Carolina Manzotti

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.

Differential etiopathogenic features of vulvar squamous cell carcinomas in sub‐Saharan Africa and Europe

AbstractTwo pathways have been described for vulvar squamous cell carcinomas (VSCC), one associated with human papillomavirus (HPV), and the other HPV‐independent. We compared the etiopathogenic features of a series of VSCC from Mozambique, a sub‐Saharan country with high prevalence of HPV and HIV, with those of Spain, a European country with low prevalence of HPV and HIV. All VSCC diagnosed at the two institutions from January 2018 to December 2020 were included (n = 35 and n = 41, respectively). HPV DNA detection and genotyping, and immunohistochemistry for p16 and p53 were performed. Tumors showing p16 positive staining and/or HPV DNA positivity were considered HPV‐associated. 34/35 tumors (97%) from Mozambique and 8/41 (19%) from Spain were HPV‐associated (P < .001). Mean age of the patients from Mozambique and Spain was 45 ± 12 and 72 ± 14, respectively (P < .001). No differences were found in terms of HPV genotypes or multiple HPV infection rates. 1/35 tumors (3%) from Mozambique and 29/41 (70%) from Spain showed abnormal p53 immunostaining (P < .001). In contrast with the predominance of HPV‐independent VSCC affecting old women in Europe, most VSCC in sub‐Saharan Africa are HPV‐associated and arise in young women. This data may have important consequences for primary prevention of VSCC worldwide.