Arch Gynecol Obstet (2015) 291:481–491 DOI 10.1007/s00404-014-3480-5

REVIEW

Site of infections associated with human papillomavirus Monique Beltra˜o • Marcela Silvestre Outtes Wanderley Nataly Amorim de Santana • Danyelly Bruneska • Jose´ Luiz de Lima Filho

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Received: 18 June 2014 / Accepted: 12 September 2014 / Published online: 23 September 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract Introduction Human papillomavirus (HPV) is the most clinically common sexually transmitted infection due to its carcinogenic power and the high number of lesions that it causes at different sites of the human body. Material and methods Genital tract organs are the most common sites where the virus can be found, but by increasing the sensitivity of diagnostic technique, it is possible to identify viral presence in different regions of the body such as the stomach, the lung, and the urinary tract. These findings break with the traditional HPV skin/ genital tropic profile and demonstrate that the virus is capable of infecting a wide variety of cells, tissues, and organs or can, at least, survive in these areas. The widespread presence of the HPV in the human body, often in latent form, led us to consider the hypothesis that HPV latency may be associated with no disease. Conclusion This observation raises further questions about the possibility of the virus not causing disease in specific sites of the human body, but rather, behaving like a commensal/opportunistic microorganism. Keywords HPV
Tumor biology
Urogenital pathology
Cancer

M. Beltra˜o (&)
M. S. O. Wanderley
N. A. de Santana
D. Bruneska
J. L. de Lima Filho Laboratory of Imunopathology Keizo Asami (LIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235 Cidade Universita´ria, Recife, PE CEP 50670-901, Brazil e-mail: [email protected] D. Bruneska
J. L. de Lima Filho Biochemistry Department, Federal University of Pernambuco (UFPE), Recife, Pernambuco, Brazil

Introduction Papillomaviruses are currently represented by 189 genotypes of which 170 were isolated from humans [1, 2]. Human papillomavirus (HPV) types can be broadly divided according to the degree of cell damage that they are able to cause, resulting in high or low risk [3]. Additionally, they can be described as cutaneous types or mucosotropic types based on their tissue tropism [4]. In this way, the aim of this review is to give an overview of HPV infection sites in the human body beyond the genital tract. Moreover, the ‘infective’ nature of this virus requires further investigation as HPV can establish latent residence in normal epithelia and in others cells without clinical sign of disease [5].

Virus biology Human infection with HPV is most focused in cervical cancer since the first site in the body in that HPV was found [6]. The infection usually begins with the entry of the virus into the basal layer cells of the epithelium (10 viral copies/ cell). When they reach 50 copies/cell, the genes E1, E2, E6, and E7 begin to be expressed, leading to viral replication with low expression of these genes, in parallel with cell replication. The amplification of viral copy number greater than 1,000 copies/cell is characterized by high expression of genes E1, E2, E4, E5, E6, and E7. Expression of L1 and L2 allows the production of capsid protein, resulting in the release of the virus by programmed cell death [3]. In benign lesions caused by HPV, the virus preserves the episomal form—free inside the cell—where after its life cycle and epithelial maturation, it is released through lysis of the cell. However, viral DNA is able to integrate into the

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Fig. 1 Diagram of human papillomavirus infection progression. a HPV has a benign profile of which in some cases no cytological alteration is detected [9, 10]. At this stage, viral episome form is characteristic and E5/E6/E7 oncoproteins are low expressed. b When

viral particles number increase, HPV has a malignant identity. Viral DNA is integrated to host DNA and higher malign transformation is the result of constant oncoprotein expression

genome of the host and initiate the carcinogenic process [7]. During the combination of the viral genome into the human genome, there is partial (E2 and L2) or total loss (E4 and E5) of some viral proteins [8]. Besides oncoprotein expression, HPV pathology seems to be DNA viral load dependent, where malign clinical stages have increased HPV quantification [9, 10]. In summary, based on different levels and time of viral genes’ expression, there are two moments in HPV infection: (a) latent, sub clinical or low risk and (b) high risk or cancer (Fig. 1).

multiple sexual partners may increase the chances of viral infection [13–18]. Because cervical cancer was the first well-established carcinoma caused by HPV, prophylactic vaccination targeted primarily the most common group, young woman. After primary prevention and following clinical trials demonstrating their efficacy and safety, two vaccines have been in global use for over 6 years with reductions in genital warts, infections, and cervical disease [19]. Besides cervix, quadrivalent HPV vaccine has been used in genital warts, vulvar intraepithelial neoplasia, or vaginal intraepithelial neoplasia patients with significant reduction of the incidence of subsequent HPV-related disease [20]. Subsequently, HPV vaccination should be extended to patients HIV-positive with anal cancer [21], oropharyngeal cancer [22], and other HPV-related diseases [23]. HPV vaccination of boys has been recommended due the results in woman vaccination. However, considering the health outcomes and costs of the different HPV-related conditions, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys [24].

Infection sites Human papillomavirus is associated with approximately 4 % of all cancers and it can be found in several other sites of infection, not only in the genital region [11, 12]. The link between HPV and anogenital cancers, as well as regions of head and neck, are well established. However, for other cancers described here, the role of HPV is still under debate concerning the relationship of this virus with other cancer sites. In Fig. 2, is shown a literature search reporting HPV infection in different body sites. The World Health Organization (WHO) estimates that the number of global cancer deaths is expected to increase by 45 % from 2007 to 2030 (from 7.9 million to 11.5 million deaths), and new cases of cancer in the same period are predicted to go from 11.3 million in 2007 to 15.5 million in 2030. Sexual activity, multi-genotypes infection, hormone replacement therapy, smoking, multiparity, and

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Uterus, vagina, vulva, and ovary Invasive squamous cell cervical cancers are preceded by a long phase of preinvasive disease, together referred to as cervical intraepithelial neoplasia (CIN). In the 1980s, the HPV types 16 and 18 had been found closely associated with human genital cancer [25] and this association was increasingly recognized with time. Persistent infection with

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Fig. 2 Literature search reporting Human papillomavirus infection in different body sites. Graphic was performed based on 10,200 articles surveyed in Scopus database and published from 2000 to 2013 describing HPV infection in specific human body area. The following MeSH (medical subject headings) terms were searched in Pubmed database: ‘‘HPV’’ cross-searched ‘‘uterus and ‘‘cervical’’, ‘‘vagina’’, ‘‘vulva’’, ‘‘ovary’’, ‘‘stomach’’, ‘‘Anus, colon and/or rectum and/or anal’’, ‘‘bladder’’, ‘‘Penis and/or prostate’’, ‘‘head and neck and/or oral cavity and/ or nose and paranasal sinuses and/or pharynx and/or larynx and/or respiratory’’, ‘‘ears’’, ‘‘lung’’, ‘‘eyes’’, ‘‘breast’’, ‘‘skin’’, ‘‘blood’’

one or more of the oncogenic subtypes of HPV is a necessary cause for cervical neoplasia. However, detection of HPV16 in women with normal histology or CIN 1 by PCR [26] suggests past-resolved virus infection or opportunist virus. The malignant role of HPV in cervical transformation is a scientific consensus, and more studies are necessary to explain the presence of HPV in patients without cytological alterations. Vaginal intraepithelial neoplasia (VAIN) is a condition that describes premalignant histological findings in the vagina characterized by dysplastic alterations. The incidence of invasive vaginal cancer is almost 1 per 100,000 women, and it is considered a rare disease [27]. Despite that, HPV is associated with 40–64 % of vaginal cancers [28] in which HPV16 and 31 are the most frequent virus types found in the population of Northeast Brazil [29]. In VAIN, thousands of HPV DNA copies per cell were found with powerful replication ability but no progression to invasive vaginal carcinoma [30]. Following this suggestion, HPV detection in the vagina before the commencement of sexual activity indicates that it is necessary to begin early vaccination to avoid further disease progression [31]. In addition, this also suggests that the virus can be a natural resident of this area. However, more studies are necessary to clarify this hypothesis. VAIN grades 1 and 2 are mostly associated with low-risk HPV infections and a high spontaneous regression rate, whereas VAIN grade 3 represents a high-risk HPV-associated lesion with capable progression into invasive carcinoma [32]. Study performed in the United States showed that three-fourths of all vaginal cancers had HPV association, among which 57 % could be

prevented by current HPV vaccines [33]. Taken together, these data presented well-established association of HPV with VAIN and remain unclear if the virus can be present without disease. Vulval intra-epithelial neoplasia (VIN) is a precancerous condition of the vulval skin. VIN is found in less than 3 % of all gynecological malignancies [34], with a higher incidence in patients aged less than 60 years [35]. Squamous cell carcinomas (SCC) are the most common histological subtype comprising more than 90 % of the VINs [36]. The exact cause of VIN is not known. However, cases of highgrade VIN are strongly linked to the HPV [37]. HPV16 is the most frequent virus type in VIN, located habitually in the region between the clitoris and urethra rather than the labia [38]. HPV16 E6 has been found in SCC and nonneoplastic epithelial disorders of the vulva, with 67 and 30 % of the cases, respectively [39]. This study showed the viral presence in non-related cancer cases. This fact is unexpected for the reason that immunohistochemistry is not a robust method to detect low levels of HPV16-E6 expression. HPV infection by itself may not cause VIN. It may be that HPV-associated VIN result in increased risk of other genital cancer conditions associated with HPV. Nowadays, VIN is classified based on HPV involvement in usual type (HPV-related) and differentiated type (not HPVrelated) [40]. HPV is well established as the precursor of high-risk HPV-related vulvar SCC; however, the involvement of other HPV types needs to be clarified. Malignant ovarian lesions include primary lesions arising from altered cells within the ovary and secondary lesions from cancers arising elsewhere in the body. Ovarian

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cancer (OC) is the seventh most common cancer in women worldwide, with 239,000 new cases diagnosed in 2012 [41] and it is strongly related to age with higher incidence in postmenopausal women. In recent years, the association of HPV with OC has been a controversial clinical issue to address as a conflicting number of studies had made this answer difficult to assess. Some works do not find HPVassociated OC while others studies identify around 50 % of HPV16 positivity in epithelial ovarian cancer [42–44]. Positive identification of viral DNA in intraepithelial carcinoma in situ of the ovary may suggest the interpretation of metastasis related to areas of the cervical tract [45]. A recent meta-analysis study proposed that HPV is unlikely to play an important role in Western European and American women [46]. However, additional studies are necessary to determine the role of HPV in the OC etiology in other populations. Stomach Gastric cancer, also known as stomach cancer, is a malignant neoplasm arising from the lining of the stomach. Stomach neoplasia is the third leading cause of cancer death worldwide, resulting in 723,000 deaths annually [47]. The most common factor that primarily contributes to the risk of developing gastric cancer is infectious agents, Helicobacter pylori and Epstein–Barr virus. Because of the epitheliotropic nature of HPV, a link between gastric cancer and intraoral squamous cell carcinoma and this virus has been the focus of some research [48, 49]. Food has been a target of study as a cofactor for cancer caused by HPV. In humans, it is known that quercetin, a flavonoid present in Pteridiumaquilinum, stops keratinocytes in G1 phase of the cell cycle, increasing the cyclin-dependent kinase inhibitor and p27Kip1, and leading to the failure of the cell cycle [50]. Through cytogenetic analysis of peripheral blood of animals with intoxication by this plant, Santos et al. [51] reported that there is a possible association between cancers caused by papillomavirus and the toxins originated from Pteridium. Using the in situ hybridization method, Xu et al. [52] were able to detected positive rate of HPV16 in 20 % (10/50) of normal gastric mucosa and 67.6 % (50/74) of gastric cancers specimens. However, this association is not consistent, because the search in 84 gastric cancer individuals for HPV by qPCR high-risk HPV test was not able to find association between oncogenic HPV and this cancer [53]. Until this moment, the role of HPV in gastric carcinoma has not been yet elucidated. Anus, colon, and rectum Anal intraepithelial neoplasia (AIN) describes the microscopic finding of dysplastic, non-malignant cells in the anal

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canal. This dysplasia has been thought to appear as a result of local contamination with HPV. Early diagnosis in HPV intra-anal warts to avoid cancer progression can be improved using anoscopy/cytology examinations and PCR HPV typing [54]. In terms of contamination, there is a higher prevalence of HPV in the anal canal of women with cervical intraepithelial neoplasias, heterosexuals, men who have sex with men, and HIV-infected men [55–57]. Koppe et al. [58] related the prevalence of AIN is higher in women with genital neoplasia. Study conducted by Edgren et al. [59] showed that women with a history of CIN grade 3 had increased risks of vaginal, vulvar, and anal cancers, but not rectal cancer. Jacyntho et al. [60] observed a strong association between anal squamous intraepithelial lesions (ASIL) and multicentric genital squamous intraepithelial lesions (GSILs). In their study were detected 17.4 % immunocompetent women with GSILs concomitant with ASIL, and the risk of ASIL was 13.1 times superior for GSIL women with three to four genital sites involved. Coherent, Tatii et al. [61] confirmed that immunocompetent women with high-grade CIN had 2 times increased change to developing AIN. Also, there is the possibility of AIN be a part of a metastatic lesions process of the lower genital tract [60, 62]. HIV-infected patients have a strong correlation with anal infection being associated with multiple HPV genotypes and HPV16 viral load [63]. Pre-cancer screening programs should be made specific, with particular emphasis on men who have sex with HIV-positive partners due to the increased risk of HPV infection [64, 65]. Additionally, Park et al. [66] described that anal infection with high-risk HPVs is common in women with high-grade genital neoplasia, but was not associated with known risk factors for genital HPV infection. In their investigation the risk factors evaluated were smoking, early age of sexual debut, and multiple sexual partners. In AIN, it is clear that infection with HPV is associated with the development of anal dysplasia [67]. Opportunely, the success of cervical cytology in screening for cervical neoplasia has led to the concept of anal cytology screening for anal neoplasia [68]. In the past decade, Papanicolaou smear and/or high-resolution anoscopy have been considered the diagnostic methods effective for detecting anal lesions and its relation with HPV infection [69, 70]. Moreover, the viral genotyping has been showed to be a more sensitive tool for this purpose mainly to detect DNA virus before that the cytological abnormalities manifest [71]. Nowadays, the challenge is to understand the relation between HPV type with specific population and HPV type as predictor of AIN lesions. Colorectal cancer is a multifactor disease with etiology in relation to genetic factors, diet, and inflammatory conditions of the digestive tract. The HPV involvement in

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colorectal carcinogenesis is controversial. Two recent meta-analysis studies provide results for an association between HPV infection and colorectal cancer risk with the HPV prevalence varied by geographical region [72, 73]. HPV overall prevalence was 31.9 % in colorectal tumors with lowest in Europe (14.1 %) and highest in South America (60.8 %) with HPV16 more prevalent in South America (58.3 %) [73]. In the past years, there have been a few good research studies showing evidence for an association between HPV and colorectal carcinogenesis. However, more studies are still necessary to characterize well this association. Bladder Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular mechanisms most important to its pathogenesis are not well defined. A variety of viral infections of the urinary tract such as HPV, human herpes virus, and the human polyoma virus families have been studied as potential risk factors for bladder carcinoma [74]. In the case of HPV infections, HPV16 is the most commonly found in bladder cancer, with a higher prevalence in men and in Asia [75]. Urothelial carcinomas of the bladder can also result from long-term of infections associated with neurogenic bladders and HPV infection [76]. HPV may have an important role in the progression of specific bladder malignancies, as observed in the transitional cell carcinoma, promoting higher stages and/or grades through the inactivation of tumor suppressors [77]. Recent studies are still controversial about HPV infection in urinary neoplasia [78, 79]; if positive association is confirmed, DNA HPV can be used as biological markers of bladder carcinoma. Penis and prostate Penile carcinoma is a rare and potentially mutilating disease and HPV is considered a possible etiologic agent for its development. According to the identification method used and geographic location, the prevalence of HPV DNA into carcinoma of the penis varies between 27 and 60 % [80, 81]. Remarkably, multiple HPV types are found in the same patients with the presence of oncogenic and nononcogenic viruses at the same time [81]. In HIV-infected patients, HPV16 and HPV6 are the most commonly infecting virus type, independent of the sexual option [82]. In a multisystem study including USA, Brazil, and Mexico, a broad range of HPV types (a-, b- and c-HPV) have been detected in the male genitals [83]. The importance of HPV detection in the penis is related to the fact that men could act as a viral reservoir, transmitting the virus to their sexual partners, since it has been also identified in the semen.

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HPV-infected sperm are viable and can deliver viral DNA in the oocyte and transmit to fertilized oocyte, which opens new ways to analyze the HPV transmission [84]. The association of HPV with prostate cancer (PCA) is still not clear with any significant difference between virus presence in benign prostate hyperplasia (BPH) and patients with prostatic cancer [85, 86]. Besides that, HPV16 E6 sequence had significantly higher copy numbers found in PCA compared with BPH [87]. Head and neck There are a variety of malignant and benign lesions of the head and neck related to HPV [88]. The mechanism of viral transmission of this type of cancer is poorly understood. Haddad et al. [89] proposed viral transmission among married couples as PCR diagnosis revealing identical viral genomes between them. In addition, HPV positive saliva specimens belonging to women with cytology finding suggest that genital HPV infection is at higher risk for asymptomatic oral HPV infection [90]. Some authors propose that women with low levels of total secretory IgA are more susceptible to HPV infection of the oral mucosa [91]. Respiratory papillomatosis was described in children with benign lesion with high probability of recurrence, which can be effectively treated with locally administered of cidofovir [92]. Interestingly, healthy children also presented HPV type 16 in buccal sample [93]. Squamous cell carcinoma of the oral mucosa associated with HPV accounts for more than 25 % of all head neck squamous cell carcinoma [94]. The patient’s age, HPV type, and numbers of surgeries are prognostic factors in the course of the disease, as well as the density of CD83? dendritic cells in cancerous laryngeal tissue [95]. In the pharynx, the lesions caused by HPV have been described as benign. But squamous cell carcinoma of the oropharynx is designated as positive for HPV16 and 33, some with long-term survival after chemo-radiation treatment [96]. Today, the role of HPV in squamous cell carcinomas of the head and neck (HNSCC) as a causative agent has resulted in a growing need and expectation for HPV testing of head and neck cancers [97] and vaccination. Ear Chronic ear infections can be attributed to bacteria, but also have been associated with the presence of HPV. Patients with middle ear chronic inflammations and neoplasm have been shown to have HPV DNA in the ear [98]. Findings demonstrated that HPV6 and 11 were reported to be present in those types of the ear lesions [99], especially in cholesteatomatous chronic otitis media. This association could be related to the fact that HPV could potentially

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replicate in cholesteatoma of the middle ear, since retraction pockets of epithelium and junction lines between squamous epithelium and mucosa occur here [100]. However, more studies are necessary to confirm HPV involvement in ear lesions. Lung Lung cancer is responsible for the most cancer deaths throughout the world. Smoking causes the majority of lung cancers, and HPV may be the second leading cause. HPV6 and 11 are largely related to the occurrence of recurrent respiratory papillomatosis, lesions that occur mainly in the larynx, with geographic variation in incidence rates worldwide [101]. In Europe and the USA, the average reported incidences are around 17 and 15 %, respectively, while Asian lung cancer samples showed 35.7 % of HPV infection rate [102]. Remarkably, breaking the idea of pathogenic, recent studies suggest that HPV-infected patients had a better survival in lung adenocarcinoma [103]. As observed for cervical cancer, patients with recurrent respiratory papillomatosis had clinical improvement after quadrivalent HPV vaccination [104], suggesting the vaccine as good therapy for these patients. Nowadays, HPV is frequently reported in pulmonary neoplasia; however, recent studies are suggesting the virus presence as signal of metastases [105, 106]. Eyes Retinoblastoma (RB) is a malignant tumor of the retina and occurs as a result of the functional absence of Rb protein (pRb), relevant target for E7 HPV oncoprotein. Despite that retinoblastoma are predominantly of hereditary cause, the viral DNA was found in 82.3 % paraffin-embedded samples of retinoblastoma (RB) tissue from Mexican patients with high prevalence of HPV6 (95.2 %) [107]. Indian patients with retinoblastoma showed 70 % prevalence of HPV in RB with pRB2/p130 expression significantly associated with HPV16 [108]. These observations suggest a role of HPV in the progression of this disease and lead some authors to believe that HPV can act as a cofactor in the RB progression by promoting nonrandom additional mutations [109]. Breast The etiology of breast cancer is not yet clarified, but it is known that some factors are associated with its pathogenesis, such as family history, hormones, smoking, age, and various viral factors [110]. The possible role of HPV in breast cancer is suggested due to the HPV detection in

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breast cancer patients [111] and metaplastic breast carcinomas [112]. Considering that breast region has a different response to steroid hormones, HPV infection can be hormone affected since steroids can interact with viral LCR, increasing transcription and transformation in infected cells [113]. In terms of HPV-type distribution in the breast, alpha-HPV types could be detected in breast fluids (colostrum and milk), whereas beta-HPV types were highly prevalent in the epidermis of the nipple [114]. However, the findings do not support the concept that HPV can be transmitted by breastfeeding and that it can play an important role in breast cancer [115]. Skin At some moment of life, most people will have some form of cutaneous wart. The prevalence of viral warts in children and teenagers has been recorded at 4–5 and in 3.5 % of adults [116]. Generally, cutaneous warts regress spontaneously, but they may progress into malignant skin cancer during immunosuppression or high viral loading where HPV117 had been found in persisting wart [117]. Common skin warts are associated with not only alpha HPV types (HPV 2, HPV 27, and HPV 57) [118], but also high-risk HPV types [119]. Skin lesions such as squamous cell carcinoma, actinic keratosis, and keratoacanthoma contain a large diversity of HPV types [120]. Ultraviolet light exposure may be risk factors for the formation of epidermoid inclusion cysts in epidermodysplasia verruciformis patients [121], which HPV10 have been associated [122]. However, in most part of cases, HPV association with skin is well clear due to natural virus history and characterized by good prognosis with spontaneous resolution and cure. Blood Circulating HPV DNA has been detected in advanced stages of cervical cancer with prevalence of HPV16 in the plasma [123]. The consolidation of viral DNA disseminated in the blood can be used as an important prognostic marker of advancing cervical disease. HPV16 was also found in lymph nodes of patients with early stage cervical carcinoma, where it was localized in mononuclear cells of 92.3 % cervical infected patients [124]. These data suggest that these cells could carry the virus through the blood. Hypothetically, HPV in plasma could be the result of bloodborne virus particles or cells necrosis resulting in release of viral DNA into the circulation [125]. For some authors, since HPV is an epitheliotropic virus, its presence in the bloodstream—associated with peripheral blood mononuclear cells—can be interpreted as a type of metastasis [126, 127].

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Others sites The HPV infection has been detected in others sites of the body, such as the hands, hair, and tongue. In 27 % of patients, an association was found between HPV type detected in fingers and genital lesion of the same patient [128]. Periungual squamous cell carcinoma (SCC) is frequently associated with alpha-HPV infections. The presence of HPV in plucked hairs from the pubic and perianal regions of patients with genital warts was investigated, since they are of clinical importance in the development of anogenital warts. HPV6 and 11 were found in 24 % of hair samples from the pubic area and 36 % from the perianal region [129]. These results suggest that hair follicles can act as an endogenous reservoir for HPV, which may play a role in recurrences of genital warts. Eyebrown hair [130], base of the tongue [131], renal cell carcinoma [132], and pancreatic neoplasms [133] are uncommon areas where HPV have been associated.

Findings of HPV without histological alterations It is important to mention that HPV infection has been related in samples without histological alterations. In this way, Shukla et al. [134] showed the prevalence of HPV infection in cancers of different organ sites in Indian populations. In women infected by HPV, 90 % of the infections resolve spontaneously; only 10 % can become persistent of which 3–4 % can progress to intraepithelial lesions [135]. Some controversial findings of viral DNA in putative uninfected samples for HPV or in control groups [136–138] lead to a reflection about the viral history. Overall HPV prevalence increased with increasing severity of cervical disease from 12.6 % in normal cytology to 89.5 % in invasive cervical cancer (ICC). HPV colonization has been suggested as protective to the host and this virus could exist as commensal or opportunistic virus without causing any detectable existence or can be lead to a verrucous structure [5, 139]. Moreover, there is a tendency to abolish the HPV type classification into high and low risk, whereas HPV6 has been isolated in cancer penile under single and multiple infections [140]. HPV16 has been found in normal cytology with 23.4 % of positivity and HPV18 with 8.9 % [141]. Therefore, it seems likely that future diagnosis of HPV risk will be correlated to the characteristics of the host through biochemical and immune imbalance, in addition to associated risk factors for HPV that are responsible for the progression of precursor lesions to cancer. Acknowledgments The authors thank Dr. Albert Leyva for grammatical corrections of this review.

487 Conflict of interest

We declare that we have no conflict of interest.

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