Revisiting the Relationship Between Tumor Size and Risk in Well-Differentiated Thyroid Cancer

Introduction: Large tumor size is associated with poorer outcomes in well-differentiated thyroid cancer, yet it remains unclear whether size >4 cm alone confers increased risk, independent of other markers of aggressive disease. The goal of this study was to assess the relationship between tumor size, other high-risk histopathological features, and survival in well-differentiated thyroid cancer and to evaluate the significance of 4 cm as a cutoff for management decisions. Methods: Patients with well-differentiated thyroid cancer were identified from the National Cancer Database (2010-2015) and categorized by tumor size (i.e., small [≤4 cm] or large [>4 cm]) and presence of high-risk histopathological features (e.g., extrathyroidal extension). First, propensity score matching was used to identify patients who were similar across all other observed characteristics except for small versus large tumor size, and a multivariable Cox proportional hazards model was used to estimate the relationship between tumor size and survival. Second, we assessed whether the presence of high-risk features demonstrates conditional effects on survival based on the presence of tumor size >4 cm using an interaction term. Finally, additional models assessed the relationship between incremental 1 cm increases in tumor size and survival. Analyses were repeated using a validation cohort from the Surveillance, Epidemiology, and End Results Program (2008-2013). Results: Of 193,133 patients in the primary cohort, 7.9% had tumors >4 cm, and 30% had at least one high-risk feature. After matching, tumor size >4 cm was independently associated with worse survival (HR 1.63, p < 0.001). However, tumor size >4 cm and one or more other high-risk features together yielded worse survival than either size >4 cm alone (MMD: 0.70, p < 0.001) or other high-risk features alone (MMD: 0.49, p < 0.001). When assessed in 1 cm increments, the largest increases in hazard of death occurred at 2 cm and 5 cm, not 4 cm. Results from the validation cohort were largely consistent with our primary findings. Conclusions: Concomitant high-risk features confer worse survival than large tumor size alone, and a 4 cm cutoff is not associated with the greatest increase in risk. These findings support a more nuanced approach to tumor size in the management of well-differentiated thyroid cancer.