Co-Occurrence of Differentiated Thyroid Cancer and Second Primary Malignancy: Correlation with Expression Profiles of Mismatch Repair Protein and Cell Cycle Regulators

SIMPLE SUMMARY: Although the incidence of thyroid cancer is increasing, improvements in treatment have resulted in more patients being confirmed to have a second primary cancer. However, studies on potential biomarkers for predicting the risk of second primary malignancy are extremely limited. Therefore, our objective was to establish molecular biomarkers for the risk prediction of second primary malignancy using routinely collected formalin-fixed paraffin-embedded tissue specimens. Our results suggest that the deficient mismatch repair phenotype, the expression of pRb, and the lack of CDK4 or CDK6 are significantly associated with co-occurrence of nonthyroid malignancy. The predictive value of these immunohistochemical profiles for the co-occurrence of nonthyroid malignancy was also assessed. The combined evaluation of a four-biomarker signature model may provide the most important predictive innovation. Our study proposes the first tissue-based screening tool for risk stratification and further active surveillance in patients with thyroid cancer. ABSTRACT: Some patients with thyroid cancer develop a second primary cancer. Defining the characteristics of patients with double primary cancers (DPCs) is crucial and needs to be followed. In this study, we examine molecular profiles in DPC. We enrolled 71 patients who received thyroid cancer surgery, 26 with single thyroid cancer (STC), and 45 with DPC. A retrograde cohort was used to develop immunohistochemical expressions of mismatch repair (MMR) proteins and cell-cycle-related markers from tissue microarrays to produce an equation for predicting the occurrence of DPC. The multivariate logistic model of 67 randomly selected patients (24 with STC and 43 with DPC) identified that the expression of deficient MMR (dMMR) (odds ratio (OR), 10.34; 95% confidence interval (CI), 2.17–49.21) and pRb (OR, 62.71; 95% CI, 4.83–814.22) were significantly associated with a higher risk of DPC. In contrast, the expression of CDK4 (OR, 0.19; 95% CI, 0.04–0.99) and CDK6 (OR, 0.03; 95% CI, 0.002–0.44) was significantly associated with a lower risk of DPC. Collectively, dMMR, pRb, CDK4, and CDK6 have a sensitivity of 88.9% (95% CI, 75.1–95.8) and a specificity of 69.2% (95% CI, 48.1–84.9) for occurrence of DPC in all 71 patients. This is the first report to demonstrate the molecular differentiation of STC and DPC. Overall, the integral molecular profile performed excellent discrimination and denoted an exponential function to predict the probability of DPC.