penile squamous cell carcinoma and human papillomavirus
The objective of this study was to to investigate the survival outcomes and prognostic factors of human papillomavirus (HPV) induced penile squamous cell carcinoma (pSCC).
Penile squamous cell carcinoma (pSCC) is a rare malignancy with limited pathogenesis and carcinogenesis, and poor survival after standard treatment. They are common in South American and African countries (the high-incidence countries), and rare in North American and European countries (low-incidence countries). Penile tumors account for less than 1% of all malignancies in men in the United States, with approximately 2,100 new cases and about 400 deaths annually.
Penile cancer has a multifactorial etiology, with HPV infection being one of the most important factors involved in its appearance. Despite the advances in understanding the tumor microenvironment, the exact mechanism of its pathogenesis has not been fully elucidated.
There have been no large studies in the United States evaluating prognostic differences in pSCC patients based on HPV. The aim of this study was to evaluate the survival outcomes and prognostic factors of pSCC based on HPV using the National Cancer Database (NCDB) registry.
Material and Methods
This retrospective review was carried out on a total of 1224 patients with known HPV staining from the National Cancer Database between 2010 and 2015. The exclusion criteria were cases with cM1 disease, missing follow-up or vital status, or treated with palliative intent. Patients who did not receive treatment were also excluded from the analysis.
The covariates analyzed were treatment year, age, race, ethnicity, Charlson- Deyo performance score, insurance status, treating facility type, hospital geographic region, and median income and education status by patient zip code. Clinical and pathologic staging data such as tumor stage, differentiation, type of primary site surgery, surgical margin status, receipt of regional lymph node (LN) surgery, and presence of extranodal extension (ENE) or lymphovascular invasion (LVI) were also considered in this study.
Overall survival (os) was determined by measuring the time in months between the initial diagnosis and the last follow-up or death.
- After exclusion criteria, 825 patients were enrolled in the study. Of these, 321 (38.9%) were HPV-positive. The median age of patients was 64 years [interquartile range (IQR: 53 -74)]. The median follow-up time was 29.9 months (IQR = 14.8 – 48.5). All HPV-positive patients were younger. The majority of them came from rural areas with lower median household incomes and had no high school degree.
- HPV positivity decreased non-significantly from 47.1% in 2010 to 37.4% in 2015. Patients with HPV + tumors presented with lower clinical T-stage (cT), poorer differentiation, and were less likely to demonstrate LVI. They were also presented with palpable adenopathy, but not statistically significant.
- Patients with HPV + tumors presented with lower American Joint Committee on Cancer clinical T- stage (cT), poorer differentiation, lower rates of lymphovascular invasion (LVI), but more node-positive disease (cN+).
- About 16% underwent regional lymph node dissection (LND). However, there were no differences in the median of LNs examined for HPV-negative vs HPV-positive patients (17 vs 16.5).
- Tumor differentiation, LVI, and performance score were independent predictors for aggressive disease.
- HPV status was not a predictor of overall survival (OS) (IPTW- HR:0.89, 95% CI, p = 0.13).
Penile cancers are mostly squamous cell carcinomas (70 – 90%). Many have demonstrated a direct relationship between HPV infection and penile SCC but very few have analyzed the impact of HPV on survival. The results of this study showed that HPV infection was neither associated with locally aggressive cancers nor with detrimental survival outcomes. There was no significant change in the HPV positivity rate over time.
In the current study, most of the HPV-positive patients presented with lower cT stage and LVI but, paradoxically, were also reported to have poorer differentiation and more palpable adenopathy. The authors also reported etiologic implications but no significant prognostic outcome.
High-risk HPV is well established as the primary cause of penile, cervical, head, neck, and vulvar cancers. The molecular pathogenesis of HPV-positive penile cancer is similar to that of cervical cancer. Mucosal HPV infection induces the binding of oncogenes E6 and E7 to tumor suppressors p53 and Rb, respectively, thereby interfering with programmed cell death. The tumor suppressor function, however, can be restored by radiation or chemotherapy.
The etiology of HPV-negative tumors is unclear, but TP53 mutations have been implicated. These tumors arise from precursor PeIN lesions and are often associated with the inflammatory skin diseases lichen sclerosus and lichen planus. Overexpression of the cyclin-dependent kinase inhibitor 16INK4A is considered an indirect marker for a transcriptionally active HPV-high-risk infection. HPV-negative penile SCC lacks p16ink4a overexpression but shows nuclear p53 expression in proliferating tumor cells.
Thus, it is apparent that HPV-positive and HPV-negative tumors arise from different molecular pathways, and a mutation leads to disruption of associated tumor-suppressing pathways.
The extent of lymph node metastases is the most important predictor of pSCC survival. Current treatment for penile squamous cell carcinomas is surgical, followed by adjuvant chemo- and/or radiation therapy. Primary chemoradiation is preferred in large inoperable squamous cell carcinomas. In this study, the authors found no significant difference in pN stage, rate of clinical upstaging, or extranodal extension in the 15 patients receiving LND.
The main limitation of this study is the selection bias due to referral patterns. For example, the database neither explains how pSCC patients received regional LND and/or surgery, nor does it detail reasons for specific therapies, recurrence outcomes, or salvage treatments. Next, the lack of a central pathological review due to the retrospective nature of the study.
A better understanding of the HPV-related carcinogenesis holds the potential for developing future prognostic markers, targeted treatment, or prevention programs.
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