There are two known pathways for tumorigenesis of vulvar squamous cell carcinoma (VSCC) – a human papillomavirus (HPV) dependent pathway characterized by p16 overexpression and an HPV-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of HPV dependency with a favourable prognosis has been proposed.
The objective of the study was to further understand the role of HPV and p53 status in VSCC and characterize its clinical relevance.
The AGO (Arbeitsgemeinschaft Gynecologic Oncology) CaRE-1 study is a retrospective cohort study of 1,618 patients with primary VSCC FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stage ≥1B treated at 29 gynecological cancer centers in Germany between 1998 and 2008. For this translational sub-study formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. HPV status and subtype were analyzed by polymerase chain reaction (PCR).
p16 immunohistochemistry was positive in 166/550 (30.2%) tumors; p53 staining in 187/597 (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); three groups were defined: p53+ (n=163), p16+/p53- (n=132) and p16-/p53- (n=116). HPV-DNA was detected in 85.6% of p16+/p53- tumors; HPV16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs.72 years for p53+ respectively 69 years for p16-/p53- tumors; p<0.0001) and showed lower rates of lymph-node involvement (28.0% vs. 42.3% for p53+ respectively 30.2% for p16-/p53- tumors; p=0.050). 2-year-disease-free (DFS) and overall survival (OS) rates were significantly different between the groups: disease-free survival: p53+ 47.1%; p16-/p53- 60.2% and p16+/p53- 63.9% (p<0.001); overall survival: 70.4%, 75.4% and 82.5% (p=0.002). In multivariate analysis the p16+/p53- phenotype showed a consistently improved prognosis compared to the other groups (HR 0.66; 95%CI 0.44-0.99; p=0.042).
p16 overexpression is associated with an improved prognosis while p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of VSCC with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.

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