ORIGINAL ARTICLE – MELANOMA Extracapsular Spread in Melanoma Lymphadenopathy: Prognostic Implications, Classification, and Management Michelle Lo, MRCS 1 , Alyss Robinson, MRes 2 , Ryckie Wade, MRCS 2,3 , Howard Peach, FRCS(Plast) 3 , Donald Dewar, FRCS(Plast) 3 , Martin Heaton, FRCS(Plast) 1 , and Marc Moncrieff, FRCS(Plast) 1,4 1 Department of Plastic and Reconstructive Surgery, Norfolk and Norwich University Hospital, Norwich, UK; 2 Faculty of Medicine and Health, University of Leeds, Leeds, UK; 3 Department of Plastic and Reconstructive Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK; 4 Norwich Medical School, University of East Anglia, Norwich, UK ABSTRACT Background. Extracapsular spread (ECS) is recognized to be a high-risk factor in melanoma patients with macro- metastatic (N?) nodal disease; however, ECS risk in sentinel lymph node (SLN) biopsy, micrometastatic stage III disease is ambiguous. Objective. The aim of this study was to examine ECS incidence and its prognostic significance. Methods. A two-center, retrospective analysis of all patients with micro/macrometastatic lymphadenopathy undergoing nodal surgery from 2008 to 2014 was per- formed. Patient demographics, tumor characteristics, nodal ECS status, and patient outcomes were collected. Results. Overall, 515 patients with nodal disease were identified (males/females = 277/238); median age was 63 years (range 17–94). There was an increased frequency of ECS disease in N? disease compared with SLN? dis- ease (52.4% vs. 16.2%; p \ 0.0001). The absolute disease- specific survival (DSS) difference for SLN? patients was approximately 30% at 10 years (66.2% vs. 37.2%; p \ 0.0001), and the prognosis of SLN?/ECS? patients was identical to N?/ECS- patients. Multivariate analysis demonstrated that ECS status was an independent prog- nostic indicator for DSS (hazard ratio 2.47, 95% confidence interval 1.87–3.26; p \ 0.0001) in patients with SLN? disease. There were significant differences in nodal burden according to ECS status between the SLN? and N? subgroups suggestive of differing biology in ECS? tumors. Conclusion. We found that ECS is a significant DSS, progression-free survival, and overall survival indicator in SLN? and N? disease. We demonstrated that ECS upstages stage III disease, similar to ulceration in primary melanoma (stage I/II disease). A simplified staging system substituting ECS for N stage accurately stages patients according to prognosis. The American Joint Committee on Cancer (AJCC) 8th edition staging system 1 has produced some significant changes in the classification of melanoma, in particular the stage III group. For the first time, stage III not only incorporates data from the ‘N’ stage but also qualifying ‘T’ data from the primary, such as Breslow thickness and ulceration status. This takes into account the fact that the risk of distant spread and subsequent death from melanoma of the stage III group is dependent on the risk of hematogenous spread from a deeply invading primary, in addition to the disease burden of the metastatic nodes, and recognizes that these two risks are often, although not always, competing and not mutually dependent. Accord- ingly, the current AJCC classification system for stage III, in terms of prognosis, is heterogeneous, with 5-year mel- anoma-specific survival rates ranging from 88% for stage IIIA disease to 24% in stage IIID disease. The reference table for the classification of stage III disease is compli- cated and may be a challenge to commit to memory for some. Ó Society of Surgical Oncology 2020 First Received: 9 November 2019 Accepted: 15 August 2020 M. Lo, MRCS e-mail: Michelle.Lo@nhs.net Ann Surg Oncol https://doi.org/10.1245/s10434-020-09099-w