In this study, we compared the characteristics of HNM patients with those of BM patients based on the data of a large SEER population. Then, we performed survival analysis of the HNM and BM groups to construct nomograms for individualized survival prediction
Hoersch et al[16] compared 844 patients with HNM and 4858 patients with BM and performed univariate and multivariate analyses, but they found no OS differences between patients with HNM and patients with BM, and the identified significant prognostic factors of HNM were inconsistent with those identified in our study. The low number of cases and different populations in that study could have led to the controversial results. Kevin et al[14] performed a comparison of 4561 pediatric patients with HNM or BM, but they did not study prognostic factors. Previous studies have identified significant independent prognostic factors of melanoma, and some nomograms were developed for predicting the OS or CSS of nonmetastatic melanoma patients, melanoma patients with brain metastases or nodular melanoma patients[6, 24-27]. To date, a specific nomogram for HNM or BM has not been developed.
A total of 70605 eligible patients in the United States from 2004 to 2015 were identified in our study. To our knowledge, this was the largest population-based study to perform a comprehensive comparison between HNM and BM, including their characteristics and survival. Furthermore, this is the first time that high-quality nomograms have been constructed for predicting the prognosis of HNM patients and BM patients, respectively.
HNM patients accounted for 21% of all eligible patients in our study, which was consistent with that in previous reports[9, 16]. According to the univariate prognostic factor analysis of all eligible patients, significant differences were seen between patients with HNM and patients with BM. Notably, the 5-year OS rate of HNM patients was over 10% less than that of BM patients. The relatively high frequency and poorer prognosis of HNM suggest that cutaneous melanoma in head and neck areas requires more attention and health management.
Both the mean and median age of patients with HNM were greater than those of BM patients. HNM was found more than twice as frequently as BM in elderly patients (age>=79). The finding that HNM occurred more frequently in elderly individuals was also observed in other population-based studies[7, 28-30]. Elderly individuals usually suffer longer chronic sun exposure than younger individuals in regions of the head and neck, explaining the higher melanoma rate. In addition, based on the subgroup analysis of age, we observed that the 5-year CSS and OS rates were lower for patients with HNM than for those with BM.
In accordance with the findings of previous studies[15, 31-33], we found significant sex differences between HNM and BM. Nearly three-quarters of patients with HNM were male, while the percentage of females was close to that of males in the BM population in our study. Usually, women are more active in the prevention of sun exposure on the head and neck, which may reduce the risk of HNM[8]. Females showed a better prognosis than males in both the HNM and BM groups in our study. Interestingly, we observed that the 5-year OS of male patients with BM was better than that of female patients with HNM. This result suggested the important role of head and neck regions.
SSM was the most common histologic subtype of melanoma in both the HNM and BM cohorts, but a higher proportion of SSM was noticed in the latter population. Notably, 31.8% of HNM patients were diagnosed with LMM, while only 6.6% of BM patients had LMM. Other population-based melanoma studies also found that a high percentage of LMM occurred on the head and neck[7, 9]. LMM has a prolonged radial growth phase before entering the vertical phase to invade the dermis[34]. Chronic sun damage to the head and neck may serve as an adverse factor in its evolution. Nodular melanoma is associated with worse prognosis than other histological subtypes[35]. Similarly, our study found that this subtype had the worst prognosis in both the HNM and BM populations. Notably, nodular melanoma on the head and neck showed markedly worse 5-year CSS and OS rates. SSM is thought to be a tumor with a better prognosis[36]. Additionally, SSM on the head and neck had a much poorer prognosis than SSM on other sites.
Previous studies[9, 14, 15, 37] reported that thicker tumors (more than 2.0 mm) were more common on the head and neck, and this result is consistent with the findings of our study. The capillary vessels and lymphatic drainage systems in these areas are rich and complex, and these specialties may facilitate the growth of tumors. In addition, more ulcerations, distant stages and metastases were found in patients with HNM, which may also be related to the complex drainage systems of the head and neck. Thickness has been identified as a prognostic factor of melanoma, and increasing thickness implies worse prognosis[15]; these results were in agreement with those of our study. As thin malignant melanomas account for a high number of melanoma fatalities owing to their large proportion[23], we divided thin melanomas (<=1.0 mm) into two subgroups: <0.6 mm and 0.6-1.0 mm. We observed that when compared with the <0.6 mm group, the latter subgroup did not show a significant impact on the 5-year survival of patients with BM but decreased the survival rate of HNM patients.
Ulceration, lymph node stage and metastasis have been identified as significant independent factors of cutaneous melanoma in previous studies and were also identified in our study[26, 27]. Notably, when presenting distant metastasis, compared to HNM patients, BM patients had worse 5-year CSS and OS rates.
Furthermore, we compared the treatment differences between patients with HNM and patients with BM. The percentage of HNM patients who underwent surgery was slightly lower, while their radiation rate was higher than that of BM patients. We did not find differences in the proportion of patients who received chemotherapy in these two groups.
Multivariate Cox proportional hazards analysis resulted in a model of HNM with age, sex, histology, thickness, ulceration, lymph node stage, metastases and surgery as independent prognostic variables. The same factors contributed to the model of BM. Furthermore, for convenient utilization of the models in clinical practice, we developed two nomograms to estimate the individual CSS and OS of patients with HNM, and we constructed another two nomograms for patients with BM.
The nomogram of HNM showed excellent predictive and discriminatory power in predicting CSS, with a C-index of 0.839 (95% confidence interval (CI), 0.834-0.844) in the training cohort and 0.848 (95% CI, 0.840-0.856) in the validation cohort. Similarly, the CSS nomogram for BM had high C-indexes of 0.895 (95% CI, 0.892-0.898) in the training cohort and 0.888 (95% CI, 0.884-0.892) in the validation cohort. The range of AUC values for the CSS nomograms was 0.854-0.924, indicating that our models had great discriminatory ability. In addition, the calibration curves in our study indicated satisfactory consistency between the actual observations and the predicted values. The OS nomograms for HNM and BM also showed good performance for prognosis prediction.
This study has the following limitations that need to be acknowledged. First, we grouped melanoma on the head and neck together as HNM for analysis and did not investigate specific anatomic subsites in this region individually. A similar problem existed in the BM analysis. Previous studies suggested that some precise areas had worse cutaneous melanoma-specific prognoses, such as the scalp and breast[3, 5]. Second, our patients were limited to the SEER program. Although the database covers approximately 28% of the US population from 18 registries, the results of our study might not be generalizable to other regional groups, and future studies are needed to externally validate the proposed nomograms. Third, we could not obtain precise data on radiotherapy and chemotherapy from the SEER database, as patients only had “Yes” or “None/Unknown” labels for these variables; thus, only surgery was included in the survival analysis. Finally, as a retrospective study, it is susceptible to some inherent biases.