The pT2–3 penile cancer is heterogeneous, and a modified staging system that includes lymphovascular embolization may help improve the prognostic accuracy for these men. We evaluated the prognostic value of the 8th AJCC-TNM staging system in a large group of patients with penile cancer from four continents. Although we confirmed the importance of the T status as a prognostic factor, our study also showed the potential for improvement of the AJCC-TNM staging system.
Penile cancer is a relatively uncommon urological malignancy [1, 2, 9, 10, 17]. Primary penile cancer has an overall incidence of < 1.00/100,000 males in developed countries [1, 2]. In contrast, the incidence is much higher in undeveloped areas, such as regions in Africa [1, 9, 10] and Asia [1, 2]. Therefore, references with more than 500 cases are rarely cited by the European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) for TNM staging [1, 2, 9, 19]. Further evaluations with larger sample sizes are needed to validate the current TNM staging system. The results of our study of 847 men are consistent with the results of previous studies that have demonstrated the overall usefulness of the TNM staging system [4, 21]. However, we found room for improvement in survival estimates among subgroups of T2–3 patients.
The most important prognostic indicators of penile cancer are pathological factors [1, 2, 9, 19]. Lymphovascular embolization is defined as either tumor embolization within the endothelium-lined spaces that are bound by a thin wall or the absence of parietal smooth muscle fibers and red blood cells [14, 15]. The presence of lymphovascular embolization is an important prognostic indicator of survival in patients with penile cancer [7, 11, 13]. However, the EAU guidelines only incorporate lymphovascular invasion and classify penile cancer with lymphovascular invasion into the T1 category . In our database, lymphovascular invasion was markedly associated with poor survival.
Distinguishing between the prognoses for T2 patients and T3 patients is difficult [6, 11, 22]. Leijte et al.  evaluated a large cohort of 489 patients in the Netherlands and demonstrated that patients with corpus spongiosum/cavernosum and urethra/prostate involvement exhibited similar survival (P = 0.570). In the study by Graafland et al. , the 5-year CSS rates of patients with pT2 and pT3–4 diseases were 60.0% and 59.0%, respectively. Ravi  noted 3-year CSS rates of 69.9% and 100.0% in patients with T2 and T3 diseases. Furthermore, the estimates of occult metastasis in T2 and T3 patients were similar [6, 11, 15, 23]. The 8th AJCC-TNM staging system for penile cancer redefined the T2 and T3 categories based on the presence or absence of corpus spongiosum and cavernosa invasion [1, 2]. However, we found that the prognoses of patients with T2 and T3 disease classified according to the 8th AJCC-TNM staging system were similar. Therefore, we stratified pT2–3 tumors by the presence of lymphovascular embolization and observed different characteristics between these subgroups in the training and external validation cohorts.
To improve the prognostic prediction, we proposed a modified staging system, which showed improved accuracy in survival prediction and was validated using multicenter data obtained globally. Differences existed between the training and external validation cohorts regarding the number of T3 patients, grade status, and follow-up period. We presume that the differences may be related to races or regions and that data heterogeneity may lead to selection bias [1, 2]. However, this heterogeneity may help confirm that the modified staging system has universal applicability across a heterogeneous population of patients from different regions. Accurate staging with appropriate subgroup classification of the disease is the first step in optimizing treatment and predicting outcomes .
The present study had some limitations. First, the data collection was retrospective and covered a long study period, which required lengthy follow-ups. The histopathological data were reviewed by an independent pathological committee. We acknowledge that the slides could not be reviewed again by a single urological pathologist, which limited the value of the study. Second, some important information was not reported in this study. Our study population was selected in a 16-year period from multiple centers. The lymph node dissection details of both cohorts were not analyzed because of the varying treatment standards during the study period. However, we ensured that the therapeutic principles were in accordance with the EAU and NCCN guidelines for penile cancer. Clinical stage and some pathological factors (e.g., tumor growth and depth, histological subtype, positive surgical margin, and front invasion) of the primary tumor that could influence the survival rates were not included in the study. Our study included a total of 847 patients who were treated at 17 centers from four continents; thus, some pathological factors were collected in a fragmentary manner. To ensure that statistical bias was minimized and to maximum the sample size of lymphovascular invasion cases, we did not perform a detailed analysis of these predictors. Third, our study contained treatment diversity. In particular, adjuvant therapies and the treatment courses varied, and adjuvant therapies and pelvic lymphadenectomy might affect other parameters. Pelvic lymphadenectomy was not routinely performed prior to 2009 because it was not recommended by the guidelines as the standard treatment for penile cancer [16,17,18]. Some patients who should have been treated with adjuvant therapies chose not to receive these regimens for various reasons [3, 4]. Because of this variability, we did not report the prognostic value of adjuvant therapies in this study. However, we believe that this type of analysis will be important in future validation studies with larger data sets. This study can be considered exploratory rather than hypothesis-driven, and thus comparisons between the various models were not explored further. We also deem it necessary to intensively study this modified staging system in the future.