Review ArticleThe prognostic value of p16 and p53 expression for survival after vulvar cancer: A systematic review and meta-analysis
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.
References (49)
- et al.
In situ and invasive squamous cell carcinoma of the vulva in Denmark 1978–2007-a nationwide population-based study
Gynecol. Oncol.
(2011) - et al.
Vulvar squamous cell carcinoma and papillomaviruses: indications for two different etiologies
Gynecol. Oncol.
(1994) - et al.
Differentiated vulvar intraepithelial neoplasia is often found in lesions, previously diagnosed as lichen sclerosus, which have progressed to vulvar squamous cell carcinoma
Mod. Pathol.
(2011) - et al.
The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Cell
(1990) - et al.
p16INK4a and p21Waf1/Cip1 expression correlates with clinical outcome in vulvar carcinomas
Gynecol. Oncol.
(2004) - et al.
Does human papillomavirus infection imply a different prognosis in vulvar squamous cell carcinoma?
Gynecol. Oncol.
(2011) - et al.
Prognostic importance of human papillomavirus (HPV) and p16 positivity in squamous cell carcinoma of the vulva treated with radiotherapy
Gynecol. Oncol.
(2016) - et al.
The prognostic significance of human papilloma virus and P16 in patients with vulvar squamous cell carcinoma treated with radiation therapy
Int. J. Radiat. Oncol. Biol. Phys.
(2012) - et al.
p53 protein expression in a population-based series of primary vulval squamous cell carcinoma and immediate adjacent field change
Gynecol. Oncol.
(1997) - et al.
Squamous cell carcinoma of the vulva in Brazil: prognostic importance of host and viral variables
Gynecol. Oncol.
(1999)
Worldwide burden of cancer attributable to HPV by site, country and HPV type
Int. J. Cancer
Cancer statistics, 2016
CA Cancer J. Clin.
Carcinoma of the vulva: epidemiology and pathogenesis
Obstet. Gynecol.
Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways
Int. J. Gynecol. Pathol.
Two distinct pathways to development of squamous cell carcinoma of the vulva
J. Skin Cancer
Recent advances in the pathology of the vulva
Histopathology
Does HPV status influence survival after vulvar cancer?
Int. J. Cancer
p16 and p53 protein expression as prognostic indicators of survival and disease recurrence from head and neck cancer
Clin. Cancer Res.
Prognostic significance of HPV and p16 status in men diagnosed with penile cancer: a systematic review and meta-analysis
Cancer Epidemiol. Biomark. Prev.
Etiological involvement of oncogenic human papillomavirus in tonsillar squamous cell carcinomas lacking retinoblastoma cell cycle control
Cancer Res.
Association of human papillomavirus types 16 and 18 E6 proteins with p53
Science (New York, N.Y.)
Carcinoma of the vulva: HPV and p53 mutations
Oncogene
Human papillomavirus, p16 and p53 expression associated with survival of head and neck cancer
Infect. Agents Cancer
Prognostic value of overexpressed p16INK4a in vulvar cancer: a meta-analysis
PLoS One
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2022, Seminars in Diagnostic PathologyCitation Excerpt :This pathogenetic distinction reflects the clinically significant prognostic differences and may also have an impact on therapeutic decision-making. Approximately one-third of vulvar squamous cell carcinomas (SCC) are associated with HPV infection and have a significantly better overall- and disease-specific survival than their HPV-independent counterparts.2,3 The majority of HPV-independent vulvar SCC harbor TP53 mutations while a small proportion of HPV-independent TP53 wild-type tumors have been found to have activating mutations in PIK3CA, HRAS, and NOTCH1.4-6
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2021, American Journal of Obstetrics and GynecologyCitation Excerpt :In preinvasive disease, there is robust evidence of a higher progression rate to VSCC in case of non-HPV-related differentiated vulvar intraepithelial neoplasia (VIN) with p53 overexpression, whereas the usual type VIN lesions show lower progression rates and lesser potential for recurrence.25 In a systematic review from Sand et al,26 p53 expression (n=310) was also associated with a poorer prognosis (hazard ratio [HR], 1.81 for overall survival [OS]) in invasive disease. Unfortunately, there are very few and small studies investigating all markers (p16, HPV, p53) in the same patient cohort to allow for a valuation with regard to distribution and prognostic differences.19,27,28
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Shared first co-authorship/contributed equally to the publication.