Human Papillomavirus Burden in Different Cancers in Iran: a Systematic Assessment

Certain types of human papillomaviruses (HPVs) are undoubtedly involved in genesis of human malignancies. HPV plays an etiological role in cervical cancer, but also in many vaginal, vulvar, anal and penile cancers, as well as head and neck cancers. In addition, a number of non-malignant diseases such as genital warts and recurrent respiratory papillomatosis are attributable to HPV. Moreover, HPV forms have detected in several other cancers including esophageal squamous cell carcinoma, lung, prostate, ovarian, breast, skin, colorectal and urinary tract cancers, but associations with etiology in these cases is controversial. The aim of this systematic assessment was to estimate the prevalence of HPV infection and HPV types in HPV-associated cancers, HPV-related non-malignant diseases and in cancers that may be associated with HPV in Iran. The present investiagtion covered 61 studies on a variety of cancers in Iranian populations. HPV prevalence was 77.5 % and 32.4% in cervical cancer and head and neck cancers, respectively. HPV was detected in 23.1%, 22.2%, 10.4%, 30.9%, 14% and 25.2% of esophageal squamous cell, lung, prostate, urinary tract cancers, breast and skin cancers, respectively. HPV16 and 18 were the most frequent HPV types in all cancers. The findings of present study imply that current HPV vaccines for cervical cancer may decrease the burden of other cancers if they are really related to HPV.


Introduction
Cancer is one of the most important mortal agents in Iran.Breast cancer, with estimated the age standardized incidence rate (ASR) 18.4, is the first common cancer and cervical cancer is the eleventh frequent cancer in Iranian women.Prostate cancer, with reported ASR 11.6, is the second most prevalent in Iranian men.Stomach, colorectum, bladder, esophagus and lung cancers are common cancers in both sex (ASR=15.6,7.6, 7, 6.8 and 6.4per 100,000, respectively) (IARC, 2008).
Certain types of Human papillomaviruses (HPVs) are undoubtedly involved in human malignancies.One of the most important HPV-related cancers is cervical cancer that is the third most frequently cancer in women worldwide (Jemal et al., 2011;Moscicki et al., 2012).Also, HPV plays an etiological role in many vaginal, vulvar, anal, penile, as well as head and neck cancers (Gillison et al., 2012d;Moscicki et al., 2012).In addition, a number of non-malignant diseases such as genital warts and recurrent respiratory papillomatosis are attributable to HPV, particularly HPV6 and 11 (Chelimo et al., 2013;Gillison et al., 2012c).Moreover, HPV detected in several other cancers including esophageal squamous cell carcinoma (Syrjanen, 2002b;Tornesello et al., 2009), lung
In the HPV-associated cancers commonly several years after the initial infection, tumors progress in the epithelia.Persistent infection with expression of some viral genes, particularly E6 and E7 is needed for development of invasive cancer.However, most HPV infections have a benign outcome because nearly half of them clear within 6 months and up to 2 years the majority of cases clear from infection, but those that persist can progress to cancer (Rodriguez et al., 2010;Moscicki et al., 2012).
The aim of this systematic review is to estimate the prevalence of HPV infection and HPV types in HPV-

Materials and Methods
A systematic review of the published studies up to November 2013 was carried out to assess the prevalence and HPV types in variety of cancers that are associated with HPV (anogenital cancers as well as head and neck cancers) or may be associated with HPV.Data were obtained by searches of PubMed, Current Contents, Scopus and national databases including IranMedex, SID, Magiran with the following search terms: ''human papillomavirus (HPV)'', ''cancer/neoplasms'', ''epidemiology'', ''prevalence'', and "Iran".
The following information were obtained from each included article: first author, year of publication, journal name, study period, sample size, age, gender, city, type of cancer, HPV detection methods, HPV prevalence, HPV genotyping methods and HPV types.
After exclusion of some studies due to duplication or irrelevant data, 61 studies were included in this study.

Results
Present systematic review was included 61 studies on variety of cancers that strongly or weekly associated with HPV.Tables 1 and 2 summarize the studies on HPV-related cancers and cancers may be associated with HPV in Iranian population, respectively.The prevalence of HPV16 and 18 types in different kind of cancers were shown in Figure 1.

HPV associated-cancers
Anogenital cancers.HPV prevalence data only were available for cervical cancer, but not for the other kind of anogenital cancers including vulva, vagina, penil and anal.Crude HPV prevalence was 77.5%, 66.9%, 65.1%, 50.5% and 6.6% among ICC, HSIL, LSIL, ASCUS and normal cases in Iran (Table 3).HPV16 was the most prevalent HPV type for all five histological types, followed by HPV18, 6/11, 31 and 33 types.Also HPV45, 58, 59, 68 and 73 types were detected in a minority of subjects.Head and neck cancers.The crude HPV prevalence 32.4% was estimated in patients with Oral cavity and oropharyngeal cancers.Also, HPV was detected in 17% and 7.2% of oral lesions and Saliva and/or oral mucosa of healthy subjects, respectively (Table 3).The most common HPV types were HPV16 and 18, followed by 6, 11 and 31.

Cancers may be associated with HPV
Esophagus squamous cell carcinoma: The overall HPV prevalence in esophageal cancer and control groups was 23.1% and 10.2%, respectively.According to HPV types, the most common type was HPV16 (40.9%) in cases.The other high-risk types were HPV18, 31, 33, 45 and 52.In contrast, in control group the prominent type was HPV18 (70%) followed by HPV16 (30%).
Lung cancer: HPV positivity in lung cancer and corresponding control groups estimated 22.2% and 8.7%, respectively.The two most frequent types were HPV16 and 18 in cases, followed by 6/11 and 31, but HPV6/11 were prominent in control group.
Prostate cancer: The crude HPV prevalence was 10.4% versus 3.8% in prostate cancer cases and benign prostatic hyperplasia subjects, respectively.Regarding to HPV types, detection of HPV16 and 18 in cases were almost equal to controls.
Urinary tract cancers: Frequency of HPV estimated 30.9% and 5.3% in urinary tract cancer and control groups, respectively.The most frequent type was HPV18, followed by HPV16 in case and control groups.However, in case group other types including HPV6, 31, 33 and 52 detected in few samples.
Breast cancer: The overall HPV prevalence in breast cancer cases and control subjects was 14% and 1.1%, respectively.The most prevalent HPV type was HPV16 in breast cancer patients, followed by HPV6, 11 and 18.In few samples the other HPV types including 15, 23, 31, 33 and 124 detected.In control group, the only one HPV detected was HPV124.
Skin cancers: HPV positivity in non-melanoma skin cancers (squamous cell carcinoma [SCC] and basal cell carcinoma [BCC]) and control groups obtained 25.2% and 6.8%, respectively.According to histological stratification, HPV detected in 22.7% and 29.3% of SCC and BCC cases, respectively.Regarding to HPV types in skin cancer patients, HPV16 and 18 were more prevalent.The other types detected were HPV6, 11, 56.In control group, HPV types did not determine.
Conjunctiva squamous cell carcinoma: HPV was detected in 92% of conjunctiva cancer, but not among control group.All samples were negative for HPV16, 18, 31 and 33.

HPV-related non-malignant diseases
There are few reports about HPV prevalence and type distribution in genital warts (GW) (Nassiri et al., 2009;Jamshidi et al., 2012) and recurrent respiratory papillomatosis (RRP) (Izadi et al., 2012) in Iran.In these studies, HPV detected in 60.4% and 96.5% of GW and RRP cases, respectively.Nearly all HPV positive cases were infected with HPV6 and 11.In genital warts group, many subjects were coinfected with HPV6/11 (44%).

Discussion
This systematic review obtained from 61 published studies estimated the prevalence of HPV infection and HPV types in HPV-associated cancers, cancers may be associated with HPV and HPV-related non-malignant diseases in Iranian population.Therefore, present study allowed us to make the inclusive estimates of HPV prevalence and HPV types in different kind of cancers in Iran.
In most studies on ICC in Iran, HPV prevalence was less than 100% prevalence that might be attributable to low sensitivity of techniques used to detect HPV DNA.The overall HPV prevalence of HSIL and LSIL were 66.9% and 65.1%, respectively.HPV prevalence was diverse among HSIL and LSIL Iranian subjects that likely are result of small sample size and using different methods to detection of HPV.The six most common HPV types were HPV16, 18, 6/11, 31 and 33 in all groups.The most frequent HPV type was HPV16 followed by HPV18 in all five different histology.It is estimated that 70.1% of ICC are caused by HPV16 or 18 worldwide (Castellsague et al., 2007).
In present study HPV detected in 44.4% of patients with head and neck cancers.The most common HPV types were HPV16 and 18.It is demonstrated that HPV infection is causally related to head and neck cancers (Kreimer et al., 2005;Strati et al., 2006;Gillison et al., 2012b;Jung et al., 2010).A strong association between HPV16 and oropharyngeal cancer has been demonstrated in frequent case-control studies (Kreimer et al., 2005;Sudhoff et al., 2011).Moreover, a small fraction of head and neck cancers may be caused by further HPV types such as HPV18, 31, 33, 35 (Gillison et al., 2012a).
In all HPV weekly associated-cancers investigated in this study HPV detected in a number of cancer cases and control subjects.However, the HPV was more prevalent in cases versus controls.HPV16 and 18 were most frequent HPV types in all cancers ranging from 50% to 84.7%.These findings are consistent to some epidemiological studies that had been reported HPV detection in variety of cancers (Syrjanen, 2002a;2002b;Iftner et al., 2003;Rezazadeh et al., 2009a;Tornesello et al., 2009;Li et al., 2011;Lin et al., 2011;Munoz et al., 2012;Simoes et al., 2012).However, detection of HPV DNA in these cancers by PCR alone is inadequate to verify causality.Therefore, to confirm the casually role of HPV in these kind of cancers, it is mandatory to investigate the biological activities of HPV such as E6/E7 expression or integration in these precancerous and cancerous lesions.Moreover, experimental models are needed to investigate the initiation and maintenance processes of tumorgenesis in these cancers.If the association of HPV with these cancers proves, it will be good news for prevention of these malignancies as current HPV vaccines will reduce dramatically the incidence of them.
In conclusion, pooled data of epidemiological studies in Iran suggest that HPV may play an important role in progression of cancers of the esophagus, skin, breast, lung, prostate and urinary tract.However, these findings should be verified by precise investigation of HPV transformational activity in these cancers.In another aspect, findings of present study imply that current HPV vaccines for cervical cancer may decline the burden of other cancers if they will really relate to HPV.

Figure 1 .
Figure 1.Prevalence of HPV16 and 18 Types in a Variety of Cancers

Table 1 . List of Studies on HPV-related Cancers (Cervical Cancer and Head & Neck Cancers) and Healthy Subjects in Iranian Population
:http://dx.doi.org/10.7314/APJCP.2014.15.17.7029HumanPapillomavirus Burden in Different Cancers in Iran: A Systematic Assessment associated cancers, HPV-related non-malignant diseases and cancers may be associated with HPV in Iranian population.