Humanes Papillomavirus und Analkarzinom

The incidence of anal cancer is increasing worldwide, especially in male homosexual patients. The main risk factor for development of anal cancer is anal infection with the human papillomavirus (HPV). The prevalence of anal HPV infection in HIV-negative homosexual men is 50–60%, while in HIV-positive homosexual men the prevalence is nearly 100%. HPV-related anal intraepithelial neoplasia (AIN) is the putative precursor of anal cancer. AIN can be found in approximately 20% of HIV-negative homosexual men and 5–10% of these patients have high-grade dysplasia (AIN II–III). The prevalence of high-grade dysplasia in HIV-positive homosexual men is, however, significantly higher being up to 50%. Despite the prevalence of HPV-related anal dysplasia and the increasing number of patients with anal cancer, there is still a lack of consensus regarding screening, surveillance and therapy of patients with AIN. The standard treatment for anal cancer is still radiochemotherapy with 5-FU and mitomycin C independent of the HPV or HIV status.     

Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men

OBJECTIVES: The incidence of anal cancer among men who have sex with men (MSM) has continued to increase since the introduction of highly active antiretroviral therapy (HAART). The prevalence of the putative anal cancer precursor, anal intraepithelial neoplasia (AIN) was high among HIV-positive MSM prior to the availability of HAART but little is known about AIN since HAART was introduced. We characterized the prevalence of AIN among HIV-positive MSM and examined the association between AIN and various factors including use of HAART. DESIGN AND METHODS: A baseline point-prevalence analyses in a prospective cohort study of AIN was performed at a university-based research clinic. A total of 357 HIV-positive MSM with no history of anal cancer completed a questionnaire detailing behaviors and medical history, anal cytology and human papillomavirus (HPV) testing, and high-resolution anoscopy with biopsy for detection of AIN. RESULTS: Eighty-one percent of participants with available CD4+ cell counts at baseline had AIN of any grade; 52% had AIN 2 or 3; and 95% had anal HPV infection. In multivariate analysis, detection of > or = 6 HPV types [odds ratio (OR), 36; 95% confidence interval (CI), 7.4-171) and use of HAART (OR, 10; 95% CI, 2.6-38) were associated with AIN after adjustment for length of time participants were HIV-positive, CD4+ cell count and HIV viral load. CONCLUSIONS: The prevalence of AIN has remained high among HIV-positive MSM after the introduction of HAART. Our data indicate that HAART is not associated with a reduced prevalence of AIN and support measures to prevent anal cancer among HIV-positive MSM whether or not they are using HAART.     

High Grade Anal Dysplasia in Visually Normal Mucosa in Homosexual Men: Seven Cases

Background: Anal cancer and anal human Papillomavirus (HPV) infection are increased in homosexual men.
Methods: We screened high risk homosexual men as part of a longitudinal study examining the effect of HIV infection on the risk of development of high grade anal intraepithelial neoplasia (AIN II, III).
Results: We found seven men who had histological evidence of AIN II-III with visually normal findings by anoscopy. Two men were HIV-seronegative, five were HIV-seropositive, and only one of the HIV-seropositive men had a low CD₄ count < 200. Abnormal cytological results seen over follow-up periods of 3 months to 2.5 yr suggest the persistence of visually inapparent anal abnormalities. Two of the men had had small internal warts at earlier examinations, and three of the seven men subsequently developed visually abnormal anal findings. All men had HPV 16 DNA detected at some point.
Conclusions: We hypothesize that high grade anal neoplasia may develop deep in the glands and can be detected by cytology before visible lesions are detected even with the aid of a colposcope. However, the implications of finding high grade anal cytology are not known at this time. Natural history studies are ongoing.     

Description of a pilot anal pap smear screening program among individuals attending a Veteran's Affairs HIV clinic

Despite the higher risk of anal cancer among HIV-infected individuals currently there are no national or international guidelines for anal dysplasia screening. We assessed acceptance and feasibility of screening for anal intraepithelial neoplasia (AIN), the rate of abnormalities, and relationship between the presence of AIN and a history of receptive anal intercourse. Eighty-two percent of HIV-patients approached during routine clinic visit agreed to participate in the study with anal Pap smear collection; 53% had abnormal cytology results and among those undergoing high-resolution anoscopy with biopsy, 55% had high-grade AIN, including 2 cases of carcinoma in situ. Anal cytology was well accepted and it was feasible to be incorporated into HIV primary care practice. Abnormal cytology was not significantly associated with history of anal intercourse (p?=?0.767). The high rate of abnormal results reinforces the need for further evaluation of the role of systematic anal Pap smear screening for HIV patients.     

HPV infection and intraepithelial lesions from the anal region: how to diagnose?

In the last years, the prevalence of HPV infection in the anal region has increased, especially in some groups like homosexual and HIV-positive people. Since this infection can be associated with the development of squamous anal cancer due to its progression from HPV infection to anal intraepithelial neoplasia (AIN) and finally to cancer, the screening and evaluation of these conditions are important. Anal cytology and high resolution anoscopy are good methods that are available and can be used. Although useful, these methods should be performed correctly and not indiscriminately in all patients. Patients for whom anal cytology screening is recommended are: HIV-infected patients, homosexuals, women who present with high-grade vulvar squamous intraepithelial neoplasia, vulvar cancer or cervical cancer. An abnormal anal cytology should be further evaluated with high resolution anoscopy.     

Anal intraepithelial neoplasia in heterosexual and homosexual HIV-positive men with access to antiretroviral therapy

BACKGROUND: Studies of human immunodeficiency virus (HIV)-positive men have demonstrated high rates of anal intraepithelial neoplasia (AIN), a precursor to anal carcinoma, mostly in white homosexual men and men not receiving effective antiretroviral therapy (ART). METHODS: Ninety-two participants--53% Latino, 36% African American, and 40% without a history of receptive anal intercourse (RAI)--were evaluated with a behavioral questionnaire, liquid-based anal cytological testing, Hybrid Capture 2 human papillomavirus (HPV) DNA assay and polymerase chain reaction, and anal colposcopy with biopsy of lesions. RESULTS: High-risk HPV DNA was identified in 61%, and this was associated with a history of RAI (78% vs. 33%; P<.001); 47% had abnormal cytological results, and 40% had AIN on biopsy. In multivariate analysis, both were associated with a history of RAI (odds ratio [OR], 10 [P<.001] and OR, 3.6 [P=.02], respectively) and lower nadir CD4(+) cell counts (P=.06 and P=.01). Current ART use was protective (OR, 0.09; P<.01 and OR, 0.18; P=.02). CONCLUSIONS: Although anal infections with high-risk HPV and AIN in HIV-positive men are associated with a history of RAI, both conditions are commonly identified in HIV-positive men without this history. Both lower nadir CD4(+) cell counts and lack of current ART were associated with AIN but not with the detection of anal HPV.     

Anal cancer: Focus on HIV-positive patients in the HAART-era

Anal cancer represents an increasing health problem, especially in immune-compromised patients, as HIV-positive patients. Notably, a significant higher incidence rate is reported among HIV infected patients with the advent of highly active antiretroviral therapy (HAART). To date, no randomised trial supports the correlation between existing screening strategies and reduced progression of anal intraepithelial neoplasia (AIN) to anal cancer or improved survival. Nevertheless, screening and treatment of AIN by topical agents should be implemented in high risk population. Data on invasive anal cancer treatment show that combined modality treatment (CMT) is the treatment of choice. Early reports on HIV-positive patients describe higher treatment toxicity and a relation with lower CD4 count and higher HIV viral load. More recently, reported outcomes seem to be similar in HIV-positive population and general population. Reports on a rise in local recurrence rates and in acute side effects along with a correlation with pre-treatment CD4 counts in HIV-positive patients, are not confirmed by all authors. The development of the first approved vaccine is a milestone in the field of anogenital cancers. However, many questions are still unresolved especially as concerns immunization in the setting of HIV infection.     

Screening and therapy of anal intraepithelial neoplasia (AIN) and anal carcinoma in patients with HIV-infection

Anal intraepithelial neoplasia (AIN) is a potential precursor of invasive anal carcinoma. Introduction of highly active antiretroviral therapy (HAART) in the treatment of HIV infection substantially reduced the incidence of some diseases associated with opportunistic viral infections. However, the incidence of AIN is reported to increase and HAART seems to have only little impact on the regression or progression of AIN. Paradoxically, improvement of survival in the HAART era results in an increased risk of anal cancer. The incidence of anal carcinoma amongst homosexual men is substantially higher compared to the normal population (35/100.000). This incidence is similar to the incidence of cervical cancer before screening for CIN with cervical cytology. Recent data suggest that the incidence of AIN and anal cancer is even higher among HIV-infected individuals. Both cancer entities share biologic similarities, including the association with human papillomavirus infection (HPV). Screening for CIN with cervical cytology and early treatment has resulted in a significant decline in the incidence of cervical carcinoma. Like cervical cancer, anal carcinoma may be preventable through identification and treatment of its precursors. Future efforts should focus on a screening protocol, training of clinicians in the diagnosis and treatment of AIN and anal carcinoma, and novel approaches to treatment of these lesions. This screening protocol could help to reduce anal cancer in HIV-infection as well as save limited resources in health care system.     

Anal cancer in renal transplant patients

Purpose A comprehensive literature review was performed to examine the prevalence of anal cancer, anal intraepithelial neoplasia (AIN) and anal human papillomavirus (HPV) infection in renal transplant recipients who are at risk of anal cancer due to iatrogenic immunosuppression.Methods Pertinent articles were identified from searches performed on the National Center for Biotechnology Information database using the following keywords: anal cancer, AIN, screening, renal transplant (or kidney transplant), organ transplant recipients and post-transplant malignancies.Results The prevalence of AIN is 20% in renal transplant patients. The prevalence of anal HPV infection in established transplant patients is 47%, and the prevalence of anal HPV infection in new transplant patients is 23%. The relative risk for anal cancer in renal transplant patients is 10.Conclusions As compared to HIV-positive male patients who practise anal intercourse, renal transplant patients showed a modest rise in relative risk for anal cancer. Screening programmes to detect AIN in HIV-positive patients who practise anal intercourse have been introduced on a preliminary basis in sexual health clinics in the US and may become standard practise in this population. The case for screening in renal transplant patients is unclear and would merit further investigation, especially with reference to the prevalence of anal HPV infection in this population. It may transpire that renal transplant patients would benefit more from HPV prophylaxis rather than screening for AIN.     

Utilidad de la detección del virus del papiloma humano en el cribado de neoplasia intraepitelial anal en pacientes con conductas de riesgo

Introduction

The incidence of intraepithelial anal neoplasia is increasing in certain risk behaviour groups, and human papillomavirus (HPV) infection is involved in its pathogenesis. The systematic use of anal cytology, and more recently HPV detection by hybrid capture and genotyping, have been introduced into screening programs in recent decades.

Material and methods

A retrospective cohort study was carried out on individuals with risk behaviours of developing intraepithelial anal neoplasia and who attended Sexually Transmitted Infections clinics in the Dermatology area of the Hospital Costa del Sol from January 2010 to December 2012. The intraepithelial anal neoplasia screening was performed using anal cytology and HPV genotyping.

Results

Half (50%) of the study population were HIV positive. A high frequency of anal dysplasia and presence of HPV in cytology (82.1%) and genotype (79%) was found. A statistically significant association (P < .005) was obtained between the presence of high-risk HPV genotypes and the presence of high-grade dysplasia in the second directed cytology. HPV genotyping enabled 17 cases (22%) of severe dysplasia to be identified that were under-diagnosed in the first cytology.

Conclusion

Cases of high-grade dysplasia can be under-diagnosed by a first anal cytology. Detection of HPV can supplement this procedure, leading to the identification of those patients most at risk of developing high-grade anal dysplasia.     

The pathology and molecular biology of anal intraepithelial neoplasia: comparisons with cervical and vulvar intraepithelial carcinoma

BACKGROUND: Anal intraepithelial neoplasia (AIN) is a well-described pathological precursor of invasive squamous cell carcinoma which has recently been detected with increasing frequency in immunocompromised patients, particularly those with seropositivity for human immunodeficiency virus (HIV). The epidemiology and natural history of this entity is somewhat unclear, since the overall prevalence in the HIV seronegative population is unknown. DISCUSSION: There is a clear etiological association between AIN and high-risk human papillomavirus (HPV) subtype infection although there is great variability in HPV DNA detection of cytological and histological material in these patients. It appears that there is an antigen-specific hyporesponsiveness by cytotoxic lymphocytes against HPV peptide sequences or recombinant proteins encoded by oncogenic HPV subtypes in these patients, which is dependent upon the stage of their HIV-associated disease. Although the molecular biology of AIN and cervical or vulvar intraepithelial neoplasia are comparable, in AIN there is less significance of tumor suppressor gene mutations, proto-oncogenic growth factor activation, and genomic instability. CONCLUSION: Current concepts in the epidemiology and etiology of AIN are discussed, as well as its immunological response in the HIV-positive population, drawing parallels where possible between other HPV-related preinvasive disorders, and concluding with a suggested management protocol     

Diagnosis,Treatment, and Prevention of Anal Cancer

Rare in the general population, anal cancer has reached epidemic proportions among HIV-infected men who have sex with men (MSM). These cancers are human papillomavirus (HPV)-associated, usually HPV type16, and are analogous to cervical cancer. At present, the rates of anal cancer in this group are 10-fold higher than that of cervical cancer occurring in women in the general population. Although there are no national guidelines for screening for anal intraepithelial dysplasia (AIN), many large HIV clinics are now performing anal cytologic screening in their at-risk patients. This paper outlines the current approach to screening for AIN and its management.     

Increased risk of high-grade anal neoplasia associated with a human papillomavirus type 16 E6 sequence variant

Expression of the E6 and E7 genes of human papillomavirus (HPV) type 16 have been implicated in the etiology of anogenital premalignant and malignant lesions. To evaluate whether variations in the HPV-16 E6 sequence were related to the incidence of high-grade anal neoplasia, 628 HPV-16-positive anal specimens from 193 human immunodeficiency virus (HIV)-positive and 59 HIV-negative participants were typed for variations in 15 E6 nucleotide positions. Although most participants were infected with a prototype strain, 15 (6%) carried the G131 variant, and 12 (5%) were infected with the Af1a variant. Two new variants not previously reported were identified as well. An elevated risk for high-grade anal squamous intraepithelial lesions was associated with infection by G131 variants, compared with the prototype strain (odds ratio, 3.4; 95% confidence interval, 1.1-10), after controlling for HIV status. These data provide further evidence for HPV strain variation as a factor in determining the natural history of anogenital neoplasia.     

Treatment of anal human papillomavirus-associated disease: a long term outcome study

Treatment for human papillomavirus (HPV)-associated anal canal disease has been unsatisfactory. The objective of our study was to determine the treatment outcome in our cohort with anal HPV disease. Overall, 181 patients were evaluated over a median period of 19.1 months (range = 2.8-125.5). Eighty-eight patients (48.6%) with high-grade anal intraepithelial neoplasia (AIN) and 82 patients (45.3%) with low-grade AIN underwent treatment. One hundred and forty-one patients (77.9%) received laser ablative treatment as an outpatient procedure. The treatment yielded cure, defined as a disease-free state at 12 months after treatment, in 63.0% (114/181). Median time to cure for the cohort was 31.5 months (95% confidence interval: 23.0-40.0). Treatment outcome showed no evidence of being affected by age, sexual preference, history of smoking or presence of high-grade disease. Median time to cure was significantly affected by a positive HIV status (P = 0.02) and the extent (volume) of the disease (P = 0.01). Contrary to the current view that treatment of HPV-related anal disease is difficult, unrewarding due to recurrences and may lead to substantial morbidity, we demonstrate that effective treatment is possible for both low- and high-grade AIN. These findings should help with the general desire to introduce screening for AIN for at-risk groups.     

High Prevalence of Anal Human Papillomavirus Infection and Associated Risky Behaviors in Men Infected with Human Immunodeficiency Virus in Taiwan

A cross-sectional study was conducted to investigate the prevalence, types, and risk factors associated with anal HPV infection among HIV-infected men in outpatient clinics at an AIDS designated hospital in Taiwan. Anal swabs were collect and PCR (polymerase chain reaction) was used to analyze the types of anal HPV infection. HPV DNA was detected in 74.2% of the 198 participants, including high-risk types (40.4%), low-risk types (18.2%) and multiple-types (6%). The most common types were HPV 16 (13.1%), 6 (10.4%), 11 (7.1%) and 18 (6.1%). The significant risk factor for being infected with any type or a high-risk type of HPV was having sexual partners (>3) in the preceding 6 months. Low-risk type of anal HPV infection was associated with a history of anal lesions. Our findings support the need for regular follow-up of all HIV/HPV coinfected patients and their partners to allow early detection of anal intraepithelial neoplasia.     

Anal intraepithelial neoplasia and other neoplastic precursor lesions of the anal canal and perianal region

Anal cancer is rare and this helps to explain why anal pre-neoplastic conditions are poorly understood, especially with regard to their natural history and management. Anal intraepithelial neoplasia is closely linked to human papillomavirus infection and is particularly common in homosexuals and in immunosuppressed patients, especially those with HIV/AIDS. The high regression rates of low-grade anal intraepithelial neoplasia may simply reflect inconsistent pathologic reporting. Higher grades of anal intraepithelial neoplasia may remain static for long periods of time in immunocompetent patients, but those with HIV/AIDS show early and rapid malignant transformation. In general, most anal pre-neoplastic conditions are best diagnosed by biopsy and treated by surgical excision, although local recurrence is a problem. In anal Paget's disease, it is important to ascertain, at the time of diagnosis, whether it is due to a primary in-situ apocrine-type of neoplasia of the anus or if the disease is secondary to an invasive primary carcinoma of the rectum.     

HPV in anal squamous cell carcinoma and anal intraepithelial neoplasia (AIN)

Background and aims Majority of cases of anal squamous cell carcinoma are human papilloma virus (HPV)-induced and result from anal intraepithelial neoplasia (AIN). This study was conducted to examine methods which may enable the routine diagnosis of HPV-induced changes in the anal rim and the consequences of such detection especially in view of a more sensitive diagnosis of AIN. Results were clinically correlated.Methods The study included biopsy samples from 87 patients who had been diagnosed with the following disease patterns: 47 invasive anal carcinoma, 33 AIN of varying severity and seven condylomatous lesions. In 52 of these cases, a tumour was clinically suspected. All biopsies were retrospectively examined for microscopic indications of HPV infection. After microdissection, additional HPV analysis via PCR was carried out.Results In 38 of 47 cases of anal carcinoma, HPV DNA could be detected via PCR (80.9%), the majority of which were HPV 16 (33/38=86.8%). In 29 of the 33 cases of AIN, HPV DNA was detected (87.9%), most of these in AIN III (15/16=93.8%). Histological markers of HPV infection were detected in all 87 cases.Discussion In our series, the clinical diagnosis of the invasive anal carcinoma had a high sensitivity of 93.6%, with a specificity of 80%. The positive predictive value was 84.6%, and the negative predictive value 91.4%. In contrast, AIN had been detected clinically in none of the cases. In this situation, especially with high-risk patients, our findings recommend anal HPV screening in combination with anal cytology and anoscopy.Conclusion Based on our results, we urgently recommend for any histological report on excision of anal lesions to include a statement whether histological markers of HPV infection were detected. In individual cases, validation via HPV PCR must be considered.     

Interobserver and Intraobserver Bias Exists in the Interpretation of Anal Dysplasia

INTRODUCTION: Natural history of progression from anal intraepithelial neoplasia to invasive carcinoma remains unproven. The risk of progression may be linked to the severity of dysplasia. Important therapeutic decisions are thus based on the severity of anal intraepithelial neoplasia. Consistency and reliability in the interpretation of anal intraepithelial neoplasia are unproven. METHODS: One hundred ninety anal biopsy specimens were identified for review of dysplasia with a six-point grade system from normal to invasive cancer, evidence of human papillomavirus infection, and quality of histology by three pathologists. RESULTS: Results revealed poor to moderate agreement on grading of quality of histology (weighted kappa score, 0.07-0.22), human papillomavirus status (weighted kappa score, 0.24-0.53), and dysplasia (weighted kappa score, 0.38-0.7). Complete agreement between the original pathology and the three pathologists was observed in only 32 percent of cases. Analysis of 86 slides previously read by one of the pathologists revealed only moderate agreement, with a weighted kappa score of 0.64. CONCLUSION: Significant interobserver and intraobserver bias exists in the interpretation of anal intraepithelial neoplasia. These inconsistencies may explain the uncertainty about the natural progression of anal intraepithelial neoplasia and the varied results of surgery reported for anal intraepithelial neoplasia in the literature.     

A trial of SGN-00101 (HspE7) to treat high-grade anal intraepithelial neoplasia in HIV-positive individuals

OBJECTIVES: To test a therapeutic vaccine consisting of a fusion of the human papillomavirus (HPV) 16 E7 protein and the Mycobacterium bovis heat shock protein 65 (SGN-00101) to treat high-grade anal intraepithelial neoplasia (HG-AIN) in HIV-positive individuals. DESIGN: A phase I/II trial with three cohorts of five participants each, sequentially assigned to receive 100, 500 or 1000 microg SGN-00101, injected three times subcutaneously in alternating thighs at 4-week intervals. Anal disease was assessed at baseline, 8, 12, 24 and 48 weeks and was classified as the more severe of anal cytology and anal biopsy. Anal HPV DNA was detected using L1 consensus primer-based PCR followed by type-specific probing and dot-blot hybridization (DBH). HPV16, 18 and 31 DNA copy numbers were measured using quantitative real-time PCR. SETTING: University-based research clinic. PARTICIPANTS: Thirteen HIV-positive men and two HIV-positive women with HG-AIN. RESULTS: There were no drug-related serious adverse events or significant changes in HIV viral load and CD4/CD8 ratio. At 48 weeks, two of five participants in both the 100 and 500 microg cohorts regressed to AIN 1 and one of five participants in the 1000 microg cohort regressed to atypical squamous cells of undetermined significance (ASC-US). All participants had at least one oncogenic HPV type at baseline. Three of five (60%) participants who regressed to AIN 1 or ASC-US became HPV-negative using DBH and real-time PCR, compared with none of 10 participants with no clinical response (P = 0.02). CONCLUSIONS: SGN-00101 was well tolerated in HIV-positive individuals, with preliminary evidence for clinical activity.     

Human papillomavirus and anal intraepithelial neoplasia

PURPOSE OF REVIEW: A review of recent developments in the understanding of the natural history of anal squamous carcinoma arising from areas of high-grade anal intraepithelial neoplasia. RECENT FINDINGS: Anal intraepithelial neoplasia is a consequence of chronic human papillomavirus infection in the anal canal and appears to be driven by high viral loads of human papillomavirus. In men who have sex with men with multiple sexual partners prevalent human papillomavirus infection does not decline with age, in contrast to heterosexual patients. Anal intraepithelial neoplasia is equally prevalent in different age groups of men who have sex with men, but in other respects what is known of its natural history resembles that of cervical intraepithelial neoplasia. Low-grade lesions frequently resolve, but high-grade lesions are much more stable. HIV-positives who practise receptive anal intercourse are at highest risk of anal intraepithelial neoplasia. Screening is easy to perform using cytology; the limitations of anal cytology being similar to those of cervical cytology. Patients with any grade of cytological abnormality require further investigation, ideally with high-resolution anoscopy, every 6 months. Successful treatments for individual small to medium-sized high-grade lesions include trichloroacetic acid, infra-red coagulation and laser. In HIV-positive patients the development of new lesions elsewhere is very likely. Topical agents for multifocal disease include imiquimod and cidofovir. SUMMARY: There is a need for large prospective cohort studies in men who have sex with men and HIV-positive patients to further our understanding of this disease and to evaluate treatment strategies.