Introduction
Human papillomaviruses (HPVs) are a large and ubiquitous group of viruses that can accompany benign, pre-malignant and malignant proliferations of the epithelium [1]. About 5% of all cancers in the world can be related to HPVs [2, 3]. More than 200 HPV types have been described and divided into five major genera: -, -, -, µ- and -papillomavirus [4]. HPVs can be divided into cutaneous types commonly found in common warts, mucosal types detected in genital condylomas and anogenital cancers and epidermodysplasia verruciformis (EV) types [5, 6]. EV is a rare genodermatosis associated with infections with specific HPVs belonging to the genus of HPV [7]. Some of the cutaneous HPVs of the genus have been suggested as a co-factor in the development of non-melanoma skin cancer (NMSC) [1, 8]. NMSCs are squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) that BCC is the most common skin malignancy and represents approximately 75% of all skin cancers, mostly in the sun-exposed areas [9, 10]. HPV is increasingly considered as an important human carcinogen, but its role in the etiology and pathogenesis of BCC in immunocompetent individuals is unclear [11]. A significant problem for investigations of an association between cutaneous HPV and non-melanoma skin cancer is that cutaneous HPV is part of the normal flora of human skin [12].
The aim of this meta-analysis study was to determine HPVs’ prevalence in the BCC patients and the risk of them in the BCC patients compared with the health controls.
Material and methods
Search strategies
A comprehensive search was done with search terms included with “basal cell carcinoma OR BCC” and “HPV or human papillomavirus” in databases of PubMed/Medline, Web of Science, Science Direct, Scopus, and Cochrane Library from January 1980 to February 2017.
Study selection
Two authors revised selection of the studies. The first author (M.S) searched the studies and then the second author (M.R) screened them. Both authors assessed the studies based on criteria for selecting the studies included in this study. The studies included the following inclusion criteria: a) case-control, cohort or cross-sectional studies; b) human studies; c) reporting of the prevalence of HPVs in serum and/or tissue of the patients with BCC of the skin; d) reporting of the incidence of HPVs in serum or tissue of the BCC patients (BCC group or BCC patients) compared with serum or tissue of the controls (control group).
Data extraction
We extracted the name of author, the year of publication, country, the number of BCC patients, the number of patients in the control group (if), the number of HPV positivity in the BCC patients, the number of HPV positivity in the health controls (if), the type of HPV, the method of HPV detection and immune status of each study included in the review.
Statistical analysis
A random-effects meta-analysis was used by Comprehensive Meta-Analysis software version 2.0 (CMA 2.0) using the event rate (ER) and Review Manager 5.3 (RevMan 5.3, The Cochrane Collaboration, Oxford, United Kingdom) using odds ratio (OR) and 95% confidence intervals (CIs) for estimation of the incidence of HPV. Heterogeneity between estimates was assessed by the Q and I2 statistic that for the
Q statistic, heterogeneity was considered for p < 0.1. Two-sided p-value < 0.05 was considered to be statistically significant in this meta-analysis study.
Results
Selection of studies
Out of 1087 studies, 92 studies evaluated for eligibility (Fig. 1). Forty-seven studies were excluded because they were case-report, review studies, didn’t report the prevalence of HPVs in BCC patients or report just one BCC patient. Therefore, 45 studies were included in the systematic review.
Characteristics of studies
Out of 45 studies reported during 1991 to 2017; two studies were reported in Australia [12, 13], one Romania [14], ten USA [15, 16, 17, 18, 19, 20, 21, 22, 23, 24], one Argentina [1], four Netherlands [25, 26, 27, 28], two Spain [8, 11], one Brazil [29], one China [30], one UK [31], one Croatia [2], four Iran [9, 32, 33, 34], one North Africa/France [35], one Germany/USA [36], two Greece [37, 38], one Sweden/Austria [39], two Germany [40, 41], five Italy [5, 42, 43, 44, 45], one Russia [46], one Germany/Poland [47], one Norway/Sweden [48] and two Sweden [49, 50] (Table I). Fifteen studies were case-control and 30 studies were cross-sectional studies. Twenty-four studies did polymerase chain reaction (PCR) [1, 2, 12, 14, 19, 20, 21, 25, 28, 29, 31, 32, 35, 36, 37, 39, 40, 41, 42, 43, 44, 46, 47, 49, 50], 2 in situ hybridization (ISH) [15, 18], 3 serology [16, 48, 24], 7 nested PCR [5, 8, 11, 26, 27, 34, 43], one loop-mediated isothermal amplification assay (LAMP)/PCR [30], 4 multiplex serology [17, 22, 38, 45], 2 immunohistochemistry (IHC) [9, 33], one multiplex serology/PCR [23] and one southern blot [13] for detection of HPV. Also, immune status were immunocompetent/immunosuppressed (IC/IS) in 7 studies [1, 8, 12, 26, 31, 40, 46], IC in 11 studies [5, 11, 14, 21, 36, 37, 38, 39, 42, 47, 49], IS in 6 studies [13, 25, 27, 35, 41, 44] and 21 studies didn’t report any status [2, 9, 15, 16, 17, 18, 19, 20, 22, 23, 24, 28, 29, 30, 32, 33, 34, 43, 45, 48, 50]. Out of 45 studies, seven studies checked HPVs on the serum [16, 17, 22, 38, 45, 48, 24] and the rest of studies on the BCC-involved and healthy tissues.
Meta-analysis
Figure 2 shows the incidence of number of HPVs in the BCC patients and controls. Some studies reported this incidence in the BCC patients and controls (case-control studies) and other studies only reported in BCC patients (cross-sectional and cohort studies).
α-HPV
Seven studies [1, 14, 16, 17, 24, 37, 43] reported the prevalence of -HPV in the BCC patients and/or controls. Out of 1121 BCC patients, 338 (30.1%) were HPV positivity and out of 1188 controls, 358 (30.1%) were HPV positivity. The pooled analysis with dichotomous data demonstrated that the incidence of -HPV was not effective in the BCC patients compared with the healthy controls [OR = 1.45; 95% CI: 0.90-2.33; p = 0.12] and [I2 = 78%; p = 0.001] (Fig. 3).
β-HPV
Seven studies [1, 16, 17, 22, 24, 32, 43] reported the prevalence of -HPV in the BCC patients and/or controls. Out of 2379 BCC patients, 951 (40%) were HPV positivity and out of 1942 controls, 863 (44.4%) were HPV positivity. The pooled analysis with dichotomous data demonstrated that the incidence of -HPV was not effective in the BCC patients compared with controls [OR = 1.10; 95% CI: 0.83-1.45; p = 0.50] and [I2 = 64%; p = 0.02] (Fig. 3).
γ-HPV
Four studies [1, 16, 24, 43] reported the prevalence of -HPV in BCC patients and/or controls. Out of 561 BCC patients, 291 (51.9%) were HPV positivity and out of 634 controls, 310 (48.9%) were HPV positivity. The pooled analysis with dichotomous data demonstrated that the incidence of -HPV was effective in the BCC patients compared with controls [OR = 1.97; 95% CI: 1.52-2.55; p < 0.00001] and [I2 = 0%; p = 0.89] (Fig. 3).
Epidermodysplasia verruciformis-HPV (EV-HPV)
Six studies [11, 25, 26, 31, 35, 36] reported the prevalence of EV-HPV in the BCC patients and/or controls. Out of 181 BCC patients, 39 (21.5%) were HPV positivity and out of 210 controls, 16 (7.6%) were HPV positivity. The pooled analysis with dichotomous data demonstrated that the incidence of EV-HPV was not effective in the BCC patients compared with controls [OR = 2.04; 95% CI: 0.52, 7.98; p = 0.31] and [I2 = 47%; p = 0.13] (Fig. 3).
α-HPV based on subgroups
Figure 4 shows the event rate of HPV 3, HPV 18, HPV 16, HPV 31, HPV 33, HPV 6 and HPV 11 in the BCC patients. Two [45, 49], six [15, 18, 19, 38, 34, 49], eleven [2, 15, 18, 19, 20, 28, 34, 38, 45, 49, 50], two [18, 49], three [18, 38, 49], four [18, 45, 49, 50], and three studies [18, 38, 49] reported the prevalence of HPV 3 (2), HPV 18 (7), HPV 16 (9), HPV 31 (9), HPV 33 (9), HPV 6 (10), and HPV 11 (10) in the BCC patients, respectively. Table II shows the pooled ER of the articles for the incidence of - HPVs in the BCC patients.
β-HPV based on subgroups
Figure 5A shows the ER of 1-HPV, HPV 5, HPV 8, HPV 12, HPV 20, HPV 24, HPV 36 and HPV 93 in the BCC patients and Fig. 5B shows the ER of 2-HPV, HPV 9, HPV 15, HPV 17, HPV 23, HPV 38, HPV 75 and HPV 107 in the BCC patients. Also, Fig. 6 shows the ER of HPV 49, HPV 76, HPV 92, HPV 96 and HPV (unlisted) in the BCC patients. Three [21, 23, 45], four [21, 23, 45, 49], three [21, 23, 45], two [21, 23], and six studies [8, 9, 13, 29, 42, 46] reported the prevalence of HPV 49 (3), HPV 76 (3), HPV 92 (4), HPV 96 (5), and HPV (unlisted type) in the BCC patients. Four [5, 21, 22, 48], five [23, 28, 45, 49, 50], seven [2, 21, 23, 28, 45, 47, 50], two [2, 21], six [2, 21, 23, 28, 45, 50], five [21, 23, 28, 45, 50], four [21, 23, 45, 50] and three studies [21, 23, 45] reported the prevalence of 1-HPV, HPV 5 (1), HPV 8 (1), HPV 12 (1), HPV 20 (1), HPV 24 (1), HPV 36 (1), and HPV 93 (1) in the BCC patients, respectively. In addition to, two [21, 48], four [21, 23, 45, 50], six [21, 23, 28, 45, 49, 50], three [21, 23, 45], three [21, 23, 45], eight [12, 21, 23, 28, 47, 45, 49, 50], three [21, 23, 45], two studies [2, 23] reported the prevalence of 2-HPV, HPV 9 (2), HPV 15 (2), HPV 17 (2), HPV 23 (2), HPV 38 (2), HPV 75 (2), and HPV 107 (2) in the BCC patients, respectively. Table III shows the pooled ER of the articles for the incidence of -HPVs in the BCC patients.
Discussion
The BCC is an immunogenic neoplasm [51] that its pathogenesis strongly associates with environmental and genetic factors [52]. We have conducted a comprehensive systematic review of studies addressing OR and ER of HPVs in the BCC of the skin in the world. There were 45 studies in this systematic review and meta-analysis that seven studies checked HPVs on serum [16, 17, 22, 38, 45, 48, 24] and 38 studies on the BCC-involved tissue. Our findings showed a significant risk of -HPV in the BCC patients compared with the healthy controls. Among -HPVs reported (3, 6, 11, 16, 18, 31 and 33) in the BCC patients of skin, the highest of ER was HPV 6 (15.5%) and lowest was HPV 33 (1.4%). With regard to ER of 1-HPV in the BCC patients (33.3%) and among subgroups of 1-HPV reported (5, 8, 12, 20, 24, 36 and 93), HPV 93 (23.8%) and HPV 12 (1.6%) had the highest and lowest of ER of 1-HPV, respectively. With regard to ER of 2-HPV in the BCC patients (44.2%) and among subgroups of 2-HPV reported (9, 15, 17, 23, 38, 75 and 107), HPV 23 (21.9%) and HPV 107 (7.2%) had the highest and lowest of ER of 2-HPV, respectively.
Correa et al. [1] demonstrated that -HPVs were the most frequently found in BCCs compared with - and -HPVs. Andersson et al. [48] reported that out of 2-HPVs, HPV9 was significantly associated with BCC. Antibodies against any HPV 5, 8, 9, 15, 20, 24, 36 and 38 showed that 48.8% BCC patients were positive while this was 53.2% among controls [50]. Escutia et al. [11] concluded -types were frequently detected in skin samples from immunocompetent patients with BCC that there were differences in the prevalence of HPV in skin biopsies of BCC tumors and normal skin. Also, one study on HPV types (mostly -HPV) [8] presented important differences in HPV prevalence between immunocompromised and immunocompetent patients. The higher prevalence of HPV types (mostly -HPV) found in healthy perilesional skin proposed that HPV DNA was widely distributed in the general population and was found no correlation between the presence of HPV and skin cancer. Another study on -HPVs [16] suggested that the combined serology and tumor DNA results showed that -HPVs may have a role in BCC. Two studies [9, 45] did not find a significant relationship between BCC and HPV and also Nahidi et al. [32] that concluded that HPV was not likely to have a major role in the pathogenesis of BCC.
In one study [14], -HPV in BCC was positive in 35% of the cases that the high-risk HPV genotypes observed in these patients were HPV 16, 35, 58 and 59. The findings of a research [5] demonstrated that 1-HPVs were the most common HPV types detected in the skin of BCC patients. Moreover, these types and mixed infections are significantly more frequent in tumor samples than in healthy perilesional skin and the results suggested that the types as well as co-infection with more than one viral type could be important in BCC.
The findings suggested that EV-HPV types could be present in a higher percentage of skin cancers [25] and that EV-HPV-directed seroresponses were induced upon skin cancer formation, rather than upon infection [28].
Also, the findings of another study suggested that high-risk mucosal HPV types recently identified as significant risk factors for non-melanoma skin cancer [34] and also represents a risk factor for non-melanoma skin cancer in a non-immunosuppressed population [36]. Other results suggested that HPVs, particularly the oncogenic potential of certain types such as HPV 8, 18, and 5 could induce non-melanoma skin cancers [38].
Conclusions
Limitations such as the variation of HPVs, reporting HPVs in serum instead of tissue in some studies, and few studies reported; were caused that the relationship between HPV types and BCC have been not well done in the meta-analysis. Although there were a few case-control studies about the risk of HPVs in the BCC group compared with the healthy control, but this meta-analysis showed that probably the risk of -HPV was more in BCC patients. Also, the rate of -HPV was higher than -, - and EV-HPVs in the BCC patients.
The authors declare no conflict of interest.
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Address for correspondence
Masoud Sadeghi
Medical Biology Research Center
Kermanshah University of Medical Sciences
Kermanshah, Iran
e-mail: sadeghi_mbrc@yahoo.com
