Comparison of the prognostic value of microscopically measured invasive width versus macroscopic width in cutaneous melanoma shows the superiority of microscopic invasive width measurement.

BACKGROUND: Invasive width, the distance between the most peripheral invasive melanoma cells on the section where Breslow thickness (BT) was measured, was recently identified as a prognostic feature. It is unclear whether a routine measurement is justified, given that macroscopic width is already included in many melanoma histopathology reports and may itself be a prognostic feature. This study sought to investigate this. METHODS: A retrospective cohort of 718 melanoma patients in which macroscopic width had been stated in the original histopathology report was used. Survival analysis was performed. RESULTS: Macroscopic and invasive widths were positively correlated (p < 0.001). Invasive width was typically smaller than the paired macroscopic width (median difference 3.7 mm, p < 0.001), a difference seen across all T groups. Both macroscopic and invasive widths were significantly associated with melanoma survival in Kaplan-Meier analysis, including overall survival, but invasive width survival curves were more widely separated. Both were significantly associated with outcome after correction for BT in Cox proportional hazards regression, but the models containing invasive width had a substantially better fit. CONCLUSIONS: This study shows that both macroscopic and invasive widths have prognostic values, but confirms that the latter is superior. It supports further investigation of this feature's prognostic value.

The Width of Invasion in Malignant Melanoma Is a Novel Prognostic Feature That Accounts for Outcome Better Than Breslow Thickness.

Breslow thickness (BT) is the cornerstone of malignant melanoma staging. However, to our knowledge no-one has ever assessed the horizontal width of invasion, measured microscopically, as a prognostic feature. This was investigated as a prognostic feature in this study. A retrospective cohort of 1329 melanoma cases was collected from patients presenting to a UK teaching hospital from January 1, 2004, to December 31, 2014. The main outcome was overall survival (OS). We found that width was associated with OS in multivariable analysis (hazard ratio=1.05, 95% confidence interval: 1.03-1.07, P<0.001) and was similarly significant for melanoma-specific survival and metastasis-free survival. Its presence rendered BT nonsignificant. The width was significantly associated with OS after adjustment for American Joint Committee on Cancer (AJCC), version 8 clinical tumor stage (hazard ratio=1.05, 95% confidence interval: 1.03-1.07, P<0.001), and bootstrap validation showed only slight model optimism. Similar associations were seen for melanoma-specific survival and metastasis-free survival. However, the combination of invasive width and BT did not account for the outcome as well as another novel histologic feature, tumor area, which was measured using the calculated tumor area method. In conclusion, this study is the first investigation of a novel histologic feature, invasive melanoma width, and demonstrates its strong independent association with outcome.

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

IMPORTANCE: Breslow 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. OBJECTIVE: To determine CTA precision and prognostic value. DESIGN, SETTING, AND PARTICIPANTS: This 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. INTERVENTION: An observational analysis of the prognostic value of CTA in patients with cutaneous melanoma. MAIN OUTCOMES AND MEASURES: Independent association of CTA with melanoma-specific survival and confounding effect of CTA on Breslow thickness in survival analysis. RESULTS: A 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 RELEVANCE: This 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.

Breslow Density Is a Novel Prognostic Feature That Adds Value to Melanoma Staging.

Histomorphologic prognostic biomarkers that can be measured using only an hematoxylin and eosin stain are very attractive because they are simple and cheap. We conceived an entirely novel biomarker of this type, the Breslow density (BD), which measures invasive melanoma cell density at the site where Breslow thickness (BT) is measured. This study assessed BD's prognostic value. In this study, BD was measured in 1329 melanoma patients. Measurement accuracy and precision was assessed using intraclass correlation coefficient (ICC). Survival was assessed with a primary end-point of melanoma-specific survival (MSS) and also overall survival and metastasis-free survival. We found that BD measurement was accurate compared with gold standard image analysis (ICC, 0.84). Precision was excellent for 3 observers with different experience (ICC, 0.93) and for an observer using only written instructions (ICC, 0.93). BD was a highly significant predictor in multivariable analysis for overall survival, MSS, and metastasis-free survival (each, P<0.001) and it explained MSS better than BT, but BT and BD together had best explanatory capability. A BD cut point of ≥65% was trained in 970 melanomas and validated in 359. This cut point showed promise as a novel way to upstage melanoma from T stage "a" to "b." BD was combined with BT to create a targeted burden score. This was a validated as an adjunct to American Joint Committee on Cancer stage. In summary, BD can be measured accurately and precisely. It demonstrated independent prognostic value and explained MSS better than BT alone. Notably, we demonstrated ways that BD could be used with American Joint Committee on Cancer version 8 staging.