Annals of Oncology Advance Access originally published online on June 16, 2008
Annals of Oncology 2008 19(10):1681-1690; doi:10.1093/annonc/mdn372
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HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007)
1 Department of Oral Sciences, Section of Oral Medicine, University of Palermo, Palermo, Italy
2 Department of Medical Biotechnologies and Forensic Medicine, University of Palermo, Palermo, Italy
3 Department of Medical Oncology, University of Palermo, Palermo, Italy
4 Department of Surgical Sciences, University of Foggia, Foggia, Italy
* Correspondence to: Prof. G. Campisi, DDS, MS, Department of Oral Sciences, Section of Oral Medicine, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy. Tel/Fax: +39-0916552236; E-mail: campisi{at}odonto.unipa.it
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Introduction: In the literature, there exists a wide range of human papillomavirus (HPV) DNA prevalence for head and neck squamous cell carcinoma (HNSCC), especially in relation to methods of viral detection and the lesion site. We estimated the pooled prevalence of HPV DNA in biopsies of HNSCC generically grouped versus oral squamous cell carcinoma (OSCC) in relation to the method of viral DNA detection, with the primary end point of verifying if these two variables (specification of tumour site and method of HPV DNA identification) influence the datum on HPV assay.
Methods: By means of MEDLINE/PubMED/Ovid databases, we selected studies examining paraffin-embedded (PE) biopsies of HNSCC and OSCC. According to the inclusion criteria, 62 studies were analyzed. The following data were abstracted: sample size, HPV DNA prevalence, methods of detection [PCR and in situ hybridization (ISH)] and HPV genotypes. After testing the heterogeneity of the studies by the Cochran Q test, metanalysis was performed using the random effects model.
Results: The pooled prevalence of HPV DNA in the overall samples (
: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%).
Conclusion: These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future investigations into viral prevalence in head and neck tumors.
Key words: biopsy, head and neck squamous cell carcinoma (HNSCC), human papillomavirus (HPV), meta-analysis, oral squamous cell carcinoma (OSCC)
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introduction |
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Head and neck (HN) cancer represents the fifth most common malignancy worldwide [1], but this term defines a heterogeneous group of malignant neoplasias, involving different subsites with similar risk factors and pathological features. The majority of HN malignancies are squamous cell carcinomas (SCC), originating from the epithelium which lines the upper aerodigestive tract (UADT) (i.e. the oral cavity, the pharynx and the larynx) [2, 3], and they are characterized by a multiphasic and multifactorial etiopathogenesis [4–13]. In recent decades, epidemiological and molecular data have indicated the involvement of high-risk human papillomavirus (HR HPV) genotypes (gt) in a subset of head and neck squamous cell carcinoma (HNSCC) [14]. The participation of HPV in oral and oropharyngeal carcinogenesis was first proposed by Syrjanen et al. [15] and then supported by several other authors [14, 16–20] on the basis of the following evidence: (i) the epitheliotropic nature of HPV [21–23]; (ii) the widely confirmed oncogenic potential of HR gt in the pathogenesis of anogenital neoplastic diseases, especially cervical squamous cell carcinoma [24, 25] and (iii) the morphological similarities between oropharyngeal and genital epithelia [26]. The oncogenic potential of HR HPV is attributable to its ability to insert specific DNA fragments (early genes E5, E6 and E7) into the host cellular genome. As a result of this integration, some key functions of tumor suppressor factors are abrogated (p21, p53 and pRb pathways, respectively), leading to defects in apoptosis, DNA repair mechanisms, cell cycle regulation and, finally, to cellular immortalization [27]. Although HPV genomic sequences have been identified in HNSCC, the wide range of viral prevalence (0%–100%) reported in the literature [28–31] does not contribute to the clarification of the relationships between HPV and HN carcinogenesis. Apart from the ethno-geographical differences among the patient groups examined, this wide range depends mainly on two variables: (i) the sensitivity of the applied diagnostic technique, in terms of specimen type (e.g. biopsy, scrape, brushing, mouth rinse), method of sample storage [e.g. fresh frozen (FF) or formalin fixed paraffin-embedded (PE) biopsy] and HPV detection procedure [e.g. less sensitivity assays: in situ hybridization (ISH), southern blot hybridization (SBH), dot blot hybridization (DBH); high sensitivity assays: PCR] and (ii) the site of lesion (oral cavity; hypo-, oro- and rynopharynx, larynx). In detail, the latter variable seems to play a critical role since various epithelial UADT surfaces (i.e. the squamous–columnar junction at the level of the tonsillar crypts and the glottides) display the greatest susceptibility to HPV [29, 32, 33] due to the exposure of the basal cells. In spite of this evidence, several authors have grouped together HNSCC as a single entity and they have neither specified the origin of tumors from this wide area nor the site-specific HPV prevalence, thereby resulting in a consequent difficulty in comparing their findings. Furthermore, the absence of this distinction in terms of site lesion justifies the current controversy regarding the role of HPV in oral carcinogenesis [29]. Taking into account this variability, we conducted a meta-analysis of studies on HPV DNA prevalence in PE histological samples of HNSCC with the aim of estimating the pooled prevalence of HPV DNA in HNSCC generically grouped HNSCC and oral squamous cell carcinoma (OSCC). A further aim was to verify if the two main variables, i.e. the classification criteria of tumor subsites and the methods of viral DNA detection (ISH and PCR), could influence this assessment.
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study selection and data abstraction
The medical literature from January 1988 to January 2007 was searched for English-language studies detecting HPV DNA in HNSCC and OSCC histological samples by means of Medline/PubMED/Ovid databases. The key words used, alone or in combination, were the following: human papillomavirus (HPV), head and neck squamous cell carcinoma (HNSCC), oral squamous cell carcinoma (OSCC), UADT squamous cell carcinoma, oral cancer, biopsy, paraffin-embedded sample, polymerase chain reaction (PCR) and in situ hybridization (ISH). Reference lists of relevant papers and reviews were examined to identify further articles. The studies were selected according to the following inclusion criteria: (i) sample size
15 cases of HNSCC; (ii) histopathological diagnosis of SCC originating from the oral cavity (OSCC), pharynx (PSCC) and/or larynx (LSCC) (excluding tumors originating from salivary glands, sinusal and nasal epithelia); (iii) type of specimens: PE histological samples (excluded FF biopsies and cytological samples) and (iv) a clear description of HPV DNA detection methods (PCR and ISH). The studies were evaluated critically by two authors (NT and SF) and the following data were abstracted: sample size, geographical location, HPV DNA prevalence, method of detection and gt. Sixty two studies met the above-reported criteria and were included in the meta-analysis.
study design
The prevalence of HPV DNA was determined with respect to the two variables considered: the manner of tumor site categorization (especially in relation to the oral origin) and the method of detection. On the basis of the first criterion, studies were distinguished in two subgroups: ‘not site-specific HNSCC’ and ‘OSCC’. The first subgroup included studies on unspecified SCC from UADT mucosae, including OSCC, PSCC and LSCC; the second subgroup only included those OSCC specimens. According to the detection method, the studies were further divided into two subgroups, named ‘ISH’ and ‘PCR’ on the basis of the molecular procedure used. If some studies reported the use of both assays, the relative findings were evaluated separately. The variable ‘detection method’ was subsequently evaluated for each site subgroup, respectively: ‘not site-specific HNSCC ISH based’ versus ‘not site-specific HNSCC PCR based’ and ‘OSCC ISH based’ versus ‘OSCC PCR based’. Regarding the not site-specific HNSCC subgroup, this analysis was conducted only on not site-specific HNSCC PCR-based studies due to the smallest number of studies using ISH [34, 35]. Finally, it was not possible to consider the distribution variable of viral types in our statistical analysis since several studies had not reported data on genotype prevalence; only a few authors have employed genetic probes specific for the most common gt (e.g. HR HPV 16 and 18).
statistical analysis
Estimates of HPV infection prevalence were calculated by means of fixed and random effects models. Heterogeneity analysis of k study results was tested by means of the Cochran Q test (1954):
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is the weighted estimator of the HPV prevalence and wi is the weight for the i-th study, obtained as the reciprocal of the variance of the HPV prevalence estimated in the i-th study [36]. The Q statistic, approximately distributed as a 
2 distribution with k-1 d.f., tested the hypothesis that true HPV prevalence was the same in all the primary studies. As a further measure of heterogeneity, the statistic I2, defined as the percentage of total variance across studies attributable to heterogeneity rather than chance, was computed. A cut-off significance level of 0.10 was chosen as suggested by Fleiss [37]. Due to the presence of a significant degree of heterogeneity, the random effect model of DerSirmonian and Laird [38] was finally chosen. Moreover, as the random effect model is more sensitive to publication bias because of the greater relative weight given to smaller studies [39], a funnel plot was assessed (Figure 1), thereby suggesting a publication bias. In order to avoid null standard errors, studies reporting HPV prevalence equal to 0 and 100 were automatically excluded by the analysis. Subgroup analyses were carried out in a stratifying way in accordance with the manner of tumor site categorization (not site-specific HNSCC and OSCC) and detection method (PCR and ISH), calculating HPV prevalence similarly for each of these categories by using a model for random effects. Analyses were carried out using Stata version 9 Intercooled (College Station, TX).
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characteristics of the studies
Tables 1 and 2 summarize the characteristics of the 62 studies examined, reporting a total of 4852 samples of HNSCC. Fifteen studies were included in the subgroup of not site-specific HNSCC (Table 1) while 47 were recorded in the ‘OSCC subgroup’ (Table 2). Thirteen studies used the ISH (two of the not site-specific HNSCC and 11 of OSCC subgroups) and 52 the PCR (13 of not site-specific HNSCC and 39 of OSCC). Three studies of OSCC subgroup use both ISH and PCR [29, 53, 66]. The papers selected denoted a marked degree of heterogeneity with respect to the sample size: the majority of these papers concerned <100 cases (45 of 62, 72.6%). Regarding geographical location, the majority of the studies regarded patients from America, Europe and Asia (21, 20 and 17 studies, respectively), while the remaining four studies were from Africa. The software excluded seven studies with HPV prevalence equal to 0% [29, 55, 56, 66, 94] or 100% [96, 97] from the statistical analysis.
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meta-analysis data
The pooled prevalence of HPV DNA was 34.5% [95% confidence interval (CI) 28.4% to 40.6%)]. Figure 2 reports the random effects model point estimates and a 95% CI for the likelihood of detecting HPV DNA in OSCC versus the wider area defined in HNSCC. The pooled HPV prevalence was greater in OSCC (38.1%; 95% CI 30.0% to 46.2%) than in not site-specific HNSCC (24.1%; 95% CI 16.8% to 31.4%) (Table 3). PCR-based studies reported a higher prevalence rate regarding the detection method than those ISH based (34.8, 95% CI 27.8% to 41.7% versus 32.9%, 95% CI 19.5% to 46.3%).
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The not site-specific HNSCC PCR-based subgroup displayed a pooled prevalence of 20.8% (95% CI 13.5% to 28.1%); it was identified as 39.9% (95% CI 30.2% to 49.8%) in the OSCC PCR-based HPV subgroup whereas ISH warranted a lower sensitivity of 29.8% (95% CI 15.8% to 43.8%) (Figure 3). In general, we noted the limitation of the calculated CIs due to their partial overlapping. Although the distribution of viral gt was found to be very difficult to assay, due to scarce reporting, HR-HPV 16 proved to be the most frequent type (44 of 62 studies), often in association with HR-HPV 18 (Table 1).
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The aim of this study was review the existing data on HPV detection in PE histological samples of HNSCC in order to estimate the pooled prevalence of HPV DNA in this tumor group by a meta-analytical method. In particular, we evaluated the possible effects of two variables representing the major factors able to bias the accuracy of HPV DNA assessment: the tumor site classification and viral detection method. In order to reduce differences due to other technical factors, we selected studies which were uniform as regards the techniques of specimen collection and storage (e.g. PE biopsies) and HPV test (PCR and ISH).
The biopsy remains one of the most common procedures of oral sampling, thanks to the possibility of using the same sample for morphological examination as well as for the HPV test. Furthermore, a biopsy provides a more representative sample of oral mucosae as compared with exfoliative cytology, and it also includes cells from the basal layer, where the virus could be present in a latent and not productive form [97]. The preservation methods of the histological specimens (PE versus FF biopsies) were also investigated as a possible bias in varying HPV prevalence, although there were no unanimous results regarding this hypothesis [31, 98]. The HPV pooled prevalence in overall UADT SCC obtained in this study (34.5%, 95% CI 28.4% to 40.6%) was in line with other similar investigations. In particular, this rate was slightly higher than that reported by Kreimer et al. [31] (25.9%; 95% CI 24.7% to 27.2%) in a recent systematic review. This difference could be due to the inclusion of studies with a major number of specimens (sample size >40), undistinguished by storage methods (including PE and FF biopsies). In order to verify the supposed relationship between the tumor site distinction and the adequacy of HPV assessment, we evaluated OSCC and not site-specific HNSCC separately; we observed a higher prevalence in the first subgroup (38.1%) compared with the second one (24.1%). The obtained HPV prevalence in OSCC specimens was lower than that reported by Miller and Johnstone [99] (46.5%), although within their 95% CI of (37.5% to 55.5%). This partial discrepancy could be explained on the basis that our prevalence is referred exclusively to PE biopsies of OSCC, while Miller and Johnstone [99], similar to Kreimer et al. [31], did not report the results on HPV prevalence in PE and FF specimens separately. Indeed, in a previous review [98], the same authors had found that HPV DNA was detected more often (P < 0.001) in FF OSCC (51.6%) than PE tissue (21.7%). However, the finding of the greater HPV prevalence in OSCC than not site-specific HNSCC suggests, as assumed by other authors [31, 100], that HPV detection could be affected by the lesion site; this confirms that the lack of a clear distinction of SCC in the HN area represents a critical source of variation in HPV prevalence rates. The aforementioned HNSCC group included different entities originating from multiple anatomical areas (oral cavity, oro-, rino- and hypopharynx and larynx). A large number of studies do not report rates of HPV detection for each site, and this factor could represent an important bias which is capable of explaining the lower prevalence rate in not site-specific HNSCC. Furthermore, when this classification was carried out, not all studies had strictly respected the distinction between carcinomas at oral and oropharyngeal sites as recommended by the American Joint Committee on Cancer [101]. Thus, a concern could be that various HPV-positive oropharyngeal SCC were frequently improperly classified as OSCC as a result of this distinction not being applied. This observation could also partly explain a possible overestimation of HPV prevalence in OSCC, as also hypothosized by Herrero et al. [100] and Kreimer et al. [31]. Furthermore, the distinction between oral cavity and oropharyngeal SCC has recently acquired great significance since HPV shows a predilection for oropharyngeal and Waldeyer's ring sites [29, 31, 98] as suggested by the most recent literature. Accordingly, future investigations should be designed to include a significant degree of standardization with respect to HNSCC sites. They should also evaluate each anatomical subtype of HN tumors separately to avoid the probable dispersion of data and to allow a greater uniformity of results from different studies.
As is commonly known, a highly sensitive system of HPV DNA detection is required due to the weak viral productivity in UADT mucosae and to obtain reliable information regarding the presence of HPV samples originating from this anatomical area. Bearing in mind this our original aim, the most sensitive PCR assay could be the technique of choice. In our study, the findings of the highest prevalence rates in PCR-based studies were in agreement with this observation. Nevertheless, a concern could be that latent infections, which are pathologically unrelated to the tumor, could be detected due to high PCR sensitivity [14, 102]; on the contrary, less sensitive ISH could facilitate the identification and localization of viral genomic sequences so as to recognize those SCC which are etiologically linked to HPV infection. For this reason, Uobe et al. [103] and Koyama et al. [95] have recently proposed two methods of HPV DNA detection in paraffin sections of SCC, e.g. the ‘in situ PCR’ and the ‘in situ PCR ISH’. The authors assert that these methods combine the sensitivity of solution PCR with the subcellular localization provided by traditional ISH. Nevertheless, there are currently insufficient data in the literature to support the adequacy and specificity of these techniques and further investigations with a wider sample size are warranted. In our study, the accuracy of HPV DNA detection was greater if OSCC were separately evaluated by means of a high sensitive assay (OSCC PCR based: 39.9%), compared with OSCC ISH based (29.8%) and not site-specific HNSCC PCR based (20.8%). These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future studies on the viral prevalence of these tumors.
The wide range of HPV DNA prevalence among studies included in our analysis may also be attributed to several other factors: (i) variegated sample sizes; (ii) differing patient groups with various social habits, genetic and geographical risk factors; (ii) technical biases, related to specimen collection and laboratory procedures, carried out by different operators, implying various degrees of sensitivity and specificity [31].
Regarding sample size, the majority of studies examined were small-medium sized (<100 patients) and they revealed a wide variation in HPV prevalence. As noted by other authors [31], generally larger studies [40, 41, 51, 64, 69, 86, 90] tend to show lower HPV prevalence (varying between 1.4% and 48.8%) than smaller studies (varying between 0% and 100%). In addition, the displayed funnel plot would suggest the existence of a publication bias, consisting in the preponderance of published studies reporting positive (rather than negative) findings. The ethno-geographical origin of patients is a well-known variability factor regarding HPV prevalence in HNSCC. Asiatic countries, in particular Japan, have probably the highest worldwide frequency [81, 91, 96, 97]. The high prevalence of HPV in the oral cancers of Asiatic patients suggests that viral infection is an important etiological factor, able to cause additional mutagenic steps in the carcinogenic process, together with dietary habits and, probably, in the presence of a given genetic predisposition [104]. The lowest prevalence of HPV infection has been recognized in Africa. Van Rensburg et al. [61, 64] and Boy et al. [29] have reported low HPV prevalence in South African patients with OSCC, varying from 0% and 11.9% [29, 105]. Also in Sudanese patients, Ibrahim et al. [66] have failed to detect HPV DNA in OSCC specimens. These findings suggest that HPV infection in this area plays a marginal role in oral carcinogenesis and that different cofactors participate in the development of OSCC.
Regarding the distribution of viral types, it is essential to highlight the underreporting of data regarding HPV gt prevalence, and this is a major limitation of several studies. This lack of information has prevented us from considering this variable in the statistical analysis, although the majority of authors have reported HR gt 16 and 18 as the most common types detected.
In conclusion, the findings of this meta-analysis support the hypothesis of the involvement of various HPVs in the onset of a subset of UADT SCC, suggesting that the assessment of HPV prevalence could be affected by the absence of any distinction of tumor site and the method of viral DNA identification. Regarding the former, further studies on HPV prevalence should be designed and significantly standardized and carried out on HNSCC adequately selected and classified with respect to the anatomical site. Moreover, to improve the accuracy of HPV DNA assessment in these lesions, themselves often characterized by low viral productivity, the elaboration of more sensitive and site-specific viral detection methods is still required. Finally, to obtain more precise information regarding HPV gt distribution, future studies should report separately the type-specific prevalence rates. Indeed, this information would be very interesting and useful in order to evaluate the long-term effects of the recent HPV vaccines in preventing UADT SCC and, also, to encourage the development of prophylactic/therapeutic HPV vaccines specific to the gt which are more frequently involved in the etiopathogenesis of this category of neoplasias.
Received for publication April 24, 2008. Accepted for publication April 29, 2008.
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