Lorena Marimon

Human papillomavirus and p53 status define three types of vulvar squamous cell carcinomas with distinct clinical, pathological, and prognostic features

IntroductionBased on their etiological relationship with human papillomavirus (HPV), the 2020 WHO classification has divided vulvar squamous cell carcinomas (VSCC) into two distinct types, HPV‐associated and HPV‐independent, and HPV‐independent tumours have recently been divided according to p53 status. Nevertheless, the clinical and prognostic significance of this classification has not been clearly established. We analysed the differential clinical, pathological, and behavioural characteristics of these three types of VSCC in a large series of patients.Methods and resultsVSCC samples from patients who underwent primary surgery at the Hospital Clinic of Barcelona, Spain, during a 47‐year period (January 1975 to January 2022) were analysed (n = 190). HPV detection, p16, and p53 immunohistochemical staining were evaluated. We also analysed recurrence‐free survival (RFS) and disease‐specific survival (DSS). Thirty‐three tumours (17.4%) were HPV‐associated and 157 (82.6%) HPV‐independent. Of these, 20 showed normal and 137 abnormal p53 expression. The two types of HPV‐independent tumours showed worse RFS in the multivariate analysis (hazard ratio [HR] = 3.63; P = 0.023 for the HPV‐independent p53 normal VSCC and HR = 2.78; P = 0.028 for the HPV‐independent p53 abnormal VSCC). Although the differences were not significant, HPV‐independent VSCC had worse DSS than HPV‐associated VSCC. Although patients with HPV‐independent p53 normal tumours had worse RFS than patients with HPV‐independent p53 abnormal tumours, the DSS was better for the former group. Only advanced FIGO stage was associated with worse DSS in multivariate analysis (HR = 2.83; P = 0.010).ConclusionThe association of HPV and p53 status have prognostic implications, reinforcing a three‐tier molecular classification of VSCC (HPV‐associated VSCC, HPV‐independent VSCC with normal p53, HPV‐independent VSCC with abnormal p53).

Vulvar squamous cell carcinoma arising on human papillomavirus‐independent precursors mimicking high‐grade squamous intra‐epithelial lesion: a distinct and highly recurrent subtype of vulvar cancer

AimsEach category of vulvar squamous cell carcinoma (VSCC), human papillomavirus (HPV)‐associated and HPV‐independent, arises on a specific intra‐epithelial precursor: high‐grade squamous intra‐epithelial lesions (HSIL) and differentiated vulvar intra‐epithelial neoplasia (dVIN), respectively. However, a subset of HPV‐independent VSCC arises on an intra‐epithelial precursor closely mimicking HSIL. We aimed to explore the clinicopathological features of the HPV‐independent tumours with HSIL‐like lesions and compare them with HPV‐independent VSCC with dVIN and HPV‐associated tumours with HSIL.Methods and resultsWe retrospectively identified 105 cases of surgically treated VSCC with adjacent intra‐epithelial precursors. The cases were classified into three groups based on the HPV status and the adjacent precursor identified: (i) HPV‐associated VSCC with HSIL (n = 26), (ii) HPV‐independent VSCC with dVIN lesions (n = 54) and (iii) HPV‐independent VSCC with HSIL‐like lesions (n = 25). We analysed the histological and clinical features including the recurrence‐free survival and disease‐specific survival in the three groups. Patients with HPV‐independent VSCC with HSIL‐like lesions and with dVIN were older than patients with HPV‐associated VSCC (76 and 77 versus 66 years, respectively, P < 0.001). HPV‐independent VSCC with HSIL‐like lesions recurred more frequently [hazard ratio (HR) = 3.87; P < 0.001] than HPV‐independent VSCC with dVIN (HR = 2.27; P = 0.1) and HPV‐associated VSCC (HR = 1). In the multivariate analysis, HPV‐independent VSCC with HSIL‐like lesions remained significant for recurrence. No differences in disease‐specific survival were observed between the three groups.ConclusionsEven though VSCC with HSIL‐like lesions are not associated with higher mortality, they are more likely to recur and might benefit from more intensive treatment strategies and closer surveillance after treatment.

Molecular Landscape of Vulvar Squamous Cell Carcinoma

Vulvar squamous cell carcinoma (VSCC) is a rare malignancy with dual pathogenesis, Human papillomavirus (HPV)-associated and HPV-independent, with a poorly explored molecular landscape. We aimed to summarize the findings of the series analyzing molecular hallmarks of this neoplasm. In January 2021, we conducted a comprehensive literature search using Pubmed Medline and Scopus to identify publications focused on genomic profiling of VSCC. Observational studies, including both prospective and retrospective designs, evaluating molecular alterations in VSCC were deemed eligible. A total of 14 studies analyzing 749 VSCC were identified. The study series were heterogeneous in HPV testing and sequencing strategies, included small sets of tumors and cancer genes, and commonly lacked survival analysis. Only one extensive targeted next-generation sequencing-based study comprised a large cohort of 280 VSCC. The mutated genes, their number, and frequencies were highly variable between the series. Overall, TP53 and CDKN2A, followed by PIK3CA, HRAS, and PTEN, were the most frequently studied and mutated genes. Mutations involved in the PI3K/AKT/mTOR pathway, including TP53, HRAS, KRAS, and PIK3CA, have been consistently reported across the studies. However, the role of individual mutations or pathways in the development of VSCC remains unclear. In conclusion, heterogeneity and the small sample size of available molecular series contribute to a limited view of the molecular landscape of VSCC. Large-scale genome- or exome-wide studies with robust HPV testing are necessary to improve the molecular characterization of VSCC.