Vulvar cancer subclassification by HPV and p53 status results in three clinically distinct subtypes

• Published in: Gynecologic oncology Vol. 159; no. 3; pp. 649 - 656
• Main Authors: Kortekaas, Kim E., Bastiaannet, Esther, van Doorn, Helena C., de Vos van Steenwijk, Peggy J., Ewing-Graham, Patricia C., Creutzberg, Carien L., Akdeniz, Kadir, Nooij, Linda S., van der Burg, Sjoerd H., Bosse, Tjalling, van Poelgeest, Mariette I.E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2020
• Subjects: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell - diagnosis; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Carcinoma, Squamous Cell - virology; Clinical Decision-Making - methods; Female; Human papillomavirus; Humans; Middle Aged; Molecular classification; Mutation; Neoplasm Recurrence, Local - epidemiology; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - virology; p16; p53; Papillomaviridae - isolation & purification; Papillomavirus Infections - epidemiology; Papillomavirus Infections - virology; Prognosis; Retrospective Studies; Risk Assessment - methods; Risk Factors; TP53; Tumor Suppressor Protein p53 - genetics; Vulva - pathology; Vulva - surgery; Vulva - virology; Vulvar Neoplasms - diagnosis; Vulvar Neoplasms - genetics; Vulvar Neoplasms - mortality; Vulvar Neoplasms - virology; Vulvar squamous cell carcinoma; Vulvectomy; Young Adult; Molecular classification; Human papillomavirus; Prognosis; p16; Vulvar squamous cell carcinoma; TP53; p53
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2020.09.024

There is great need for better risk stratification in vulvar squamous cell carcinoma (VSCC). Our aim was to define the prognostic significance of stratifying VSCC based on p16 and p53 immunohistochemistry (IHC) as surrogate markers for HPV and TP53 mutations.
A large retrospective cohort of surgically treated women with primary VSCC was used. VSCC were classified into three subtypes: HPV-positive (HPVpos), HPV-negative/p53 mutant (HPVneg/p53mut), and HPV-negative/p53 wildtype (HPVneg/p53wt). Overall survival (OS), relative survival (RS), and recurrence-free period (RFP) were depicted using the Kaplan-Meier method and survival curves for relative survival; associations were studied using univariable and multivariable Cox proportional hazard models.
Of the 413 VSCCs, 75 (18%) were HPVpos, 63 (15%) HPVneg/p53wt, and 275 (66%) HPVneg/p53mut VSCC. Patients with HPVneg/p53mut VSCC had worse OS and RS (HR 3.43, 95%CI 1.80–6.53, and relative excess risk (RER) of 4.02; 95%CI 1.48–10.90, respectively, and worse RFP (HR 3.76, 95%CI 2.02–7.00). HPVpos VSCC patients showed most favorable outcomes. In univariate analysis, the molecular subtype of VSCC was a prognostic marker for OS, RS and RFP (p = 0.003, p = 0.009, p < 0.001, respectively) and remained prognostic for RFP even after adjusting for known risk factors (p = 0.0002).
Stratification of VSCC by p16- and p53-IHC has potential to be used routinely in diagnostic pathology. It results in the identification of three clinically distinct subtypes and may be used to guide treatment and follow-up, and in stratifying patients in future clinical trials.
•Management of women with vulvar squamous cell carcinoma (VSCC) presents clinical challenges, impacting quality of life.•Better tools are needed for individual risk assessment and treatment guidance.•Classification of VSCC based on p16- and p53-immunohistochemistry identifies three prognostic distinct subtypes.•HPVpos VSCC have best clinical outcome, and HPVneg/p53 mutant VSCC have highest risk for death and recurrence.