We hypothesized that contemporary non-SCC penile cancer patients may differ from historical cases that were heavily weighted towards Kaposi’s sarcomas. Moreover, we tested for CSM differences between non-SCC and SCC penile cancer patients and made several important observations.
First, we recorded important baseline characteristic differences in non-SCC vs. SCC penile cancer patients. Specifically, we noted a median age at diagnosis of 68 years, highest prevalence in Caucasians (75%), and most diagnoses occurring at a localized stage (65%). These observations are particularly different from the population-based report by Bhambhvani et al., relying on the SEER database 1975–2016, in which over 42% of patients were diagnosed prior to year 2000 and without excluding non-invasive and precursor lesions . For example, in this more historical report, mean age of non-SCC patients was 61 years. Moreover, proportions of Caucasians were higher and rates of localized disease in non-SCC were lower.
Second, we made important observations regarding non-SCC penile cancer histologies. The most frequent non-SCC histology were melanomas (41%), followed by basal cell carcinomas (34%). This observation differed from historical observations that were heavily weighted towards Kaposi’s sarcomas. It is also of note that within non-SCC cohort, patient characteristics strongly differed between histological subtypes. Specifically, age of adenocarcinoma patients was 66 years vs. 83 years of neuroendocrine patients. Moreover, respectively 40 and 30% of adenocarcinoma non-SCC patients were Hispanic and African Americans. Conversely, all neuroendocrine non-SCC patients were Caucasian. To the best of our knowledge, we are the first to report on non-SCC characteristics within individual histological subtypes. In consequence, our data cannot be directly compared to previous publications. However, in the population-based report by Bhambhvani et al. most non-SCC patients harbored Kaposi’s sarcomas, followed by melanomas and basal cell carcinomas . Within the current analyses, we exclusively focused on most contemporary patients (2004–2016) with non-SCC and excluded non-invasive and precursor lesions. Interestingly, no Kaposi’s sarcoma patients were identified. This observation is important and validates the SEER database in the context of its accuracy even in very rare diagnosis.
Second, we also made important observations regarding CSM stage-specific comparisons between non-SCC vs. SCC patients. Specially, we identified no significant differences in CSM between non-SCC vs. SCC penile cancers across all penile cancer stages. This was further validated in propensity score matched and multivariate competing risks regression analyses. However, non-SCC penile cancers are a heterogeneous group of variant histologies. In consequence, it is possible that specific non-SCC penile cancer histologies may exhibit more or less favorable outcomes relative to SCC penile cancer patients. For example, penile melanoma and genitourinary sarcoma are known to be very aggressive cancers and exhibit poor prognosis and have high disease recurrence, even after surgery [16–19, 24–26]. In our study, we reported a five-year CSM of 31.2% in penile melanoma (n = 51). However, due to small sample size, comparisons between individual variant non-SCC penile cancers histologies, such as penile melanoma and sarcoma (n = 2), could not be directly compared to SCC. In the population-based report by Bhambhvani et al., melanoma non-SCC patients diagnosed between 1975 and 2016 displayed a CSM disadvantage relative to SCC patients. The disadvantage persisted even in the most recent subgroup of patients diagnosed between 2000 and 2016 . Conversely, relying on the same methodology, no CSM differences were recorded between basal cell carcinoma vs. SCC penile cancer patients diagnosed between 2000–2016. These observations indicate specific patterns within different variant histologies in non-SCC patients. However, our data suggest that on average and as a whole, non-SCC patients display similar CSM as SCC patients.
Third, we observed that the temporal trends of non-SCC penile cancer did not change over time between 2004 and 2016. Conversely, rates of SCC penile cancer increased with an EAPC of + 3.5% per year between 2004 and 2016. This trend is contrary to the more historically reported negative trend in overall age-adjusted SCC incidence rates between 1973–2002 in the United States, where Barnholtz-Sloan et al. relied on the SEER database . In comparison, there has been increased incidence in Denmark, the United Kingdom, Germany, and Norway [6, 7, 27, 28]. For example, in Germany, Schoffer et al. noted an age-standardized incidence rate of penile cancer of 1.2 per 100,000 in 1961 compared to 1.8 per 100,000 in 2012, with a corresponding increase in EAPC of + 4.6% (CI: 0.62–8.86) between 2003–2012. Similarly, in Norway, Hansen noted an increased EAPC of + 0.8% (CI: 0.46–1.15) between 1956–2015. Given that penile cancer incidence increases with age, this tendency may partly be explained by increasing life-expectancy of the populations in these countries [1, 2].
Taken together, our study demonstrated that non-SCC and SCC penile cancer patients have similar population characteristics in terms of age at diagnosis and disease stage. Furthermore, we observed no differences in five-year CSM between non-SCC vs. SCC penile cancer across localized, locally advanced, and metastatic stages. However, non-SCC penile cancer represents a heterogenous group of variant histologies. In consequence, individual histologies may have relatively more or less favorable CSM compared to SCC. Finally, we observed no increase in non-SCC penile cancer rates over time, but an increase in temporal trends of SCC penile cancer.
Our work has limitations and must be interpreted in the context of its retrospective and population-based design. Second, sample sizes of variant histologies of penile cancer were small and made it impossible to perform matched and multivariate CSM comparisons according to individual variant histologies. Because of these small sample sizes, we grouped patients within variant histologies. As a result, it is possible that some of these individual histologies may have more favorable survival than others or vice versa. In consequence, specific conclusions regarding comparisons of CSM between individual histologies cannot be made. Finally, we were unable to adjust for tumor grade, despite it being recognized as a significant prognostic factor, as there is no established standardized grading for variant histologies .