting the use of the calcium stimulation test in highly selected cases with indeterminate CT values (10–100 pg/mL) with a sex-oriented and personalized approach.