Development and Initial Validation of Calculated Tumor Area as a Prognostic Tool in Cutaneous Malignant Melanoma

Key PointsQuestionWhat is the prognostic value of calculated tumor area-a novel, simple microscopic feature and a 2-dimensional surrogate for tumor size-and is it a possible upgrade for the 1-dimensional criterion standard measurement, Breslow thickness? FindingsIn this cohort study of 1239 patients with melanoma, calculated tumor area had independent prognostic value with greater relative importance than Breslow thickness. Stratification of melanoma into groups based on calculated tumor area had better prognostic value than T category, which is based on Breslow thickness. MeaningThese findings suggest that calculated tumor area should be prioritized for investigation to verify its prognostic value and to assess its applicability and acceptability in routine practice. This cohort study investigates the precision and prognostic value of calculated tumor area among patients with cutaneous malignant melanoma. ImportanceBreslow thickness is a 1-dimensional surrogate prognostic feature for tumor size, yet tissue sections have 2 dimensions. Therefore, a 2-dimensional feature, calculated tumor area (CTA), was devised. ObjectiveTo determine CTA precision and prognostic value. Design, Setting, and ParticipantsThis retrospective cohort of patients with cutaneous melanoma presented to the Leicester and Nottingham National Health Service hospital trusts in the United Kingdom. Eligible patients in the Leicester development sample had available primary tumor tissue; a diagnosis from January 1, 2004, through December 31, 2011; invasive disease; and Leicestershire residency. Patients in the Nottingham validation sample had an anonymized spreadsheet with primary melanoma diagnosed from January 1, 2003, through December 31, 2005, or from January 1, 2008, through December 31, 2010. From a starting population of 1463 patients in both data sets, a total of 224 (15.3%) were excluded to yield a study population of 1239. Data were analyzed from April 30, 2018, through January 10, 2019. InterventionAn observational analysis of the prognostic value of CTA in patients with cutaneous melanoma. Main Outcomes and MeasuresIndependent association of CTA with melanoma-specific survival and confounding effect of CTA on Breslow thickness in survival analysis. ResultsA total of 1239 patients with melanoma were assessed, including 649 (52.4%) women, with a median age of 60 years (interquartile range, 47-71 years). An intraclass correlation coefficient for CTA on 13 cases was 0.99. In 918 patients in the Leicester cohort, CTA was an independent prognostic factor in Cox proportional hazards regression models after adjusting for Breslow thickness, age, sex, ulcer, mitotic rate, and microsatellites (hazard ratio [HR], 1.87; 95% CI, 1.49-2.34; P<.001). Validation in 321 patients in the Nottingham cohort showed an HR of 1.55 (95% CI, 1.15-2.09; P=.005) and in the combined 1239 cases, an HR of 1.70 (95% CI, 1.43-2.03; P<.001). Breslow thickness was significant in multivariable analysis only when CTA was not in the model. The relative importance of CTA was shown by its retention in all 100 bootstrap multivariable models with backward selection, whereas Breslow thickness was retained in only 53. Melanomas stratified by CTA showed wider separation of survival curves than those stratified by Breslow thickness using the American Joint Committee on Cancer Staging Manual, 8th Edition (HRs, 1.00 to 41.46 vs 1.00 to 36.95, respectively), and the model with CTA categories had a Bayesian information criterion difference of 13.9 compared with T category, indicating substantially better fit. This model had a Harrell C index of 83.7%, and bootstrap analysis showed little evidence of model optimism, with a corrected calibration slope of 0.99. Conclusions and RelevanceThis study provides a novel microscopic feature, CTA, with evidence of its independent prognostic value. This evidence suggests that CTA should be a priority for further study.