Patterns of recurrence and implications for follow-up in human papillomavirus-associated versus human papillomavirus-independent vulvar squamous cell carcinoma
To inform follow-up protocols, we investigated differences in incidence, number, and timing of recurrence by site between human papillomavirus (HPV)-Independent and HPV-associated vulvar squamous cell carcinoma. A retrospective clinicopathological single-institution cohort study was conducted of 471 patients with vulvar squamous cell carcinoma between 1990 and 2020. Tumors were classified as HPV-independent or HPV-associated, and the number, site, and time to recurrence were compared. Kaplan-Meier curves were developed for recurrence-free survival by stage, disease-specific survival by recurrence site, and cumulative incidence of recurrence for each tumor type. A total of 471 consecutive vulvar squamous cell carcinomas were identified during the study period; 251 HPV-independent and 208 HPV-associated, with 12 tumors unable to be classified. The median follow-up time was 41 months (range; 0-326). The median time to first recurrence was 22 months for HPV-independent and 43.5 months for HPV-associated (p = .014). In all-stage cancers, any type of recurrence occurred in 38.2% HPV-independent and 8.7% HPV-associated cases (p < .001). The cumulative recurrence rate (any site) for HPV-independent tumors at 5 years was 44% (95% confidence interval [CI] 37% to 52%) and 7% (95% CI 4% to 13%) for HPV-associated tumors. Local recurrence occurred in 29.5% of HPV-independent and 7.7% HPV-associated cases (p < .001), groin recurrence in 14.3% of HPV-independent and 1.4% of HPV-associated cases (p < .001), and distant recurrence in 8.4% of HPV-independent and 2.4% of HPV-associated cases (p = .006). HPV- independent tumors had a significantly higher number of multiple recurrences (18.7% vs 1.9%, p < .001). Following a first local recurrence, disease-specific survival was 86% (95% CI 33% to 98%) at both 3 and 5 years for HPV-associated tumors, compared with 61% (95% CI 47% to 73%) at 3 years and 48% (95% CI 33% to 62%) at 5 years for HPV-independent tumors. HPV-independent tumors have a 4.4-fold increased risk of any type of recurrence, with the first recurrence occurring 21 months earlier and with ongoing lifelong risk. Surveillance could be tailored by HPV status, extended for HPV-independent and reduced or patient-initiated for HPV-associated tumors.