Key words : Anal neoplasm, Human papillomavirus, Immunosuppression

Introduction

De novo neoplasia represents one of the most threatening complications after solid-organ transplant (SOT). Specifically, data from transplant recipients have shown a 2-fold increased risk for development of any type of cancer compared with that shown in the general population.¹ A depressed immune system represents the main cause mediating risk for development of neoplasia, although a complex interac-tion of factors may also contribute (e.g., comorbidities, social habits, viral infections, and genetic predispositions). Anal squamous cell carcino-ma (ASCC) is one of the most frequent histotypes in the anal tract of immunocompromised patients, such as SOT recipients and patients who are HIV positive. A recent meta-analysis showed an incidence rate (IR), as cases per 100 000 person-year, of 13 (95% CI 12-15) for ASCC in SOT, reaching 24.5 and 49.6 for male and female patients, respectively, >10 years posttransplant.² Furthermore, in a large population-based cohort study conducted using the Danish National Patient Registry and the Danish Cancer Registry, data confirmed an increased risk of ASCC, in particular among renal transplant recipients (standard incidence ratio [SIR] of 14.4; 95% CI, 7.0-26.4).³ Persistent infection with high-risk human papillomavirus (HPV) types (e.g., HPV-16 and HPV-18) has been largely recognized as one of the most important causes for the development of precancerous anal lesions (e.g., low-grade and high-grade intraepithe-lial lesions)⁴ and for anal cancer in the general population. Despite the identification of risk factors such as isolation of high-risk HPV and several other factors (e.g., older age, cigarette smoking, receptive anal intercourse, and number of partners), there remains uncertainty on the pathophysiological determinants of ASCC in SOT recipients. Reports on the incidence of anal tract lesions in transplant recipients often present several limitations, including the absence of widely, routinely available screening tests, leading to the risks of disease underes-timation.^3,5,6 In addition, to date, the mechanisms of carcinogenesis and cancer progression of ASCC in transplant recipients have been poorly studied, and the interpretation of the related biological data remains suboptimal.⁵

Here, we conducted a comprehensive literature review to evaluate the mechanisms involved in the development of ASCC after SOT, which was aimed at elucidating the pathogenesis of ASCC and its biological interplay with HPV infection.

Materials and Methods

Based on inclusion and exclusion criteria, the studies were considered eligible if they concerned ASCC following SOT. Any type of data related to cancer pathogenesis, including weak or partially discussed, were considered a critical aspect for inclusion. All studies that exclusively reported data on pediatric populations or on preclinical work, in addition to those that exclusively described intra-operative techniques or epidemiological reports, were excluded. When duplicate publications reporting on similar data were considered, only the most complete and recent data set was included.

Search strategy
The MEDLINE, Thomson Reuters Web of Science, Scopus, and Cochrane Database of Systematic Reviews medical databases were consulted, with date of inclusion until June 1, 2020. The search string was discussed with a qualified librarian.

As shown in Table 1, key words and medical subject headings (MeSH) included “anal neoplasm” AND “organ transplantation”. Moreover, attempts to include additional studies were also made by manual search of citations in published studies. Only clinical studies in English were selected. A manual cross-reference search for eligible papers was performed to identify additional relevant articles. Two researchers (AC and AB) independently reviewed and selected the studies obtained from the initial search results, with matching of inclusion criteria. Unpublished data or findings published in conference collected abstracts were not used. Also, we decided to concentrate on the interpretation of patterns of increased risk rather than to focus on specific factors handled by a single report. Whenever there was discordance about study inclusion, the 2 researchers negotiated an agreement. Disagreements over the eligibility of particular studies were resolved through discussion with a third reviewer.

Quality assessment of articles
The methodological quality of the articles was independently assessed by the same 2 researchers mentioned above. Included randomized controlled trials were assessed for bias using the Cochrane Collaboration’s tool, whereas cohort/observational studies were assessed with the Newcastle-Ottawa scale. The quality assessment list consisted of the following variables: clear indication of de novo ASCC in transplant patient, relevant data on anal carcinogenesis in the study, and number of patients (greater or fewer than 10 cases).

Data extraction
Data were extracted only from original articles using a preformatted electronic sheet with the following predefined parameters: clinical characteristics, etiology, and pathogenesis.

Results

Study selection
Figure 1 outlines the study selection process. The initial search yielded 497 articles, 469 of which did not meet the inclusion criteria. In addition, 362 papers were excluded on the basis of their title alone as these indicated topics unrelated to ASCC in SOT or were duplicate papers. Another 38 articles were excluded as they summarized case reports or review articles without original data. Of 57 candidate articles, 36 were excluded after full text evaluation. The resulting 21 studies included in our analyses are listed chronologically in Table 2: 13 were retrospective series, and 8 were prospective studies.

Baseline study characteristics
Summary information regarding ASCC from the included studies is provided in Table 2. Clear identification of transplant populations and the type of solid organs that were transplanted are described in 19 articles. Among the studies selected, the data mainly related to the incidence and clinical aspects of anal lesions; basically, the general mechanisms of pathogenesis of the tumor were analyzed but not in depth. In addition, most of them, except for few selected studies, addressed risk factors associated with ASCC. In consideration of the specific aim, no studies were acceptable for a meta-analysis report, and the authors agreed to restrict the work to a systematic review of the published reports.

Anal squamous cell carcinoma in solid-organ transplant
We found that ASCC was mostly related to the combined effects of immunosuppression and persistent infection with high-risk HPVs, especially HPV-16 and HPV-18.^7,8 The current data were mainly related to kidney transplant, with a smaller number of reports on liver transplant and 3 studies that evaluated all SOTs, which included heart and lung populations; this population remains remarkably understudied (Table 2).

One of the largest registers, the US Transplant Cancer Match Study,⁹ calculated a significantly increased incidence of invasive HPV-associated cancers after transplant, especially for anal cancer, with an SIR of 5.4. The comparison of cancer occurring in patients with HIV infection versus transplant recipients elucidated a relationship between immune-surveillance, viral infection, and cancer and showed an increased risk in both populations with a significant risk for anal cancer (SIR of 81.1 for HIV patients).¹⁰ A longer time since transplant (over 5 years) has been considered related to a higher incidence of development of anal cancer.⁹ In a retrospective study conducted between January 2000 and December 2015, the authors showed that, among 394 female SOT recipients, 19 (4.8%) developed noncervical lower genital tract dysplasia (vulvar, vaginal, or anal dysplasia), with 13 (3.3%) diagnosed with high-grade dysplasia and 3 with anal carcinoma. Black race was significantly associated with dysplasia occurrence (odds ratio [OR] of 2.86; 95% CI, 1.33-6.13).¹¹

In a 1994 prospective case control study, which was one of the first on kidney transplant and which included 133 kidney transplant recipients, intraep-ithelial lesions were present in 26 of 133 transplant recipients (20%) versus 1 of 145 nontransplant patients (0.7%).¹² A UK study on prevalence of HPV infection in the anal canal of kidney transplant recipients found a strong correlation between precancerous lesions and HPV infection, with high-grade intraepithelial lesions or low-grade intraepithelial lesions found in 5.8% of recipients and anal HPV infection in 21.3% of transplant recipients.¹³ In a prospective case control study that reported on liver transplant recipients versus a healthy control group, 10 cases (prevalence of 17%) with abnormal cytology were reported in the liver transplant group versus the control group (P = .005).¹⁴ Among the few reports on thoracic organ transplant,^15,16 data confirmed an increased incidence of in situ anal cancer (incidence rate ratio [IRR] of 1.8).

In a study from Australia,¹⁵ HPV infection was also prevalent in anal lesions and was mainly related to sociodemographic, lifestyle, and clinical characteristics of kidney transplant recipients.¹⁵ The vast majority of infections occurred via direct person-to-person transmission, with anal infections being a common sexually transmitted infection. Therefore, this subgroup of patients carries an increased risk of HPV infections and related complications.

Pathogenesis in transplant recipients: human papilomavirus infection
Almost 90% of ASCCs were shown to be related to high-risk HPV, confirming a strict association with virus infection.¹⁷ The high-risk HPV-16 was found to be the single subtype in 42% of HIV-positive patients compared with 78% of HIV-negative patients, which may be explained by the particular ability of HPV-16 to evade host immune control.¹⁸ Basically, once HPV has infected epithelial cells, its persistence may play a critical role in the progression to dysplasia and cancer. The integration of HPV into the human genome seems to be fundamental, although not necessary, for the development of cancer. All studies underlined this interplay, identifying subgroups of patients at risk. In 2012, an interesting work related to transplant patients was published¹⁹; the authors highlighted, as previously assumed, that HPV infection may be more aggressive and have faster evolvement in kidney transplant recipients. This was also confirmed with HPV-related cervical carcinoma in kidney transplant recipients.²⁰ Moreover, although not confirmed by all reports, transplant recipients may present with repeated or recurrent infections (with different HPV genotypes), with multifocal and independent evolving lesions.^21,22 None of the selected studies in our review was exclusively focused on the detailed mechanisms of pathogenesis, although carcinogenesis and risk factors in organ transplant were often outlined. Nevertheless, as confirmed by several other works, E6/E7 proteins  constitute one of the most important tumor-suppressive pathways in immunocompromised patients, resulting in an irreversible proliferative activity in HPV-positive cancer cells.^23-25

Interplay of human papillomavirus and immune system
The role of cell-mediated immunity was highlighted in a systematic review of population-based registry studies in patients with HIV and transplant recipients.⁸ This report suggested that immune deficiency plays one of the most important roles in the increased risk of HPV-associated neoplasm. All of our selected papers agreed that depressed immuno-surveillance favors HPV infection to run off the host immune response. The immunocompromised status and the lack of an inflammatory response seem to play crucial roles to support a prolonged infection cycle and viral replication. These aspects emerged as important cofactors to precancerous lesions. On the basis of its intrinsic characteristics, HPV localizes to the mucosal surface away from the vascular and lymphatic system, where adaptive immune responses might be soon activated. Interestingly, a cell-mediated immune response against early viral proteins represented the host reaction to resolution, and a CD4+ T-cell Th1 response was the main component. A large study that included US transplant and cancer registry data hypothesized a correlation between the degree of donor-recipient immune incompatibility and the intensity of immunosup-pression required to prevent rejection.⁹ Immune compatibility has been expressed by human leucocyte antigen (HLA) mismatch (family group variables for HLA-DRB), and some authors argued that carriage B:44 correlates with an increased incidence of anal cancer (in situ IRR of 1.8 and invasive IRR of 1.7).⁹ However, none of the other selected studies argued about the role of the major histocompatibility complex system in terms of ASCC pathogenesis in transplant recipient. An interplay between HPV and HLA has been hypothesized, where oncoprotein E5 appears to assist HPV immune evasion.²⁵ E5 has been involved in major histocompatibility complex/HLA class 1 downregu-lation and interference with cytokine production, a process typically requiring a long time period of several decades after initial infection.

Immunosuppression and anal cancer
Limited data exist on the role of immunosuppressive drugs and anal cancer. Among the studies selected, however, different contents have emerged according to immunosuppressant drugs, protocols, and type of solid organ. In a US study, cyclosporine and azathioprine were stated to be related to an increased incidence of invasive anal cancers and tacrolimus and mycophenolate with a decreased incidence; in addition, corticosteroid use was shown to be associated with a strongly increased incidence of in situ anal cancer (IRR of 5.3) but not of invasive anal cancer (IRR of 1.2).⁹ In the setting of liver transplant,¹⁴ there were no significant risk factors reported that were related to a specific immunosup-pressant strategy. In contrast, in a single-center review of renal transplant recipients over a 40-year period, T-cell-depleting induction with antithymocyte globulin was identified as an independent risk factor for the development of anogenital cancer.²⁶ Although none of the selected works in our review mentioned mammalian target of rapamycin (mTOR) inhibitors, the role of the mTOR pathway remains uncertain and deserves further investigations.^27,28 Signaling of mTOR may be a reason for the ability of HPV cancer cells to efficiently modulate senescence upon E6/E7 repression. A functional interplay between p53, pRb (retinoblastoma), and the mTOR pathway in HPV cancer cells has been hypothesized, and inhibition of mTOR signaling may interfere with the ability of HPV-positive cancer cells to evade senescence.²⁷

Despite the type of immunosuppressant strategy and administered drugs, all authors among our selected studies agreed that transplant recipients are exposed to a higher risk of developing de novo cancer over time resulting from a longer life expectancy on immunosuppression.

Other risk factors and anal cancer
Although no targeted studies have been conducted to identify other causes for anal cancer development among SOT recipients, some authors suggested that additional factors could participate with HPV to induce carcinogenesis.^29,30 These factors are not necessarily limited to epigenetic changes within the cell but could be linked to the cross talk with external cofactors, for example, the microbiome.³⁰

The recognition of high-risk groups evidenced in published works is still limited to single-center reports and different clinical datasets; however, sexual transmission and a lifetime number of sexual partners have been recognized as risks for anal HPV infection.^21,22 A prospective case control study reported smoking as an independent factor for abnormal cytology (OR of 5.87; 95% CI, 1.22-28.12; P = .027) in the univariate logistic regression analysis.¹⁴ A statistical tendency for the presence of hepatitis B virus (HBV) infection as a risk factor for HPV infection was observed, although significance was not reached and no evidence of a molecular interplay had emerged.14 However, in a study of liver transplant recipients, HBV was significantly associated with an increased prevalence of HPV infection (P = .038).³¹ Nevertheless, such associations definitely need to be considered, given the well-established role of sexual transmission in spreading of HBV infection.

Discussion

Most of the selected studies in our analyses were retrospective, with results mainly discussing the incidence and clinical aspects of anal lesions; few reports detailed the pathogenesis of ASCC. Although most of the selected studies highlighted the association of ASCC with HPV and immunosup-pression, the mechanisms of development of anal cancer were not always detailed. In our literature review to evaluate the mechanisms involved in the development of ASCC after SOT, we found an IR, as cases per 100 000 person-year, of 13 (95% CI 12-15), reaching 24.5 for male patients and 49.6 for female patients >10 years after transplant.² Among our selected studies, all authors agreed that the combination of immunosuppression and persistent infection with high-risk HPV represented the main factor in the increased incidence of ASCC in SOT recipients.^7,8,32 Different HPV proteins emerge to modulate tumor-suppressive pathways, determining an irreversible proliferative activity in HPV-positive cancer cells.^23-25 The “E” region has been shown to have utmost importance for HPV-associated carcinogenesis because it encodes proteins E6 and E7.²³ One of the main abilities of proteins E6 and E7 consists of inactivating, respectively, the p53 and pRb tumor suppressor pathways in a cooperative manner. In cancer cells, E6 and E7 have critical roles in the formation of protein complexes (E6/E6AP/p53 complex and E7/pRb complex), which interact in the inhibition of senescence and then determine the activation of cell-cycle-promoting E2F genes.²³ However, as “hallmarks” of cancer promotion can be multifacetated,24 E6 also contains a PDZ binding motif that can mediate its binding to other cellular proteins, namely, tumor suppressor proteins, leading to their proteolytic degradation or altering their subcellular localization. Usually, this process requires a long time period for the development of human cancers, or, conversely, premalignant lesions might regress due to an immune response.

Although shown in the general population, a molecular mechanism seems to be favored in the immunocompromised patient, where a defeated immunosurveillance favors HPV infection to run off the host response. The immunocompromised status and the lack of inflammatory response seem to play crucial roles in a prolonged infection cycle and viral replication, especially those related to the CD4+ T cell-dominated Th1 response.⁹

An altered CD4+-to-CD8+ ratio in HPV-positive cervical cancer tissue has been suggested33; however, further research is needed to evaluate the expression of T cells and other molecules involved in the regulation of T-cell responses and their implications in anal cancer progression. In a Turkish study that evaluated posttransplant malignancy with de novo tumors, among squamous cell carcinomas, the degree of lymphocytic infiltration around the tumor was significantly lower in the transplant recipient group.³⁴ Although we found no evidence among reports on anal cancer, we suggest that T-cell depleting agents may represent a remarkable risk factor for the development of cancer, due to their impairment in clearing the infected cells during the elimination phase. Although no specific studies have been conducted with the particular aim to stratify risk factors, some authors have suggested a determinant role of immunosuppressive drugs in anal cancer.^9,26 To our knowledge, however, none of the standard immunosuppressant drugs have been identified as independent risk factors for the development of cancer. In addition, the role of mTOR inhibitors in HPV-positive patients has not yet been clearly elucidated.

Nevertheless, the increased incidence of ASCC in SOT recipients over a long-term posttransplant period⁹ confirmed that a deficient immunosur-veillance may sustain the process of carcinogenesis in prolonged HPV infection. Additional events or external cofactors are considered necessary for cancer development in immunocompromised patients.

To date, no data exist on patients analyzed according to the type of transplanted organ, although most of the reports were related to abdominal transplant procedures, especially kidney transplant. Because immune suppression can vary during the natural history of different SOTs, the degree of immune deficiency may also vary across type of transplanted organ and should be further investigated.

The recognition of high-risk groups in published works is still limited to single-center reports and different clinical contexts.^14,31 The association with HBV may be related to how the infection was transmitted and risk of HPV infection may be related to severely ill patients³¹; the validation of these statements requires further studies. This correlation may also be based on socioeconomic factors, access to medical care, transplant wait times, differences in rates of comorbidities, differences in HLAs, and differences in immune response to transplant. These factors may also not be limited to epigenetic changes within the cell but could be linked to cross talk with external cofactors, for example, the microbiome.³⁰ Thus, there is a concern when comparing studies that have different sets of population characteristics, such as differences in age, sexual habits, pretransplant HPV lesions, and comorbidities. For this reason, we decided to concentrate on the interpretation of patterns of increased risk rather than focusing on specific factors handled by a single report.

The selected studies demonstrated that almost 90% of ASCC is related to high-risk HPV, with a strict association with virus infection and persistence in a long-term period.¹⁷ Because of its strong association with HPV infection, anal cancer may be potentially preventable through screening of patients with high-risk HPV infections. Further studies are needed to determine whether screening of HPV infections in patients waiting for SOT would reduce the risk of anal cancer and whether it is cost-effective. Although there is so far no consensus for anal cancer screening in patients after SOT, some centers already perform routine annual pelvic examinations.³⁵ We would advise the use of an anal Pap test, especially in high-risk cohorts, as proposed by the American Society of Transplantation Infectious Disease Community of Practice.³⁶ In addition, HPV vaccinations on selected population were shown to decrease the incidence of premalignant lesions.³⁷

Conclusions

The development of ASCC has been shown to be increased in HPV-positive transplant recipients. Some of the selected studies in this review reported data on ASCC incidence using large national databases.^3,9,38,39 In this literature review, we highlighted some aspects of pathogenesis, although more studies are necessary to provide a more detailed biology of ASCC in this cohort of patients.

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