Extranodal Spread is Associated with Recurrence and Poor Survival in Stage III Cutaneous Melanoma Patients

Inconsistent data suggests extranodal spread (ENS) is an adverse prognostic factor in Stage III melanoma patients but it remains contentious. By rigorously matching cohorts, this study sought to clarify associations with recurrence and survival. Melanoma patients with lymph node metastases (AJCC Stage III), with or without ENS, sub-classified on the basis of known (MKP) or unknown primary (MUP), were identified from a single institution prospective database. Of 725 ENS patients identified, 567 were able to be precisely matched 1:1 with a non-ENS cohort. Clinicopathologic factors were analyzed for associations with outcome. There were 481 MKP and 86 MUP patients in each cohort. ENS, compared to non-ENS, was an independent predictor of worse melanoma specific survival (MSS) (HR = 1.71, 95% CI = 1.39-2.11, P < 0.0001) with median MSS 56.4 versus 175.2 months, P < 0.001; worse disease free survival (DFS) (HR = 1.16, 95%CI = 1.00-1.34, P = 0.044) with median DFS 15.6 versus 21.5 months, P = 0.009; and worse post-recurrence survival (PRS) (HR = 1.66, 95%CI = 1.37-2.02, P < 0.0001) with median PRS 20.1 versus 51.1 months, P < 0.001. ENS was also associated with reduced time to distant recurrence (Distant Disease Free Survival [DDFS]) (HR = 2.00, 95% CI = 1.24-3.24, P = 0.0047), however median time to distant recurrence not reached within the study time period. ENS represents a significant independent predictor of worse MSS, DFS, PRS and DDFS in Stage III melanoma patients. ENS should be considered in the stratification of patients in adjuvant therapy trials.