Primary Melanoma Histologic Subtype: Impact on Survival and Response to Therapy

Abstract

Background: Two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting.

Methods: We examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided.

Results: NM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated.

Conclusions: Our data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.

Figure 1.

Survival curves stratified by primary melanoma histologic subtype. A) Kaplan-Meier survival curves for melanoma-specific survival (P < .001) in the Surveillance, Epidemiology, and End Results cohort. B) Recurrence-free survival (P < .001) in the NYU cohort. C) Melanoma-specific survival (P < .001) in the NYU cohort. All P values were calculated using a two-sided log-rank test.

Figure 2.

Genomic sequencing of nodular and superficial spreading melanoma. A) Prevalence of known BRAF and NRAS melanoma driver mutations among nodular melanoma and superficial spreading melanoma (P < .001 from two-sided χ² test for NRAS). B) Distribution of nonsynonymous, nonsense, and splice-site single nucleotide variants among the most commonly mutated genes identified in nodular melanoma and superficial spreading melanoma. NM = nodular melanoma; SNV = single nucleotide variant; SSM = superficial spreading melanoma.

Figure 3.

Clinical outcomes of BRAF-targeted therapy in metastatic melanoma stratified by histologic subtype. A) Kaplan-Meier survival curves for metastatic nodular melanoma and metastatic superficial spreading melanoma from the initiation of BRAF-targeted therapy (log-rank P = .003). B) Distribution of responses to BRAF-targeted therapy between nodular melanoma (NM) and superficial spreading melanoma (SSM; P = .02). C, D) Swimmer plots demonstrating the duration of treatment among SSM and NM (P = .01), with arrows indicating continuation of therapy. All P values were calculated using a two-sided log-rank test. CR = complete response; NM = nodular melanoma; POD = progression of disease; PR = partial response; SD = stable disease; SSM = superficial spreading melanoma.