Department of Medicine.
Interdisciplinary Melanoma Cooperative Group.
J Natl Cancer Inst. 2019 Feb 1;111(2):180-188. doi: 10.1093/jnci/djy086.
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.
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.
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.
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.
两种主要的组织学亚型，即浅表扩散型黑色素瘤（SSM）和结节型黑色素瘤（NM），构成了所有皮肤黑色素瘤的大部分。NM 与更差的预后相关，这归因于其在就诊时的厚度增加，并且广泛认为 NM 和 SSM 在转移后会表现出类似的行为。在此，我们检验了以下假设：主要组织学亚型是生存的独立预测因子，并可能影响转移性疾病的治疗反应。
我们检查了最新的监测、流行病学和最终结果（SEER）队列（n = 118508）和纽约大学（NYU）队列（n = 1621），并对其进行了基于协议的随访。根据主要组织学，在原发性和转移性疾病中，对 BRAF 靶向治疗和免疫治疗进行了研究。我们对 NM 和 SSM 病例的已知驱动突变进行了特征描述，并使用下一代测序对其中的一个子集进行了 140 个基因的检测。所有的统计检验都是双侧的。
NM 是 SEER（风险比 [HR] = 1.55，95%置信区间 [CI] = 1.41 至 1.70，P <.001）和 NYU（HR = 1.47，95% CI = 1.05 至 2.07，P =.03）队列中死亡的独立危险因素，在控制厚度、溃疡、分期和其他变量后。在转移性疾病中，NM 在接受 BRAF 靶向治疗时仍然是死亡的独立危险因素（HR = 3.33，95%CI = 1.06 至 10.47，P =.04），但与免疫检查点抑制无统计学显著差异。NM 与更高的 NRAS 突变率相关（P <.001），高通量测序揭示了 NM 中 NOTCH4、ANK3 和 ZNF560 的特异性基因组改变，这些改变得到了独立验证。
我们的数据揭示了 NM 和 SSM 之间的明显的临床和生物学差异，支持重新审视原发性组织学亚型在皮肤黑色素瘤治疗中的预后和预测影响。
