Beyond Tumor Diameter: Exploratory Cohort-Derived Calcitonin Secretory Categories and Invasive Pathology in Medullary Thyroid Carcinoma

Background: Serum calcitonin is commonly interpreted as a marker of tumor burden in medullary thyroid carcinoma (MTC), but patients with comparable tumor diameters may show markedly different calcitonin levels. This exploratory study aimed to derive cohort-specific, tumor diameter–adjusted calcitonin secretory categories and examine their relationship with invasive pathological features. Methods: This retrospective single-center study included 70 unique patients with histopathologically confirmed MTC. Seventeen patients with preoperative serum calcitonin below the assay reporting limit (<2 pg/mL) were evaluated separately. In 53 patients with detectable calcitonin, residuals from a log-linear model of calcitonin according to dominant tumor diameter were divided into tertiles to define exploratory hyposecretory, normosecretory, and hypersecretory categories. Sensitivity analyses accounted for sex, metastatic lymph-node count, documented distant metastatic disease, and restriction to patients with pN0 disease and no documented distant metastasis. Results: Preoperative calcitonin correlated with dominant tumor diameter (Spearman rho = 0.644, p < 0.001), and the primary model explained 45.2% of calcitonin variability (R2 = 0.452). The cohort-derived categories included 18 hyposecretory, 17 normosecretory, and 18 hypersecretory tumors. In a hypothesis-driven exploratory contrast, lymphovascular invasion (55.6% vs. 25.7%; nominal p = 0.040) and perineural invasion (33.3% vs. 8.6%; nominal p = 0.048) were more frequent in the hypersecretory category. However, the global three-group comparisons were not statistically significant (p = 0.135 and p = 0.117, respectively), and both false-discovery-rate-adjusted q values were 0.072. The tumor diameter–calcitonin relationship remained significant after adjustment for sex and metastatic burden and in the pN0 subgroup without documented distant metastasis. Conclusions: The exploratory, cohort-derived hypersecretory category showed hypothesis-generating enrichment for lymphovascular and perineural invasion, but these associations did not meet the false-discovery-rate-adjusted significance threshold. External validation is required before these categories can be considered biologically established or clinically applicable.