HPV-independent Differentiated Vulvar Intraepithelial Neoplasia (dVIN) is Associated With an Aggressive Clinical Course

Abstract

Differentiated vulvar intrapeithelial neoplasia (dVIN) is an human papillomavirus (HPV)-independent precursor of squamous cell carcinoma (SCC), and the aim of this study was to better characterize its natural history. Cases of dVIN were identified from the pathology archives. Outcomes of patients with dVIN only, without associated invasive SCC, were compared with a cohort of patients with high-grade squamous intraepithelial lesion [HSIL(VIN3)]. Eighteen patients diagnosed with dVIN with adjacent invasive SCC (SCC/dVIN) and 7 patients with dVIN only, without invasive carcinoma, were identified. Mean age in both cohorts was 75 yr. All lesions but 1 were unifocal. In 35% of SCC/dVIN cases the surgical resection margins were positive for SCC, with 75% and 60% having margins positive for dVIN in the SCC/dVIN and dVIN-only cohorts, respectively. In total, 23/25 women with dVIN only or dVIN/SCC, for whom there was follow-up information, experienced either progression to or recurrence of invasive SCC, respectively, at a median of 1.1 yr, including all but 1 case of dVIN only, where the median time of progression to invasive SCC was 1.9 yr. A total of 22/25 women died of disease with a median overall survival of 3.4 yr. The outcome (i.e. progression to invasive carcinoma) of patients with dVIN only was significantly worse than that of a comparison group of 18 patients with HSIL(VIN3) (progression-free survival log-rank, P<0.001; disease-specific survival, P=0.04; overall survival, P=0.01). Six of 7 patients with dVIN only developed invasive carcinoma on follow-up, compared with 0 of 18 patients with HSIL(VIN3). The diagnosis of dVIN indicates the presence of a high-risk human papillomavirus-negative precursor of invasive SCC. These patients are likely to progress to invasive carcinoma over a relatively short period, at which point their prognosis is guarded.

Does HPV status influence survival after vulvar cancer?

“…Additionally, some studies have shown that HPV-negative vulvar intraepithelial neoplasia (VIN) has a more aggressive clinical presentation with higher progression rate compared to HPV-positive VIN. 4,45,51,52 These findings could indicate that HPV-positive vulvar neoplasia in general develops through a less aggressive pathway and has a more favorable prognosis in all stages of carcinogenesis.…”

“…However, results from studies evaluating the radiosensitivity of HPV‐positive vulvar SCCs compared to HPV‐negative are conflicting and thus, we have not yet a full understanding of the molecular basis of a possibly higher radiosensitivity in HPV‐positive vulvar cancers. Additionally, some studies have shown that HPV‐negative vulvar intraepithelial neoplasia (VIN) has a more aggressive clinical presentation with higher progression rate compared to HPV‐positive VIN . These findings could indicate that HPV‐positive vulvar neoplasia in general develops through a less aggressive pathway and has a more favorable prognosis in all stages of carcinogenesis.…”

Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-analysis

“…It has been suggested that the presence of viral infection in HPV-associated cancers might confer an increased immune surveillance, which consequently makes the HPV-positive cancers less aggressive compared with those without viral epitopes (28). Studies have suggested that HPV-negative vulvar precancerous lesions have a more aggressive clinical presentation and higher progression rate compared with HPV-positive lesions (44,45), indicating that HPV-related precancerous lesions generally develop through a less aggressive pathway and have a more favorable prognosis in all stages of the carcinogenesis. Furthermore, for head and neck cancers it has been suggested that HPV-positive cancers could have a lower degree of gross genetic alterations or that the HPV status of the tumor might determine the molecular profile of the cancer, which could potentially influence the response to therapy (15,46,47).…”

Molecular heterogeneity in human papillomavirus‐dependent and ‐independent vulvar carcinogenesis

“…Studies have shown that, in contrast to the majority of VSCC being HPV‐negative, the majority of high‐grade VIN is HPV‐positive . Different factors might explain this paradoxical situation: (1) compared to HPV‐positive VIN, HPV‐negative VIN is both clinically and histopathologically less likely to be identified, and (2) HPV‐negative VIN appears to have a higher cancer progression risk of at least 30%‐35% with a shorter time interval between the precancerous VIN phase and invasive cancer . For HPV‐positive VIN, the cancer progression risk has been estimated between 3% and 9% in treated patients and about 16% in untreated patients …”