ABSTRACT:

Introduction:

Colorectal cancer is one of the most prevalent types of tumors worldwide. Deaths caused by these malignant tumors remain high and have stayed practically at the same level for the last few decades. Among the established risk factors for the development of cancer are infections due to pathogens or viruses. Among the viruses, the human papillomavirus (HPV) is the most prevalent, with over 180 strains, 40 of which are directly related to anogenital infections.

Objective:

Systematically assess the main studies which link HPV to colorectal cancer with meta-analysis.

Methods:

The search strategy adopted was the logic based on specific descriptors (English language), in combination with the Boolean operators (AND/OR). The search was conducted in the following databases: PubMed, ScienceDirect, and Scientific Electronic Library Online (SciELO), between April and May 2015.

Results:

1,549 samples were assessed, with 956 (61.7%) being males. Six hundred thirty out of 1,358 cases of colorectal cancer due to HPV were diagnosed (51.9%). From these, 408 of 767 (51.9%) were male and 404 of 598 (67.5%) were linked to HPV 16 and 18, with tumor prevalence in the area of the cervix (253 of 411; 61.3%). From the total of 598 samples for the prevalence estimate of HPV 16 and 18, the number of cases with similar numbers was 204 (31.7%) and 200 (35.8%), respectively. Relatively significant numbers were found in the area of the cervix, 253 (61.3%), and the area of the rectum, 158 (38.7%).

Conclusion:

After conducting the present study, the link between HPV and colorectal cancer was made evident, without a distinction between the sexes, with similar values between HPV 16 and HPV 18.

Keywords:
Colorectal cancer; Human papillomavirus; HPV 16; HPV 18; Prevalence; Epidemiology

INTRODUCTION

Human papillomavirus (HPV) infection has come to be considered the most frequent worldwide. In the last two decades, studies conducted in China, the United States, Turkey, Belgium, Iran, Argentina, Peru, and Brazil (Table 1) have been indicating the concern with the number of new cases (incidence of the disease), a phenomenon that tends to rise significantly throughout the years, both in men and women, due to the elevated number of partners, homosexual relations, hygiene practices, smoking, and poor attention to protection during sexual contact¹1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87(12): 4990-7..

There are currently over 180 types of cancer, each with specific clinical and biological characteristics, those of which should be assessed for accurate diagnosis and adequate treatment of the disease¹1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87(12): 4990-7.. Cancer is a disorder that is characterized by the loss of control over cellular division and the capacity to invade other organic structures²2. Almeida VL, Leitão A, Reina LCB, Montanari CA, Donnici CL, Lopes MTP. Câncer e agentes antineoplásicos ciclo-celular específicos e ciclo-celular não específicos que interagem com o DNA: uma introdução. Quím Nova 2005; 28(1): 118-29. DOI: http://dx.doi.org/10.1590/S0100-40422005000100021
https://doi.org/10.1590/S0100-4042200500... . Invasive cancer neoplasia corresponds to this form of non-controlled cellular growth, known as “malignant tumors³3. Hollingsworth AB, Stough RG. Multicentric and contralateral invasive tumors identified with pre-op MRI in patients newly diagnosed with ductal carcinoma in situ of the breast. Breast J 2012; 18(5): 420-7. DOI: 10.1111/j.1524-4741.2012.01273.x
https://doi.org/10.1111/j.1524-4741.2012... .”

Despite the advances in diagnosis and treatment, deaths caused by these tumors continue to be high and have remained at the same level for the last four decades⁴4. Urban LABD, Schaefer MB, Duarte DL, Santos RP, Maranhão NMA, Kefalas AL, et al. Recommendations of Colégio Brasileiro de Radiologia e Diagnóstico por Imagem, Sociedade Brasileira de Mastologia, and Federação Brasileira das Associações de Ginecologia e Obstetrícia for imaging screening for breast cancer. Radiol Bras 2012; 45(6): 334-9. DOI: http://dx.doi.org/10.1590/S0100-39842012000600009
https://doi.org/10.1590/S0100-3984201200... . Average overall survival in the last five years has been described as around 55% for developed countries and 40% for countries in development⁵5. Lassance FAC, Lassance PMS, Garicochea B, Cotti GC, Cutait R. Câncer colorretal e síndromes hereditárias. Rev Med Saúde Brasília 2012; 1(1): 34-50..

Colorectal cancer is one of the most prevalent worldwide⁶6. Oliveira RG, Faria FF, Lima Junior ACB, Barros AC, Rodrigues FG, Andrade MMA, et al. Surgery in colorectal cancer: surgical approach of 74 patients from the Brazilian National Health System with colorectal cancer in a postgraduate program (residency) in coloproctology. Rev Bras Coloproct 2011; 31(1): 44-57.. In the United States, the disease is the third most diagnosed neoplasia⁷7. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clinic 2011; 61(2): 69-90. DOI: 10.3322/caac.20107
https://doi.org/10.3322/caac.20107... , whereas in Brazil it is among the six most prevalent types of cancer⁸8. Souza DL, Jerez-Roig J, Cabral FJ, Lima JR, Rutalira MK, Costa JAG. Colorectal cancer mortality in Brazil: predictions until the year 2025 and cancer control implications. Dis Colon Rectum 2014; 57(9): 1082-9. DOI: 10.1097/DCR.0000000000000186
https://doi.org/10.1097/DCR.000000000000... . The most common symptoms are changes in bowel habits, weight loss, abdominal pain, hematochezia, and anemia⁹9. Fedrizzi EN. Epidemiologia da infecção genital pelo HPV. Rev Bras Pat Trato Gen Inf 2011; 1(1): 3-8.. Most colorectal cancers develop slowly and gradually¹⁰10. Souto R, Falhari JPB, Cruz AD. O papilomavírus humano: um fator relacionado com a formação de neoplasias. Rev Bras Cancerol 2005; 51(2): 155-60.. Infections through pathogens or viruses are among the risk factors for the development of this cancer¹¹11. Siegel R, DeSantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clinic 2014; 64(2): 104-17. DOI: 10.3322/caac.21220
https://doi.org/10.3322/caac.21220... . It is estimated that at least 50% of sexually active individuals will come in contact with HPV at some point in their lives⁹9. Fedrizzi EN. Epidemiologia da infecção genital pelo HPV. Rev Bras Pat Trato Gen Inf 2011; 1(1): 3-8.. Regarding men and women in Brazil, the prevalence varies between 35 and 72%, with high-risk HPVs being responsible for 25-56% of cases. When the precancerous lesions and lesions linked to cancer are assessed, it is observed that HPV 16 and 18 are responsible for approximately 55% of the cases with high-risk lesions and around 70% of cases of cervical cancer, both in South America and in Brazil⁸8. Souza DL, Jerez-Roig J, Cabral FJ, Lima JR, Rutalira MK, Costa JAG. Colorectal cancer mortality in Brazil: predictions until the year 2025 and cancer control implications. Dis Colon Rectum 2014; 57(9): 1082-9. DOI: 10.1097/DCR.0000000000000186
https://doi.org/10.1097/DCR.000000000000... .

Another risk factor is the genetic predisposition, such as familial adenomatous polyposis or first degree relatives with colorectal cancer¹²12. Win AK, Walters RJ, Buchanan DD, Jenkins MA, Sweet K, Frankel WL, et al. Cancer risks for relatives of patients with serrated polyposis. Am J Gastroenterol 2012; 107(5): 770-8. DOI: 10.1038/ajg.2012.52
https://doi.org/10.1038/ajg.2012.52... . In addition, environmental factors such as smoking, alcohol consumption, and obesity, combined with the elevated consumption of red meat, are also understood as risk factors. Age is also an eminent factor in the appearance of colorectal cancer, and the incidence increases significantly between the ages of 30 and 50¹³13. Fu Z, Shrubsole MJ, Smalley WE, Wu H, Chen Z, Shyr Y, et al. Lifestyle factors and their combined impact on the risk of colorectal polyps. Am J Epidemiol 2012; 176(9): 766-76. DOI: 10.1093/aje/kws157
https://doi.org/10.1093/aje/kws157... .

During the clinical assessment, it is important to try to determine the stage of the disease utilizing the classification “tumor,” “lymph node,” and “metastasis,” which allow for the planning of treatment and facilitates the study of the results of the therapy employed. The purpose of the staging of the neoplastic disease is to identify not only the locoregional extension of the primary lesion, but also its extension and distance for the decision of the best treatment option¹⁴14. van der Zaag ES, Bouma WH, Tanis PJ, Ubbink DT, Bemelman WA, Buskens CJ. Systematic review of sentinel lymph node mapping procedure in colorectal cancer. Ann Surg Oncol 2012; 19(11): 3449-59. DOI: 10.1245/s10434-012-2417-0
https://doi.org/10.1245/s10434-012-2417-... .

Over 180 types of HPV have already been identified, and 40 of them are related to anogenital infections. Among the HPVs with high oncogenic risk are types 16 and 18¹⁵15. Leto MGP, Santos Júnior G, Porro AM, Tomimori J. Infecção pelo papilomavírus humano: etiopatogenia, biologia molecular e manifestações clínicas. An Bras Dermatol 2011; 86(2): 306-17. DOI: http://dx.doi.org/10.1590/S0365-05962011000200014
https://doi.org/10.1590/S0365-0596201100... . HPV 16 has been identified in up to 59.8% of invasive cancers and in over 50% of non-invasive cancers. Meanwhile, HPV 18 has been found in 15% of invasive neoplasias and in over 50% of adenocarcinomas¹⁶16. Rodrigues DA, Pereira ER, Oliveira LSS, Speck NMG, Gimeno SGA. Prevalence of cytological atypia and high-risk human papillomavirus infection in Panará indigenous women in Central Brazil. Cad Saúde Pública 2014; 30(12): 2587-93. DOI: http://dx.doi.org/10.1590/0102-31l'1X00152713
https://doi.org/10.1590/0102-31l'1X00152... .

The recurring HPV lesion is considered preneoplastic, in the form of a wart with koilocytosis, and is characterized by vegetating, non-keratotic, moist lesions, with a central nucleus of connective tissue and cauliflower-like appearance⁹9. Fedrizzi EN. Epidemiologia da infecção genital pelo HPV. Rev Bras Pat Trato Gen Inf 2011; 1(1): 3-8.. The lesion can have some malignant changes, reaching, many times, alarming proportions. Isolated or grouped, they manifest fibrous proliferations covered by pink thickened epithelial cells, without chronicity, located especially on the external genitals in the perianal area, as well as the mucous membrane¹1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87(12): 4990-7..

For an individual to develop a disease, the presence of the specific agent in their organism is not enough¹¹11. Siegel R, DeSantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clinic 2014; 64(2): 104-17. DOI: 10.3322/caac.21220
https://doi.org/10.3322/caac.21220... . Other factors, which are capable of provoking the disease along with the specific agents, need to take action. Due to HPV detection in most of the analyzed tissue with malignant tumors, there is a possible correlation with carcinogenesis in glandular cells of the colorectal mucosa¹1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87(12): 4990-7..

Thus, the present study has the objective of assessing, systematically and through meta-analysis, the main studies that link colorectal cancer to HPV.

METHODS

The study is characterized by a systematic review with meta-analysis. The study logic employed consisted in three health databases to identify the main studies that assessed the prevalence of colorectal cancer associated with HPV.

For the diagnosis of the disease, the implementation of polymerase chain reaction (PCR) of HPV through material embedded in paraffin wax is comparable to in situ hybridization⁴4. Urban LABD, Schaefer MB, Duarte DL, Santos RP, Maranhão NMA, Kefalas AL, et al. Recommendations of Colégio Brasileiro de Radiologia e Diagnóstico por Imagem, Sociedade Brasileira de Mastologia, and Federação Brasileira das Associações de Ginecologia e Obstetrícia for imaging screening for breast cancer. Radiol Bras 2012; 45(6): 334-9. DOI: http://dx.doi.org/10.1590/S0100-39842012000600009
https://doi.org/10.1590/S0100-3984201200... . Thus, PCR utilizing specific initiators can detect and amplify specific portions of the HPV genome of up to 119 base pairs (BP) of HPV fragments of the types 16 and 18, which represent part of the E6 or E7 of HPV.

INCLUSION CRITERIA

To be included in the systematic review, the papers should be cross-sectional studies or a control case linking colorectal cancer to HPV. Papers without any links or reviews (narrative, systematic, or meta-analysis), case reports or guidelines were excluded.

RESEARCH STRATEGY

For the research strategy, logic based on specific descriptors was adopted (English Language) in combination with Boolean operators (AND/OR), with the aid of parentheses, to define intercalation within the same logic, and quotations marks, to identify compound words. The search was conducted in the following manner: (HPV OR “Human Papillomavirus”) AND (Colorectal OR Rectal OR Colon) AND (Cancer). The databases utilized were: PubMed (Medline), ScienceDirect (Elsevier), and Scientific Electronic Library Online (SciELO) (Bireme), between April and May 2015.

To avoid the excessive inclusion of papers, the search was limited to the following fields: title, keywords, and abstract. This way, the descriptors must be contained in at least one of the three search fields (limitation filters were not added, for example: language of the paper, target audience, or date limit).

For the purpose of recruiting studies, after exporting the selected papers in the databases, a software that is specific for systematic reviews was utilized: State of the Art through Systematic Review (StArt)¹⁷17. Zamboni A, Di Thommazo A, Hernandes E, Fabbri S, editors. StArt: uma ferramenta computacional de apoio à revisão sistemática. In: Congresso Brasileiro de Software (CBSoft'10). Salvador, Brazil; 2010., which served as the base for identifying duplicate papers, both the included and excluded ones. These analyses were conducted separately by two researchers (T.P.; C.P.D.) and verified by a third editor (C.R.).

As eligibility criteria for the papers, three steps were adopted for the inclusion and exclusion: (a) papers selected by both researchers were included; (b) articles that were not selected were excluded; (c) articles included by only one researcher were analyzed by the editor, who authorized the inclusion if they fit the proposed framework.

To conduct the meta-analysis, after the eligibility of the papers and identifying the outcome variables, OpenMeta[Analyst]¹⁸18. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Soft 2010; 36(3): 1-48. software was utilized, with randomized statistical proportion being applied (univariate), with a confidence interval of 95% (CI95%), for colorectal cancer due to HPV prevalence estimates, as well as links to HPV 16 and 18, genders (male/female), and tumor region (cervix/rectum). For the case control group, randomized statistical proportion (bivariate) was employed, with odds ratio and CI95%, for prevalence estimates for colorectal cancer due to HPV between the case control groups.

To systematically record data, the study was previously registered on the following website: Centre for Reviews and Dissemination/International Prospective Register of Systematic Reviews (PROSPERO) (http://www.crd.york.ac.uk/PROSPERO), under the identification number CRD42015023199.

RESULTS

Initially, 431 papers were recovered (PubMed: 325; ScienceDirect: 92; SciELO: 14) by means of electronic searches. From these, 39 were excluded due to being duplicates and 327 due to being observational studies and not fitting within the proposed framework. Thus, 65 papers were read in their entirety, with 47 being excluded because they did not meet the eligibility criteria, resulting in a total of 18 eligible papers for the systematic review (14 cross-sectional studies and four case control studies), as demonstrated in the flowchart (Figure 1).

From the 18 eligible studies¹⁹19. Bodaghi S, Yamanegi K, Xiao SY, Costa M, Palefsky JM, Zheng ZM. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res 2005; 11(8): 2862-7. DOI: 10.1158/1078-0432.CCR-04-1680
https://doi.org/10.1158/1078-0432.CCR-04... ^,2019. Bodaghi S, Yamanegi K, Xiao SY, Costa M, Palefsky JM, Zheng ZM. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res 2005; 11(8): 2862-7. DOI: 10.1158/1078-0432.CCR-04-1680
https://doi.org/10.1158/1078-0432.CCR-04... ^,2121. Chen TH, Huang CC, Yeh KT, Chang SH, Chang SW, Sung WW, et al. Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer. World J Gastroenterol 2012; 18(30): 4051-8. DOI: 10.3748/wjg.v18.i30.4051
https://doi.org/10.3748/wjg.v18.i30.4051... ^,2222. Cheng J, Sheu LF, Meng CL, Lee WH, Lin JC. Detection of human papillomavirus DNA in colorectal carcinomas by polymerase chain reaction. Gut 1995; 37(1): 87-90.^,2323. Damin DC, Caetano MB, Rosito MA, Schwartsmann G, Damin A, Frazzon A, et al. Evidence for an association of human papillomavirus infection and colorectal cancer. Eur J Surg Oncol 2007; 33(5): 569-74. DOI: 10.1016/j.ejso.2007.01.014
https://doi.org/10.1016/j.ejso.2007.01.0... ^,2424. Deschoolmeester V, Van Marck V, Baay M, Weyn C, Vermeulen P, Van Marck E, et al. Detection of HPV and the role of p16INK4A overexpression as a surrogate marker for the presence of functional HPV oncoprotein E7 in colorectal cancer. BMC Cancer 2010; 10(1): 117. DOI: 10.1186/1471-2407-10-117
https://doi.org/10.1186/1471-2407-10-117... ^,2525. Giuliani L, Ronci C, Bonifacio D, Di Bonito L, Favalli C, Perno CF, et al. Detection of oncogenic DNA viruses in colorectal cancer. Anticancer Res 2008; 28(2B): 1405-10.^,2626. Karbasi A, Borhani N, Daliri K, Kazemi B, Manoochehri M. Downregulation of external death receptor genes FAS and DR5 in colorectal cancer samples positive for human papillomavirus infection. Pathol Res Pract 2015; 211(6): 444-8. DOI: 10.1016/j.prp.2015.02.001
https://doi.org/10.1016/j.prp.2015.02.00... ^,2727. Liu F, Mou X, Zhao N, Lin J, Teng L, Xiang C. Prevalence of human papillomavirus in Chinese patients with colorectal cancer. Colorectal Dis 2011; 13(8): 865-71. DOI: 10.1111/j.1463-1318.2010.02335.x
https://doi.org/10.1111/j.1463-1318.2010... ^,2828. Pérez LO, Abba MC, Dulout FN, Golijow CD. Evaluation of p53 codon 72 polymorphism in adenocarcinomas of the colon and rectum in La Plata, Argentina. World J Gastroenterol 2006; 12(9): 1426-9.^,2929. Pérez LO, Barbisan G, Ottino A, Pianzola H, Golijow CD. Human papillomavirus DNA and oncogene alterations in colorectal tumors. Pathol Oncol Res 2010; 16(3): 461-8. DOI: 10.1007/s12253-010-9246-x
https://doi.org/10.1007/s12253-010-9246-... ^,3030. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... ^,3131. Quinn R, Salvatierra J, Solari V, Calderon M, Ton TG, Zunt JR. Human papillomavirus infection in men who have sex with men in Lima, Peru. AIDS Res Human Retroviruses 2012; 28(12): 1734-8.^,3232. Ranjbar R, Saberfar E, Shamsaie A, Ghasemian E. The aetiological role of human papillomavirus in colorectal carcinoma: an Iranian population-based case control study. Asian Pac J Cancer Prev 2014; 15(4): 1521-5.^,3333. Salepci T, Yazici H, Dane F, Topuz E, Dalay N, Onat H, et al. Detection of human papillomavirus DNA by polymerase chain reaction and southern blot hybridization in colorectal cancer patients. J BUON 2009; 14(3): 495-9.^,3434. Sayhan N, Yazici H, Budak M, Bitisik O, Dalay N. P53 codon 72 genotypes in colon cancer. Association with human papillomavirus infection. Res Commun Mol Pathol Pharmacol 2001; 109(1-2): 25-34.^,3535. Soares PC, Ferreira S, Villa LL, Matos D. Identificação do papilomavírus humano em doentes com carcinoma de células escamosas do canal anal e sua relação com o grau de diferenciação celular e estadiamento. Rev Bras Coloproct 2011; 31(1): 8-16. DOI: http://dx.doi.org/10.1590/S0101-98802011000100002
https://doi.org/10.1590/S0101-9880201100... ^,3636. Sun ZQ, Wang HJ, Zhao ZL, Wang QS, Fan CW, Fang F. Significance of HPV infection and genic mutation of APC and K-ras in patients with rectal cancer. Asian Pac J Cancer Prev 2013; 14(1): 121-6., 7 (38.9%) were conducted in the United States (1), in Brazil (3), in Argentina (2), in Peru (1), 5 (27.8%) in Europe, and 6 (33.3%) in Asia. From the 18 articles written in the last 20 years, 16 (88.9%) were published in the last 10 years (Table 1).

During this period, 1,549 samples were assessed, with 956 (61.7%) being male samples. From these, 630 cases of colorectal cancer due to HPV (51.8%) were diagnosed, of which 408 (51.9%) were males. In addition, 404 (67.5%) cases were linked to HPV 16 and 18, with tumor prevalence in the area of the cervix, 253 (61.3%), and the majority of patients were identified in stages II and III (103, 31.6%; 121, 37.8%, respectively), as exposed in Table 2.

Figure 2 presents the total prevalence of colorectal cancer due to HPV with an estimate of 51.8% (CI95% 35.7 - 66.0). When comparing cases and controls (98/262; 28/224, respectively), in 4 of the 18 studies²²22. Cheng J, Sheu LF, Meng CL, Lee WH, Lin JC. Detection of human papillomavirus DNA in colorectal carcinomas by polymerase chain reaction. Gut 1995; 37(1): 87-90.^,3030. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... ^,3232. Ranjbar R, Saberfar E, Shamsaie A, Ghasemian E. The aetiological role of human papillomavirus in colorectal carcinoma: an Iranian population-based case control study. Asian Pac J Cancer Prev 2014; 15(4): 1521-5.^,3535. Soares PC, Ferreira S, Villa LL, Matos D. Identificação do papilomavírus humano em doentes com carcinoma de células escamosas do canal anal e sua relação com o grau de diferenciação celular e estadiamento. Rev Bras Coloproct 2011; 31(1): 8-16. DOI: http://dx.doi.org/10.1590/S0101-98802011000100002
https://doi.org/10.1590/S0101-9880201100... , the estimate of the difference of colorectal cancer risk due to HPV was 24.3% (CI95% 4.5 - 44.0), with odds ratio values of 4.661 (CI95% 2.500 - 8.688) (Figure 2).

When comparing genders, 10 out of the 18 eligible papers were assessed, from the total of 767 samples, for the estimate of colorectal cancer prevalence, indicating similar values for males and females, 408 (51.9%; CI95% 46.5 - 57.3) and 359 (48.1%; CI95% 42.7 - 53.5), respectively.

Meanwhile, for the estimate of prevalence due to HPV 16 and 18, 16 of the 18 eligible papers were assessed (Figure 3), from the total of 598 samples, presenting very similar numbers for the types of manifestation of the virus, 204 (31.7%; CI95% 18.6 - 44.7) and 200 (35.8%; CI95% 22.0 - 49.5), in this order.

In the assessment of the estimate of colorectal cancer prevalence by region, eight of the 18 papers²¹21. Chen TH, Huang CC, Yeh KT, Chang SH, Chang SW, Sung WW, et al. Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer. World J Gastroenterol 2012; 18(30): 4051-8. DOI: 10.3748/wjg.v18.i30.4051
https://doi.org/10.3748/wjg.v18.i30.4051... ^,2323. Damin DC, Caetano MB, Rosito MA, Schwartsmann G, Damin A, Frazzon A, et al. Evidence for an association of human papillomavirus infection and colorectal cancer. Eur J Surg Oncol 2007; 33(5): 569-74. DOI: 10.1016/j.ejso.2007.01.014
https://doi.org/10.1016/j.ejso.2007.01.0... ^,2424. Deschoolmeester V, Van Marck V, Baay M, Weyn C, Vermeulen P, Van Marck E, et al. Detection of HPV and the role of p16INK4A overexpression as a surrogate marker for the presence of functional HPV oncoprotein E7 in colorectal cancer. BMC Cancer 2010; 10(1): 117. DOI: 10.1186/1471-2407-10-117
https://doi.org/10.1186/1471-2407-10-117... ^,2525. Giuliani L, Ronci C, Bonifacio D, Di Bonito L, Favalli C, Perno CF, et al. Detection of oncogenic DNA viruses in colorectal cancer. Anticancer Res 2008; 28(2B): 1405-10.^,2626. Karbasi A, Borhani N, Daliri K, Kazemi B, Manoochehri M. Downregulation of external death receptor genes FAS and DR5 in colorectal cancer samples positive for human papillomavirus infection. Pathol Res Pract 2015; 211(6): 444-8. DOI: 10.1016/j.prp.2015.02.001
https://doi.org/10.1016/j.prp.2015.02.00... ^,2929. Pérez LO, Barbisan G, Ottino A, Pianzola H, Golijow CD. Human papillomavirus DNA and oncogene alterations in colorectal tumors. Pathol Oncol Res 2010; 16(3): 461-8. DOI: 10.1007/s12253-010-9246-x
https://doi.org/10.1007/s12253-010-9246-... ^,3030. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... ^,3232. Ranjbar R, Saberfar E, Shamsaie A, Ghasemian E. The aetiological role of human papillomavirus in colorectal carcinoma: an Iranian population-based case control study. Asian Pac J Cancer Prev 2014; 15(4): 1521-5., from the total of 411 samples, presented relatively expressive values for the cervical area, 253 (61.3%; CI95% 50.4 - 72.3) and for the rectal area, 158 (38.7%; CI95% 27.7 - 49.6).

DISCUSSION

After analyzing the published manuscripts from the last two decades, it became evident that there is a link between colorectal cancer and HPV. Expressive values were observed in the prevalence of HPV (51.8%) (Figure 2), especially for types 16 and 18 (Table 2 and Figure 3), due to late diagnosis, seeing that the confirmation of the disease is more frequent in stage III (Table 2). Another factor that was observed is the lack of evidence in the differences between genders regarding the prevalence of colorectal cancer due to HPV, seeing that both sexes presented similar values.

Based on the complete reading of the 18 eligible papers for the systematic study¹⁹19. Bodaghi S, Yamanegi K, Xiao SY, Costa M, Palefsky JM, Zheng ZM. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res 2005; 11(8): 2862-7. DOI: 10.1158/1078-0432.CCR-04-1680
https://doi.org/10.1158/1078-0432.CCR-04... ^,2019. Bodaghi S, Yamanegi K, Xiao SY, Costa M, Palefsky JM, Zheng ZM. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res 2005; 11(8): 2862-7. DOI: 10.1158/1078-0432.CCR-04-1680
https://doi.org/10.1158/1078-0432.CCR-04... ^,2121. Chen TH, Huang CC, Yeh KT, Chang SH, Chang SW, Sung WW, et al. Human papilloma virus 16 E6 oncoprotein associated with p53 inactivation in colorectal cancer. World J Gastroenterol 2012; 18(30): 4051-8. DOI: 10.3748/wjg.v18.i30.4051
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https://doi.org/10.1016/j.ejso.2007.01.0... ^,2424. Deschoolmeester V, Van Marck V, Baay M, Weyn C, Vermeulen P, Van Marck E, et al. Detection of HPV and the role of p16INK4A overexpression as a surrogate marker for the presence of functional HPV oncoprotein E7 in colorectal cancer. BMC Cancer 2010; 10(1): 117. DOI: 10.1186/1471-2407-10-117
https://doi.org/10.1186/1471-2407-10-117... ^,2525. Giuliani L, Ronci C, Bonifacio D, Di Bonito L, Favalli C, Perno CF, et al. Detection of oncogenic DNA viruses in colorectal cancer. Anticancer Res 2008; 28(2B): 1405-10.^,2626. Karbasi A, Borhani N, Daliri K, Kazemi B, Manoochehri M. Downregulation of external death receptor genes FAS and DR5 in colorectal cancer samples positive for human papillomavirus infection. Pathol Res Pract 2015; 211(6): 444-8. DOI: 10.1016/j.prp.2015.02.001
https://doi.org/10.1016/j.prp.2015.02.00... ^,2727. Liu F, Mou X, Zhao N, Lin J, Teng L, Xiang C. Prevalence of human papillomavirus in Chinese patients with colorectal cancer. Colorectal Dis 2011; 13(8): 865-71. DOI: 10.1111/j.1463-1318.2010.02335.x
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https://doi.org/10.1007/s12253-010-9246-... ^,3030. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... ^,3131. Quinn R, Salvatierra J, Solari V, Calderon M, Ton TG, Zunt JR. Human papillomavirus infection in men who have sex with men in Lima, Peru. AIDS Res Human Retroviruses 2012; 28(12): 1734-8.^,3232. Ranjbar R, Saberfar E, Shamsaie A, Ghasemian E. The aetiological role of human papillomavirus in colorectal carcinoma: an Iranian population-based case control study. Asian Pac J Cancer Prev 2014; 15(4): 1521-5.^,3333. Salepci T, Yazici H, Dane F, Topuz E, Dalay N, Onat H, et al. Detection of human papillomavirus DNA by polymerase chain reaction and southern blot hybridization in colorectal cancer patients. J BUON 2009; 14(3): 495-9.^,3434. Sayhan N, Yazici H, Budak M, Bitisik O, Dalay N. P53 codon 72 genotypes in colon cancer. Association with human papillomavirus infection. Res Commun Mol Pathol Pharmacol 2001; 109(1-2): 25-34.^,3535. Soares PC, Ferreira S, Villa LL, Matos D. Identificação do papilomavírus humano em doentes com carcinoma de células escamosas do canal anal e sua relação com o grau de diferenciação celular e estadiamento. Rev Bras Coloproct 2011; 31(1): 8-16. DOI: http://dx.doi.org/10.1590/S0101-98802011000100002
https://doi.org/10.1590/S0101-9880201100... ^,3636. Sun ZQ, Wang HJ, Zhao ZL, Wang QS, Fan CW, Fang F. Significance of HPV infection and genic mutation of APC and K-ras in patients with rectal cancer. Asian Pac J Cancer Prev 2013; 14(1): 121-6., it was found that the location where HPV is most predominant is the cervical area, the vulva, the vagina, and the anus, since they are associated with chronic infections, preceded by non-malignant precursor lesions, like the cervical squamous intraepithelial lesion (CSIL) and the anal squamous intraepithelial lesions (ASIL), with predilection being shown for the zone of cellular transition of glandular squamous cells, seeing that both have common biological characteristics, including histopathological aspects.

In the assessed studies, the samples from the patients diagnosed with colorectal carcinomas pointed to one or more copies of viral HPV DNA, since viral HPV presents tropism through glandular epithelial cells and is the cause of skin and mucosal infections. According to Giuliani et al.²⁵25. Giuliani L, Ronci C, Bonifacio D, Di Bonito L, Favalli C, Perno CF, et al. Detection of oncogenic DNA viruses in colorectal cancer. Anticancer Res 2008; 28(2B): 1405-10., taking into consideration the known molecular mechanisms of these individual viruses, there is a possibility that they will alter the control mechanisms of the cellular cycle, inhibiting apoptosis, causing chromosomal instability, and promoting colorectal oncogenesis.

Bodaghi et al.¹⁹19. Bodaghi S, Yamanegi K, Xiao SY, Costa M, Palefsky JM, Zheng ZM. Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res 2005; 11(8): 2862-7. DOI: 10.1158/1078-0432.CCR-04-1680
https://doi.org/10.1158/1078-0432.CCR-04... , Damin et al.²³23. Damin DC, Caetano MB, Rosito MA, Schwartsmann G, Damin A, Frazzon A, et al. Evidence for an association of human papillomavirus infection and colorectal cancer. Eur J Surg Oncol 2007; 33(5): 569-74. DOI: 10.1016/j.ejso.2007.01.014
https://doi.org/10.1016/j.ejso.2007.01.0... , and Sun et al.³⁶36. Sun ZQ, Wang HJ, Zhao ZL, Wang QS, Fan CW, Fang F. Significance of HPV infection and genic mutation of APC and K-ras in patients with rectal cancer. Asian Pac J Cancer Prev 2013; 14(1): 121-6. affirm that, although the number of HPV DNA copies may be low, viral HPV plays an active role in the pathogenesis of the colorectal carcinoma, displaying higher prevalence of type 16, followed by type 18. Thus, it is possible to affirm that, overall, the viral cause favors genetic instability and contributes to carcinogenesis.

The dot blot hybridization has been utilized in various studies with the intention of detecting HPV DNA in material extracted through biopsies. This method presents lower sensibility and specificity when compared to the Southern blot hybridization. This data can explain the variation noted worldwide regarding the prevalence of HPV in the most varied areas of the human body, due to the techniques employed to detect HPV DNA (Table 1).

It is a well-established fact that the accumulation of genetic alterations can lead to the development of cancer. This phenomenon has been extensively investigated by various authors, above all regarding colorectal cancer, whose model is considered ideal for the comprehension of the carcinogenic process, due to the progression from pre-malignancy to malignancy. However, Picanço-Júnior et al.³⁰30. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... did not find a correlation between staging and cellular differentiation with the presence of HPV 16, despite being evident in other systematic studies that HPV infection can be a risk factor for the increase of colorectal cancer prevalence. It is possible that the discrepancy in the results found by Picanço-Júnior et al.³⁰30. Picanço-Júnior OM, Oliveira ALT, Freire LTM, Brito RB, Villa LL, Matos D. Associação do papilomavírus humano com o adenocarcinoma colorretal e sua influência no estadio tumoral e no grau de diferenciação celular. ABCD Arq Bras Cir Dig 2014; 27(3): 172-6. DOI: http://dx.doi.org/10.1590/S0102-67202014000300003
https://doi.org/10.1590/S0102-6720201400... is linked to the use of different techniques or inadequate material, which causes the lack of evidence in these studies.

CONCLUSION

During the research period of this study, colorectal cancer owing to HPV was diagnosed in 51.8% of cases. Of these, the majority was linked to HPV 16 and 18, with tumor prevalence in the cervical area and a similarity between genders. Therefore, HPV infection, as nowadays it is one of the most common sexually transmitted diseases worldwide and as it is linked to colorectal cancer, has become an important method in early diagnosis for the prevention of new cases, and it also enables new studies to facilitate the prognostic and treatment of the disease.

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