HPV-independent Vulvar Squamous Cell Carcinoma is Associated With Significantly Worse Prognosis Compared With HPV-associated Tumors

Abstract

Vulvar squamous cell carcinomas (VSCC) represent the most common carcinoma of the female external genitalia, with increasing incidence. Although high-risk human papillomavirus (HPV) infection has long been implicated in the majority of cervical and anal squamous cell carcinomas, there is uncertainty about its prevalence and prognostic impact in VSCC. In this study, we conducted a retrospective integrated morphologic and multimodal HPV analysis of a cohort of 114 VSCC cases treated at the Princess Margaret Cancer Centre/University Health Network, Toronto, Canada between 2000 and 2010. VSCC histology was reviewed. We analyzed the cohort for HPV using polymerase chain reaction based method, and tissue microarray DNA and RNA in situ hybridization (ISH), and p16 immunohistochemistry. Among the 114 cases (age 70±16 yr), 36.7% of cases were classified as having histomorphology of HPV infection. HPV was detected in 31.9% (polymerase chain reaction), 14.0% (DNA ISH), and 27.3% (RNA ISH) of cases. p16 immunohistochemistry was positive in 37.8% of cases. On univariate analysis, HPV morphology (P=0.009), p16+ (P=0.00013), DNA ISH+ (P=0.021), and RNA ISH+ (P=0.00061) were associated with better 5-yr progression-free survival. DNA ISH+ (P=0.049) was associated with better 5-yr overall survival. On multivariate analysis, HPV morphology (P=0.033), p16+ (P=0.01), and RNA ISH+ (P=0.035) were associated with better 5-yr progression-free survival. In conclusion, a subset of VSCC is associated with HPV, which correlates with better outcome. Relatively inexpensive tests such as histomorphologic evaluation, p16 immunohistochemistry, and HPV RNA ISH can be used to predict outcome in VSCC. Therefore, routine reporting of HPV status in VSCC is recommended.

Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence

“…This implies that E7-positive tumors should respond better to radiation therapy, as hypoxia is expected to be less radioprotective in such tumors. This hypothesis is supported by several recent meta-analysis reports from different tumor sites that indicate better survival outcome for patients with HPV-related tumors [ 77 , 78 , 79 ]. Interestingly, while there are no differences in hypoxia extent and distribution between HPV-positive and HPV-negative head and neck tumors, evaluated with F-Miso and 15-gene hypoxia classifier, hypoxic treatment modification with nimorazole have been shown to be less effective and proved to be an unnecessary treatment option for HPV-positive tumor patients [ 80 ].…”

Vulval squamous cell carcinoma and its precursors

“…It has emerged that HPV-associated VSCC has a more favourable prognosis than HPV-independent VSCC in most 10,11,14,[21][22][23][24] but not all studies. 9,25,26 It would not be surprising for HPV-associated VSCC to be associated with better outcomes, given that a similar relationship between HPV status and outcomes has been observed for squamous cell carcinomas of the head and neck.…”

Major p53 immunohistochemical patterns in in situ and invasive squamous cell carcinomas of the vulva and correlation with TP53 mutation status

“…Recent large-scale studies have shown that HPVindependent VSCC is associated with worse clinical outcomes compared with HPV-associated VSCC [8][9][10][11][12]. The prognostic value of p53, a key tumor suppressor, on the other hand, has not been agreed upon.…”