Only a handful of studies have evaluated the clinicopathological features of the rare cancers VuM and VaM, and none of them was conducted in the Japanese population. Therefore, in this retrospective observational study, we analyzed 109 cases of VuM and 108 cases of VaM treated over a period of 20 years at various centers in Japan and aimed to characterize those cases and identify predictors for OS and PFS. According to our study, the OS for VuM and VaM in Japan were 43.6 months and 31.1 months respectively, which is comparable to a US population-based study (53 months for VuM and 16 months for VaM) [30] and to a Canadian study (45 months for VuM and 10.48 months for VaM) [15]. The median PFS was 16.8 months in patients with VuM (95% CI 23.1–87.7) and 15.6 months in patients with VaM (95% CI 8.4–12.6). Even though both the OS and PFS in our study were worse for VaM, the observed differences were not significant. As there were no significant differences between VuM and VaM in patient characteristics in terms of staging according to AJCC, age, or the treatment received, we can conclude that the poorer OS and PFS observed in patients with VaM can be attributed to the melanoma subtype and that it needs to be studied further.
Various studies have evaluated the risk factors for OS and PFS in VaM and VuM with different results. A study by Sinasac et al. reported that clinical stage, maximum tumor size, tumor thickness, lymphovascular space invasion status, clinically enlarged lymph nodes, sentinel lymph nodes, lymph node status, and radiation treatment are associated with OS [15], and Huang Q et al. reported that macroscopic tumor growth and the treatment method are independent prognostic factors for OS [31]. Multivariate progression analysis in a retrospective review of 100 cases of VuM identified the tumor thickness, dermal mitotic rate, lymphovascular invasion, microscopic satellite, and absence of precursor nevus as predictors of poor survival [32].
In order to understand the risk factors in the Japanese population, we performed independent analyses of the factors associated with the OS and PFS for VuM and VaM. In a multivariate analysis, we identified that an AJCC stage > 4 is associated with poor PFS and that an unknown surgical margin is associated with poorer OS. Even though the management and treatment of VuM and VaM follow the same guidelines, there are clear differences in the OS, PFS, and risk factors associated with each subtype. Due to the nature of the cancer type, both subtypes are treated either by a dermatologist or a gynecologist. However, multivariate analysis showed that management by a gynecologist significantly decreased the OS of VaM (HR = 2.235, 95% CI = 1.127–4.433). In contrast, the univariate analysis demonstrated that the management by a gynecologist in the VuM significantly increased the OS (HR = 0.564, 95% CI = 0.329–0.967). According to multivariate analysis, factors that are associated with the OS and PFS in each subtype also differ. The positive and unknown surgical margin, and the presence of microsatellites are the factors associated with poor OS in VaM and VuM respectively. Factors associated with poor PFS are an AJCC stage > 4 and the presence of lymph node metastasis in VaM and VuM, respectively.
In our study, surgery was performed in 84.3% of the women with VuM and 83.3% of those with VaM; the study demonstrated the selection of surgery as a first-line treatment regardless of the disease stage. Moreover, surgery was identified as a positive prognostic factor for OS in VaM (HR = 0.539, 95% CI = 0.284–1.022) and negative surgical margins as a prognostic factor for better OS and PFS in all groups. However, the survival benefits of radical initial surgery for primary VaM have not been demonstrated yet [33]. Adjuvant chemotherapy and radiotherapy were used in 62.7% and 15.7% of cases, respectively. The relationship between the selected therapy and survival rates was not the objective of this study, and may be explored in further studies.
Overall, we have demonstrated that the survival rates for VuM and VaM remain poor in Japan, and that there are significant differences between these subtypes.
Our study has several limitations, the primary one being the inherent limitations of its retrospective design. Salient unmeasured biases that could impact outcomes include medical comorbidities, pathological diagnoses, performance status, surgeons’ experiences, patient compliance, and the decision-making processes at multiple participating institutions; all of these factors could affect the treatment approach, operational performance, and survival. In addition, while this study included a diverse range of hospitals in Japan, not all hospitals in Japan participated, which may have resulted in a selection bias. Furthermore, due to the relatively long duration of the study (21 years), there may have been changes in treatment methods resulting in non-uniformity that could have affected the overall survival.
In conclusion, we conducted a large-scale survey and a detailed review of the treatment and clinicopathological features of malignant melanomas of the vulva (VuM) and vagina (VaM) in Japan. Our results show that the overall outcomes of VuM and VaM remain poor in Japan, and that the AJCC stage and surgical margin are significant predictors of survival. The results of this study could be used as a basis for decision-making in routine clinical practice and as data for future prospective clinical trials.