Anal cancer is relatively uncommon, accounting for about 2.7% of all reported gastrointestinal cancers in the United States (US) [1]. In 2022, it is expected that there will be 9440 new cases and 1670 deaths due to anal cancer [1].

The anal canal is a short (3–4 cm) segment located distal to the rectum, commencing at the anorectal ring and extending to the anal verge. There are different types of epithelium located in this region, including, from proximal to distal: (1) colorectal-like columnar epithelium; (2) stratified columnar epithelium, which is similar to transitional epithelium of the genitourinary tract; (3) non-keratinized squamous cell epithelium [2]. A hair-bearing squamous epithelium commences at the anal verge, and the region located within 5 cm of the anal verge, is defined as perianal skin [2]. The tumors located in anal region are classified as anal canal and anal margin cancers [2]. Anal squamous cell cancer (SCC) occurs most frequently, accounting for approximately 80% to 85% of all anal canal cancers ^[3][4].

The importance of understanding the pathogenesis and risk factors for anal cancer has been recognized over the last several decades due to an increase in incidence that has been noticed worldwide.

Human papillomavirus (HPV) infection, female sex, total lifetime number of sexual partners, a history of sexually transmitted viral infections, cigarette smoking, receptive anal intercourse, and HIV infection are all risk factors for anal cancer ^[4][5]. Patients taking immunosuppressive therapy, e.g., after organ transplantation, have an increased risk of developing anal cancer as well. Risk factors related to female sex include history of high grade vulvar intraepithelial neoplasia, vulvar or cervical cancer ^[4][5].

2. Inflammation and Cancer

In 1863, Rudolf Virchow established the first hypothesis about the association between inflammation and cancer based on the presence of leukocytes in neoplastic tissue ^[5][6]. Since then, the role of inflammation in tumorigenesis has been extensively investigated. However, its exact impact has not yet been fully elucidated. According to the literature, only 10% of cancers are caused by germline mutations, while others are related to somatic mutations and environmental factors. It is considered that nearly 20% of cancers are associated with chronic infection ^[6][7]. Infections, autoimmune diseases, and inflammatory diseases of unknown etiology cause chronic inflammation and an increased risk of tumorigenesis ^[5][6]. Chronic inflammation has been associated with different pathophysiological mechanisms that lead to cellular transformation and several changes in immunological response, allowing tumor cells to avoid apoptosis and immune surveillance ^[7][8]. These findings highlight the significance of prevention and early detection of infection. Continuous education and implementation of screening programs might result in the prevention of the development of chronic infection and inflammation and thus reduce rates of cancer associated with inflammation.

3. HPV Infection and Anal Cancer

Human papillomavirus (HPV) is a double stranded DNA virus that is transmitted through skin or mucosal lesions due to direct skin or mucosal contact with the infected area. HPV infection is considered the most common sexually transmitted infection ^[4][5]. According to the available data, the risk of being infected at least once in a lifetime for both men and women is 50% ^[8][9]. Risk factors for HPV infection, particularly oncogenic types, are younger age, “men having sex with men” (MSM) population, presence of two or more sexually transmitted infections, and immunosuppression ^[9][10]. The established role of HPV infection in cervical cancer pathogenesis has provoked an interest in elucidating its potential role in the pathogenesis of other cancers. Therefore, it has been widely recognized as an important factor in the tumorigenesis of epithelial squamous cell cancers of different locations, especially of the oropharynx and anogenital tract. HPV infection is recognized as one of the most significant factors included in anal SCC tumorigenesis. According to a recent systematic review, 72% of patients diagnosed with anal cancer were HPV DNA positive ^[4][5]. In addition, several studies have reported a presence of HPV infection in 80% to 97% of patients with diagnosed anal cancer ^{[3][10][11][12][13][14]}[4,11,12,13,14,15]. In women with diagnosed cervical HPV infection, especially caused by high risk HPV types 16 and 18, screening for anal cancer should be considered. However, there is no consensus in guidelines regarding screening for AIN and anal cancer. The decision should be made according to the presence of symptoms, risk factors, concomitant diseases—especially the presence of other HPV-related diseases—and/or medications. Other established risk factors, such as a high lifetime number of sexual partners and receptive anal intercourse, essentially increase the risk of exposure to HPV, which can lead to persistent infection and potential anal intraepithelial neoplasia (AIN) formation ^[10][11]. Drug-induced immunosuppression and immunodeficiency caused by HIV promote anal HPV infection. Exposure to the risk factors has significantly increased over the past few decades due to social, cultural, and lifestyle changes. At this point, it is important to highlight the influence of HIV stigmatization on seeking medical attention and early detection of other diseases in HIV-infected individuals. According to a recent study ^[15][16], HIV-infected women in Nigeria who experienced HIV stigmatization stated that it impeded their cervical screening acceptance. People living with HIV often face stigma and discrimination in their community, but also in healthcare settings. It is important to implement a continuous HIV/AIDS education program for community members and healthcare providers in order to raise awareness of the problems HIV-infected individuals face in everyday life and to enable their appropriate medical treatment. There are over 200 known HPV strains. Among them, types 6, 11, 16, and 18 are associated with anal infection ^[3][13][4,14]. Besides these types, some researchers discovered a connection between types 31, 33, and 45 and anal cancer ^[16][17]. Types 6 and 11 are considered “low risk” strains, as they mainly cause the development of papillomas, whose progression to invasive anal cancer in immunocompetent individuals is uncommon ^[13][17][18][14,18,19]. However, types 16 and 18 are related to a higher risk of AIN and cancer development ^[19][20]. Type 16 is thought to be responsible for up to 75% of invasive anal cancers ^[3][4]. The transitional squamocolumnar epithelium is considered the most vulnerable zone to HPV infection ^[20][21]. Chronic HPV infection with a high viral load enhances the possibility of AIN development. HPV infects basal epithelial cells and stimulates transcription of a few “early” and “late” viral proteins ^[21][22]. E1–E8 are known as “early” viral genes, and they promote viral replication and viral protein translation ^[13][14]. Oncoproteins E6 and E7 reduce tumor suppressor protein p53 and the retinoblastoma protein (Rb) activity in epithelial cells, which causes viral genome replication and epithelial cell proliferation. These changes lead to dysplasia, which can progress to invasive anal cancer ^[13][14]. Progression of AIN grade III to invasive cancer has been observed in up to 13% of patients over a 5-year period and in about 50% of immunosuppressed patients ^[22][23]. Education about sexually transmitted diseases and promotion of vaccination against HPV in both girls and boys are of great importance and should be implemented in everyday clinical practice. It is considered that up to 80% of anal cancers could be prevented by vaccination against oncogenic HPV (against HPV types 6, 11, 16, and 18) ^[10][11].

4. HIV Infection and Anal Cancer

HIV infection has been established as an independent risk factor for anal cancer. HIV-infected individuals have a 15 to 40–fold higher risk of being diagnosed with anal cancer in comparison to the general population ^[4][23][5,24]. In addition, according to one study, HIV-infected individuals had a 120-fold higher risk when compared to HIV-negative individuals ^[24][25]. It is especially common among HIV-infected MSM ^[25][26]. According to the current literature, AIN prevalence ranges from 26% to 89% in HIV-infected patients ^[3][4]. In addition, a higher rate of AIN progression into invasive cancer has also been reported in HIV-infected individuals, even in those without AIDS ^[13][14]. After 1996, the anal cancer incidence increased in comparison to the rates before this period, 75–135 vs. 15 per 100,000 person-years, respectively ^[4][10][5,11], and it is now being recognized as the fourth most common cancer in HIV-infected individuals ^[26][27]. Interestingly, highly active antiretroviral therapy (HAART) does not have an effect on the anal cancer incidence rate in this population ^[27][28]. Implementation of anal cancer screening programs in HIV-infected individuals has shown no benefit in incidence and mortality reduction ^[28][29]. However, some guidelines recommend routine screening for AIN in this population.

5. HPV and HIV Coinfection in Anal Cancer

It is well established that HPV infection occurs more often in HIV-infected individuals. According to the current literature, over 90% of HIV positive MSM have HPV coinfection ^[29][30]. Furthermore, an increased rate of anal SCC has been observed in patients with HIV and HPV coinfection ^[30][31][31,32]. The immunological and cellular changes due to HPV and HIV coinfection are complex and have not yet been fully elucidated. Previously, it was thought that HIV infection enhances HPV’s oncogenic potential by reducing the immune response. However, recent studies suggest that an increased oncogenic potential is a consequence of microenvironmental changes in the anal epithelium ^[32][33]. It is considered that increased risk is not only the result of a low circulating CD4+ cells, because higher rates of anal cancer have been observed among HIV-infected individuals even when their CD4+ cell count is normal. This observation leads to the conclusion that other pathways are likely involved in the etiology of anal cancer associated with HPV and HIV coinfection. Therefore, recent studies have investigated the role of CD8+ cells and the PD-1/PD-L1 axis ^[13][14]. According to the new findings, coinfection occurs locoregionally, in the anal epithelium. HIV impairs epithelial integrity and thus facilitates HPV infection ^[33][34]. HIV enters the cells via CD4, CXCR4, and CCR5 receptors ^[34][35]. Immune cells with these receptors are especially present in the distal part of the gastrointestinal tract ^[35][36]. As a result, anal epithelial cells are exposed to infected immune cells and HIV infection at a local level ^[13][14]. The HIV Tat protein is a significant factor included in pathophysiological mechanisms. HIV-infected immune cells secrete the HIV Tat protein, which is believed to enter anal epithelial cells and promote viral DNA transcription and replication ^[36][37][37,38]. HIV Tat protein binds not only RNA polymerase II but also several other proteins involved in the transcription of integrated viral DNA ^[32][38][33,39]. The HIV Tat protein stimulates viral genome replication by enhancing the expression of proteins E6, E7, and E2 ^[13][39][40][14,40,41]. In addition, it has been discovered that it also lowers p53 levels in cervical carcinoma ^[41][42]. Furthermore, HPV infection also facilitates HIV infection. CD4+ cells, dendritic cells, and macrophages are considered HIV target cells. According to studies, the presence of these cells has been reported in HPV-associated anal lesions ^[42][43].