Rethinking the definition of stage III disease in adrenocortical carcinoma: Assessing the impact of clinical lymph node positive disease

Introduction: Stage III adrenocortical carcinoma encompasses both lymph node positive (TanyN1M0) and negative (T3-4N0M0) disease. Given the disease's rarity, the current staging paradigm's estimates of survival are supported by limited evidence. Consequently, we examined the impact of clinical lymph node positivity on survival outcomes in the context of the current staging of advanced adrenocortical carcinoma. Methods: We identified patients with clinical stage III and IV disease from the National Cancer Database. Kaplan-Meier methods and Cox proportional hazards models estimated overall survival for stage III lymph node negative, stage III lymph node positive, and stage IV disease. Results: We identified 917 patients with adrenocortical carcinoma – 322 (35.1%) stage III lymph node negative, 67 (7.3%) stage III lymph node positive, and 528 (57.6%) stage IV. 3-year overall survival for patients with stage III lymph node negative, stage III lymph node positive, and stage IV disease was 48.6%, 29.4%, and 15.6%, respectively. On univariable analysis, patients with stage III lymph node positive disease were associated with worse survival than those with stage III lymph node negative disease (HR 1.72, 95% CI 1.26-2.37, P < 0.001); however, this relationship did not maintain significance in multivariable analysis (HR 1.27, 95% CI 0.88-1.83, P = 0.21). Conclusion: Our study finds that patients with clinical stage III lymph node positive adrenocortical carcinoma may have worse survival outcomes than stage III patients without lymph node involvement. The results of this study suggest the need for an updated, more nuanced staging paradigm, which differentiates stage III disease by lymph node positivity.