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Association of Histologic Regression With a Favorable Outcome in Patients With Primary Cutaneous Melanoma
abstract
This abstract is available on the publisher's site.
Access this abstract nowImportance
Although regression is commonly observed in cutaneous melanoma, it is uncertain whether it is associated with patient prognosis.
Objective
To determine whether histologically confirmed regression was associated with better or worse survival in patients with primary cutaneous melanoma.
Design, Setting, and Participants
This cohort study analyzed data from 2 large cohorts of adults (one in the Netherlands and the other in Australia) with histologically proven, stage 1 and 2 primary, invasive cutaneous melanoma with known regression status treated between 2000 and 2014, with median follow-up times of 4.5 and 11.1 years for the Dutch and Australian cohorts, respectively. For the Dutch patients, population-based data from PALGA, the Dutch Pathology Registry, were used, and follow-up data were retrieved from the Netherlands Cancer Registry. For the Australian patients, data from the database of a large, specialized melanoma treatment center were used.
Main Outcomes and Measures
Multivariable Cox proportional hazards analyses were performed per cohort to assess recurrence-free survival (RFS) and overall survival (OS), and subgroup analyses according to Breslow thickness category and melanoma subtype were performed.
Results
A total of 17 271 Dutch patients and 4980 Australian patients were included. In both cohorts, survival outcomes were better for patients with disease regression. For Dutch patients, the hazard ratio (HR) for those with disease regression was 0.55 (95% CI, 0.48-0.63; P < .001) for RFS and 0.87 (95% CI, 0.79-0.96; P = .004) for OS; for the Australian patients, the HR was 0.61 (95% CI, 0.52-0.72; P < .001) for RFS and 0.73 (95% CI, 0.64-0.84; P < .001) for OS. Subgroup analyses showed that the presence of regression improved RFS within thin and intermediate Breslow thickness melanomas in both cohorts. For patients with superficial spreading melanoma (SSM) subtype, regression improved RFS and OS in both cohorts. For Dutch patients with SSM, the HR for those with disease regression was 0.54 (95% CI, 0.46-0.63; P < .001) for RFS and 0.86 (95% CI, 0.76-0.96; P = .009) for OS; for the Australian patients with SSM, the HR was 0.67 (95% CI, 0.52-0.85; P = .001) for RFS and 0.72 (95% CI, 0.59-0.88; P = .001) for OS.
Conclusions and Relevance
In 2 large patient cohorts from 2 different continents, regression was a favorable prognostic factor for patients with stage 1 and 2 melanomas, especially in those with thin and intermediate thickness tumors and those with SSM subtype.
Additional Info
Disclosure statements are available on the authors' profiles:
Association of Histologic Regression With a Favorable Outcome in Patients With Stage 1 and Stage 2 Cutaneous Melanoma
JAMA Dermatol 2020 Dec 23;[EPub Ahead of Print], MA El Sharouni, K Aivazian, AJ Witkamp, V Sigurdsson, CH van Gils, RA Scolyer, JF Thompson, PJ van Diest, SN LoFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Prior studies evaluating the impact of melanoma regression on prognosis have shown divergent results and many limitations, including small sample size and short follow-up. Those who found a worse prognosis associated with regression suggest that Breslow depth of invasion, measured to the deepest invasive tumor cell, may be an underestimate because the deepest melanoma cells have regressed, whereas those finding improved survival argue that regression is due to helpful activation of the immune system.
This is the largest cohort (over 20,000) of stage 1 and 2 cutaneous melanoma patients evaluated to determine the impact of regression on prognosis. Divergent populations predominantly from the Netherlands, but also Australia, were included and were diagnosed over a 14-year period (2000–2014). Follow-up times ranged from 3.1 to 17.9 years. The authors concluded that histologic regression was associated with improved relapse-free and overall survival.
Regression is generally defined as a decrease in invasive melanoma cells in association with vascular fibrosis, inflammatory infiltrate, melanophages, and epidermal effacement, in the absence of prior trauma. However, as mentioned by the authors, there is a lack of uniformity in the reporting of histopathologic regression. Nearly 800 pathologists were involved in the reporting of the melanomas in this study, with variable levels of training and a binary determination of presence or absence of regression. The subjectivity of interpretation of the histologic features aside, how much is enough? As a dermatopathologist reading melanomas every day, I find myself forced to check the box present or absent when reporting melanomas. However, regression isn’t like pregnancy, you either are or you are not pregnant; regression on the other hand comes in degrees. When complete regression is present it is impossible to determine if the regressed lesion was even melanocytic, much less melanoma. Therefore, melanomas diagnosed with regression show varying degrees of regression involving less than 100% of the tumor. Similarly, there are stages in the evolution of regression from dense lymphocytic infiltrate to cell-poor vascular fibrosis. Perhaps further study with more standardized histopathologic features that include subcategorization by stage of regression and/or percentage of tumor involved will elucidate a clearer relationship.