Elsevier

Gynecologic Oncology

Volume 152, Issue 1, January 2019, Pages 208-217
Gynecologic Oncology

Review Article
The prognostic value of p16 and p53 expression for survival after vulvar cancer: A systematic review and meta-analysis

https://doi.org/10.1016/j.ygyno.2018.10.015Get rights and content

Highlights

  • Women with p16 positive vulvar cancers had better survival compared to p16 negative.

  • p53 positive vulvar cancers had a less favorable survival compared to p53 negative.

  • p16 and p53 may be clinically useful prognostic markers for vulvar cancer patients.

Abstract

The tumor suppressor proteins p16 and p53 have been suggested to have prognostic value in some human papillomavirus (HPV)-associated cancers, however, this has been less well established for vulvar cancer. The aim of this review and meta-analysis was to examine the prognostic value of p16 and p53 expression status on survival after vulvar squamous cell carcinoma (VSCC). We conducted a thorough systematic literature search of multiple databases to identify studies examining survival after histolocally verified VSCC that were tested for p16 and/or p53. A total of 18 eligible studies were included. Using a fixed-effects model we calculated study-specific and pooled hazard ratios (HRs) of 5-year overall survival (OS). In the analyses of OS, we included 475 VSCC cases tested for p16 expression of which 38% were p16 positive. The pooled HRp16 was 0.40 (95% CI: 0.29–0.55). In addition, the majority of results from studies with adjusted analyses on the prognostic value of p16 indicated that p16 expression status could be an independent prognostic marker for OS in women diagnosed with VSCC, and the same pattern was seen for disease specific survival (DSS). We also included 310 VSCC cases tested for p53 expression of which 54% were p53 positive. The pooled HRp53 was 1.81 (95% CI: 1.22–2.68) indicating that p53 positive VSCC have a significantly lower 5-year OS compared to p53 negative. The results in relation to p53 reported from adjusted analyses OS and on DSS and disease free survival were more equivocal. This meta-analysis and review suggests that p53 and especially p16 expression status are of prognostic importance in women diagnosed with VSCC. This may be clinically important in the future design of targeted therapy and when planning the optimal follow-up strategy. Future studies should include the combined use of biomarkers such as p16, p53 and HPV status.

Introduction

Vulvar cancer accounts for approximately 5% of gynecological cancers and in 2012, 34,000 women were diagnosed with vulvar cancer worldwide [1,2]. In recent years, the incidence of vulvar cancer has increased, especially among younger women [3]. Squamous cell carcinoma (SCC) is the most common histological type of vulvar cancer, and represents 80%–90% of the cases [4]. Vulvar squamous cell carcinoma (VSCC) develop through two distinct pathways [5,6], of which one is associated with human papillomavirus (HPV), has basaloid and warty morphology and occurs in younger women. The other type is non-HPV related, and occurs more frequently in older women and is often associated with lichen sclerosis [[7], [8], [9]].

In a recent meta-analysis we found that HPV positive vulvar cancers have a significantly more favorable survival compared to HPV negative [10]. In HPV-associated cancers, the tumor suppressor proteins p16 and p53 have also been suggested to be possible prognostic markers [11,12]. Integration of high-risk HPV DNA into host genome causes overexpression of E6 and E7 oncoproteins. E7 binds to hypo-phosphorylated retinoblastoma protein (pRb), which affects the cell cycle control and consequently leads to upregulation of the tumor suppressor protein p16 [13]. The oncoprotein E6 promotes rapid degradation of p53 protein [14,15]. In addition, mutation of the p53 gene can result in dysfunctional p53 protein expression, which is often seen in HPV negative vulvar cancers [16]. Immunohistochemical (IHC) detection of p53 expression represents the presence of dysfunctional p53 protein, as normal p53 protein has a very short half-life and consequently often is undetectable by IHC. The prognostic significance of p16 is relatively well established in some HPV-related cancers e.g. head and neck cancer and penile cancer [11,12,17], however, for vulvar cancer this is less well established. Furthermore, p53 has been shown to be a possible prognostic marker in head and neck cancer [11,17], but it is uncertain whether the same applies to vulvar cancer.

In a previous meta-analysis, including three studies based on 143 vulvar cancer cases, Cao et al. [18] found that overexpression of p16 was correlated with a superior survival (combining two studies of overall survival (OS) and one study of disease specific survival (DSS)). We have conducted a thorough review of all existing literature on multiple survival outcomes (OS, DSS, and disease free survival (DFS)) after VSCC according to p16 expression status and made an updated meta-analysis, including four new studies of overall survival and more than three times more cases compared to the previous meta-analysis. In addition, we conducted, to our knowledge, the first systematic review and meta-analysis on the prognostic significance of p53 in women diagnosed with VSCC.

Section snippets

Search strategy

We conducted a systematic literature search of the databases PubMed, Embase and Cochrane covering the period up to April 4, 2018. We used a combination of search terms for vulvar cancer, survival, p16 and p53. Medical subject headings and Emtree headings as well as text and keywords were applied in the search. Publications were eligible for inclusion if they were published in English language, included more than five samples and if survival outcomes after histologically verified VSCC in

Search results

We identified 209 records in PubMed, Embase and Cochrane Library (Fig. 1). After removal of duplicates, 153 records were screened for potential relevance, of which 61 records were excluded after review of title, and 29 were excluded after evaluation of abstract. Of the remaining 63 records, we excluded 45 after full text review. The reasons for excluding records based on abstract and full text are specified in Fig. 1. A total of 18 studies were included in the review and meta-analysis. Two

Discussion

In the present review and meta-analysis of the association between different measures of survival and p16 expression status, we found that women with p16 positive VSCC had a significantly better OS compared to women with p16 negative VSCC. The majority of the studies on OS performed analyses with adjustment for other prognostic factors, supporting that p16 expression status could be an independent prognostic marker for OS in women diagnosed with VSCC. The same pattern was observed when the

Conflict of interest statement

SKK has received lecture fees from Sanofi Pasteur MSD and Merck, scientific advisory board fee from Merck, and research grants through her institution from Merck.

FLS has received support for conference participation and speakers' fees from Becton Dickinson Diagnostics GmbH.

Author contribution section

SKK designed the study. DMBN and FLS performed the literature search and reviewed titles, abstracts and full-text articles. DMBN, FLS, CLR and SKK designed the data extraction. DMBN and FLS extracted the data. MHF performed the statistical analyses. DMBN, FLS, and SKK drafted the manuscript and CLR, and MHF critically revised subsequent drafts.

Financial support

No specific funding was obtained for this study.

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