Anal Cancer Precursors Research Articles

Citologia anal para rastreamento de lesões pré-neoplásicas

High grade intra-epithelial neoplasias (HAIN) are probable precursors of anal carcinoma, with association to high-risk types of Human Papillomavirus (HPV). This progression could be related to severity of the dysplasia and, albeit not yet confirmed, treatment of these lesions would prevent the evolution to cancer. Standardization and improvement of screening methods should therefore be essential to treat or prevent precursor lesions, mainly in patients at risk such as seropositives to Human Immunodeficiency Virus (HIV). The aim of this study was to evaluate if anal cytology, with a cytobrush, could be useful to screen clinic and pre-clinic lesions provoked by HPV. Brushes were used to obtain smears from the anal canal of 102 HIV-positive patients with proctologic complaints. There were 86 males and 16 females with a mean age of 37 years. HPV infection was denied by 33 patients, 14 had treated anal warts in the past, 28 had condylomas in the anal verge, seven had internal clinical lesions and 20 had both internal and external condylomas. The smears were submitted to Pappanicolaou and hematoxilin-eosin stains to identify cytological changes including HAIN. T CD4+ lymphocyte counts were also evaluated to check if the immunologic status caused more advanced dysplasia. One smear only proved insufficient. All the others revealed cellular patterns varying from normality to HAIN. Low grade AIN (LAIN) occurred in 30 and HAIN in 13 patients. One patient with HAIN, without a history of HPV infection in the past, presented an anal canal ulcer which at biopsy was diagnosed as invasive squamous-cell carcinoma. T CD4+ cells averaged 281/mm(3) for LAIN patients and 438/mm(3) for HAIN patients. Analyses disclosed a statistical difference, showing that despite expectations, more advanced dysplasias occurred in patients with higher counts of T CD4+ cells. This fact demonstrated that isolated systemic immunity did not seem to interfere in the genesis of these lesions, suggesting that aspects of local immunity should be studied. Statistical analyses by a 2x2 table revealed sensibility of 74% and specificity of 61%. Results suggest that cytology could be used to diagnose anal cancer precursors.

The prevalence, and predictive value, of abnormal anal cytology to diagnose anal dysplasia in a population of HIV-positive men who have sex with men

Due to the increasing incidence of anal cancer in HIV-positive men who have sex with men, and the potential to detect and treat high-grade anal dysplasia--the putative anal cancer precursor--we have introduced an anal cytology screening service. Patients with abnormal anal cytology have follow-up high-resolution anoscopy (HRA) with biopsy of lesions clinically suspicious for high-grade dysplasia. In total, 244 men were screened and 235 (96%) of the samples were adequate for cytological interpretation using the Bethesda 2001 system. One hundred and sixty-four (67%) men had abnormal anal cytology, and 93 of them had follow-up HRA and anal biopsy. The positive predictive value for any anal cytological abnormality to predict any degree of anal dysplasia was 95.7+/-2.1%, and for any anal cytological abnormality to predict high-grade anal dysplasia was 55.9+/-5.1%. Abnormal anal cytology was highly predicative of anal dysplasia on biopsy.

HIV/AIDS: Screening HIV‐Infected Individuals for Anal Cancer Precursor Lesions: A Systematic Review

Individuals with human immunodeficiency virus (HIV) infection are at increased risk for human papillomavirus-related squamous cell cancer of the anus. Screening HIV-infected patients for squamous cell cancer of the anus and human papillomavirus-related anal dysplasia may prevent excess morbidity and mortality. We have conducted a systematic review of the indirect evidence in the literature regarding the utility of anal Papanicolau (Pap) smear screening of HIV-infected individuals in the highly active antiretroviral therapy era. Although there are no published studies evaluating the efficacy of anal Pap smear screening for preventing squamous cell cancer of the anus or anal intraepithelial neoplasia, we reviewed data regarding the burden of disease, anal Pap smear sensitivity and specificity, the prevalence of anal dysplasia, and 1 cost effectiveness study. The available evidence demonstrates that HIV-infected individuals have an increased risk for squamous cell cancer of the anus and anal intraepithelial neoplasia. This review identifies important areas for further study before routine anal Pap smear screening can be recommended.

Illustrated Instructions for Self-Collection of Anorectal Swab Specimens and Their Adequacy for Cytological Examination

Self-collection of anorectal swab specimens would facilitate screening for anal cancer precursors and sexually transmitted rectal infections among men who have sex with men (MSM). However, pictorial guides for self-collection were not previously available. Develop and field test a set of illustrated self-collection instructions. Cross-sectional study of community-recruited MSM who were naïve with regard to collection of specimens for anal cytology. Among 222 self- and clinician-collected swab pairs provided by mostly human immunodeficiency virus (HIV)-1 seronegative MSM (median age, 31.5 years), most specimens were adequate for cytologic evaluation, though self-collected swabs were less likely to be so (83% versus 92%, P = <0.001). The illustrated instructions were reportedly essential, but having used them, men rated their understanding of the self-collection procedure as very high. Provided with illustrated instructions, most MSM who are naïve to the technique can self-collect anorectal swab specimens that are suitable for screening.

Self-Screening for Anal Cancer Precursors in Men who have Sex with Men

Self-Screening for Anal Cancer Precursors in Men who have Sex with Men

Randomized clinical evaluation of self-screening for anal cancer precursors in men who have sex with men

BackgroundSelf-collection of anorectal swab specimens could greatly facilitate the completion of prerequisite studies and future implementation of anal cancer screening among men who have sex with men (MSM). We therefore compared self- versus clinician- collection procedures with respect to specimen adequacy for cytological evaluation, concordance of paired cytological results, and concordance of cytological with biopsy results.MethodsPaired self- and clinician- collected anorectal Dacron® swabs for liquid-based (Thin Prep®) cytological evaluation were collected in random sequence from a mostly HIV-1 seronegative cohort of young MSM in Vancouver. Slides were reviewed by one cytopathologist. Presence of any cytological abnormality (atypical squamous cells of uncertain significance, ASCUS, or above) prompted referral for high-resolution anoscopy and possible biopsy.ResultsAmong 222 patient-clinician specimen pairs, most were adequate for cytological evaluation, though self-collected specimens were less likely to be so (83% versus 92%, McNemar's test p < 0.001). Cytological abnormalities, noted in 47 (21%) of self-collected and 47 (21%) of clinician-collected specimens (with fair agreement, kappa = 0.414) included, respectively: ASCUS (5%, 5%), and low-grade (13%, 13%) and high-grade (3%, 3%) squamous intraepithelial lesions. Among 12 men with biopsy-confirmed high-grade neoplasia, most had abnormal cytological results (including 6 patient and 9 clinician swabs) but few (2 patient and 1 clinician swab) were high-grade.ConclusionSelf-collection of anorectal swab specimens for cytologic screening in research and possibly clinical settings appears feasible, particularly if specimen adequacy can be further improved. The severity of biopsy-confirmed anorectal disease is seriously underestimated by cytological screening, regardless of collector.

Age-related Prevalence of Anal Cancer Precursors in Homosexual Men: The EXPLORE Study

Age-related Prevalence of Anal Cancer Precursors in Homosexual Men: The EXPLORE Study

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

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. 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. 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. 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.

Age-Related Prevalence of Anal Cancer Precursors in Homosexual Men: The EXPLORE Study

Infection with human papillomavirus (HPV) is causally linked to the development of anal and cervical cancer. In the United States, the incidence of anal cancer among men who have sex with men (MSM) is higher than the incidence of cervical cancer among women. Anal squamous intraepithelial lesions (ASILs) are anal cancer precursors comprising low-grade squamous intraepithelial lesions (LSILs) and high-grade squamous intraepithelial lesions (HSILs). The prevalence of cervical cancer precursor lesions peaks at around 30 years of age. The age-related prevalence of ASILs in HIV-negative MSM is unknown. We conducted a cross-sectional analysis of the prevalence and determinants of ASILs in 1262 HIV-negative MSM aged 18-89 years recruited from four U.S. cities. Anal cytology and behavioral data were obtained. Anal HPV infection status was assessed by polymerase chain reaction. Independent predictors of ASILs were identified using logistic regression. All statistical tests were two-sided. The prevalences of LSILs and HSILs were 15% and 5%, respectively, and did not change with age. In a multivariable analysis, the risk of LSILs was associated with having more than five male receptive anal sex partners (P = .03), any use of poppers (alkyl nitrites) in the previous 6 months [odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.1 to 2.5; P = .03] or use of injection drugs two or more times per month during the previous 6 months [OR = 19, 95% CI = 1.3 to 277; P = .03], older age at first receptive anal intercourse (P = .004), and infection with a greater number of HPV types (P < .001 for linear trend). The risk of HSILs was associated with any anal HPV infection (OR = 3.2, 95% CI = 1.1 to 9.4; P = .039) and infection with an increasing number of HPV types (P < .001 for linear trend). Sexually active HIV-negative MSM in all age groups have a high prevalence of ASILs, possibly reflecting their ongoing sexual exposure to HPV.

Anal intraepithelial neoplasia

Anal intraepithelial neoplasia (AIN) is believed to be a precursor of anal squamous cell cancer and its incidence is rising in high-risk groups, particularly those infected with the human immunodeficiency virus (HIV). The natural history of AIN is unclear and management strategies are lacking. This review is based on a literature search (Medline and PubMed) with manual cross-referencing of all articles related to AIN. The aetiology of AIN is intricately linked with human papilloma viruses. The pathological processes involved in the progression of AIN are becoming clearer but the natural history, particularly the rate of progression to invasive cancer, remains unknown. There is no standard management for AIN and this is mainly due to difficulties in both diagnosis and treatment. A variety of treatment options have been tried with varying success. Surgery is associated with significant recurrence, particularly in HIV-positive patients. Non surgical approaches with imiquimod, photodynamic therapy and vaccination are appealing, and further work is required. Long-term follow-up of these patients is essential until the natural history of AIN becomes clearer.

High prevalence of anal squamous intraepithelial lesions and squamous-cell carcinoma in men who have sex with men as seen in a surgical practice

Anal high-grade squamous intraepithelial lesions are probable invasive anal squamous-cell cancer precursors, and although unproved, treatment of high-grade squamous intraepithelial lesions may prevent progression to anal squamous-cell cancer. Men who have sex with men are often treated for benign anorectal disorders without consideration given to the possibility of concurrent high-grade squamous intraepithelial lesions or anal squamous-cell cancer. We determined the prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer in an urban surgical practice of men who have sex with men referred for treatment of anal condyloma and other benign noncondylomatous anal disorders. One hundred thirty-one HIV-positive and 69 HIV-negative men who have sex with men referred for surgical treatment of presumed benign anorectal disease were evaluated by anal cytology, high-resolution anoscopy, and biopsy. Anal cytology and histology were reported with a modified Bethesda classification. One hundred fifty-seven patients (79 percent) were referred for condyloma, 4 (2 percent) for anal squamous intraepithelial lesions (anal high-grade squamous intraepithelial lesions) diagnosed by primary care providers, and 39 (19 percent) for other benign anorectal disorders. One hundred forty-three patients (93 percent) had abnormal anal cytology, with 107 (54 percent) having high-grade squamous intraepithelial lesions on cytology. Biopsy results revealed 120 patients (60.0 percent) with high-grade squamous intraepithelial lesions and 5 patients (3 percent) with invasive squamous-cell carcinoma. Four of five men with anal squamous-cell cancer were HIV positive. Fourteen men (36 percent) who have sex with men referred for noncondylomatous benign anal disorders had high-grade squamous intraepithelial lesions, and three (8 percent) had anal squamous-cell cancer. High-grade squamous intraepithelial lesions and anal squamous-cell cancer were seen most often at the squamocolumnar junction. Men who have sex with men referred for treatment of either condyloma or noncondylomatous benign anorectal disease had a high prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer. All men who have sex with men referred for treatment of benign anorectal disease should have high-resolution anoscopy and aggressive biopsy of all abnormal areas. Treatment of external lesions alone could miss high-grade squamous intraepithelial lesions or anal squamous-cell cancer.

The endogenous interferon system in anal squamous epithelial lesions with different grades from HIV-positive individuals.

Anal intraepithelial lesions (ASILs) are considered as precursors of anal cancer. The incidence of high-grade ASIL (HSIL) and progression of low-grade ASIL (LSIL) to HSIL are high in HIV-positive men. Endogenous cytokines, such as interferons (IFNs) play an important role in the regulation of proliferation and immune responses in epithelial cells, and thus, they might control the above-mentioned progression events. Accordingly, we determined mRNA levels of IFN-gamma and IFN-gamma receptors, levels of IFN-gamma receptor-associated kinases (JAK1 and TYK2) and signalling molecules (signal transducer and activator of transcription-1 [STAT1], STAT3, interferon-responsive-factor-1 [IRF-1] and IRF-2) as well as inhibitors of cytokine signalling (protein inhibitor of activated STAT1 [PIAS1] and suppressor of cytokine signalling 2 [SOCS2]) in biopsies of anal condylomas, LSILs as well as HSILs from HIV-positive individuals by a semi-quantitative reverse transcribed polymerase chain reaction (RT-PCR) method. We found that HSIL significantly differs in expression of these genes from LSIL and condylomas. Expression profile of HSIL samples showed activation of STAT3 signalling, probably accounting for the observed high levels of genes that support cellular proliferation (IRF-2, c-fos and c-myc). Decreases in levels of suppressors (IFN-gamma and IRF-1) and JAK1 kinase, but increases in levels of inhibitors of cytokine signalling (PIAS1 and SOCS2) might also contribute to the altered cytokine signalling in HSIL biopsies. These findings might reveal important molecular events associated with progression of LSIL to HSIL in HIV-infected men.

Anal cytology as a screening tool for anal squamous intraepithelial lesions.

Anal squamous intraepithelial lesions (ASIL) are common in homosexual and bisexual men, and high-grade ASIL (HSIL) in particular may represent an anal cancer precursor. Cervical cytology is a useful screening tool for detection of cervical HSIL to prevent cervical cancer. To assess anal cytology as a screening tool for anal disease, we compared anal cytology with anoscopy and histopathology of anal biopsies. A total of 2958 anal examinations were performed on 407 HIV-positive and 251 HIV-negative homosexual or bisexual men participating in a prospective study of ASIL. The examination consisted of a swab for anal cytology and anoscopy with 3% acetic acid and biopsy of visible lesions. Defining abnormal cytology as including atypical squamous cells of undetermined significance and ASIL, the sensitivity of anal cytology for detection of biopsy-proven ASIL was 69% (95% confidence interval: 60 to 78) in HIV-positive and 47% (95% confidence interval; 26 to 68) in HIV-negative men at their first visit and was 81% and 50%, respectively, for all subsequent visits combined. The absence of columnar cells did not affect the sensitivity, specificity, or predictive value of anal cytology. Anal cytology may be a useful screening tool to detect ASIL, particularly in HIV-positive men. The grade of disease on anal cytology did not always correspond to the histologic grade, and anal cytology should be used in conjunction with histopathologic confirmation.

Evidence of vitamin E deficiency in patients with malabsorption or alcoholism and the effects of therapy.

<h3>Introduction</h3> Most anal cancers are associated with HPV, particularly HPV 16. The incidence of anal cancer is increased among men who have sex with men (MSM) compared with the general population. Screening and treatment of anal intraepithelial neoplasia (AIN), the anal cancer precursor, are not yet standard of care, and prevention efforts are needed to reduce the incidence of anal cancer. We tested the quadrivalent HPV vaccine to determine its ability to reduce the incidence of AIN/anal cancer. <h3>Methods</h3> 598 MSM aged 16–26 years with five or fewer lifetime sex partners were randomised to receive vaccine or placebo at enrolment, month 2 and month 6. Subjects underwent detailed anogenital exams and HPV sampling from the penis, scrotum, perineal/perianal and anal canal at enrolment, month 7 and at 6-month intervals afterwards. Efficacy analyses were performed in a per-protocol (PPE) population (sero-negative and DNA-negative from day 1 through month 7 to the relevant vaccine HPV type) and in all enrolees in an intent-to treat (ITT) analysis. Median follow-up of the PPE population was 2.5 years (post-dose 3). <h3>Results</h3> Vaccine efficacy against HPV 6/11/16/18-related AIN and anal cancer in the PPE population was 77.5% (95% CI 39.6 to 93.3) (5 vaccine cases vs 24 placebo cases). Efficacy against high-grade AIN (AIN 2+) was 74.9% (95% CI 8.8 to 95.4). In the ITT population the efficacy was 50.3% (95% CI 25.7 to 67.2) and 54.2% (95% CI 18.0 to 75.3), respectively. No anal cancer was seen in either treatment group. <h3>Conclusions</h3> These results demonstrate that the quadrivalent HPV vaccine is efficacious in preventing AIN related to HPV 6/11/16/18 in MSM subjects naïve to vaccine HPV types at enrolment, as well as in an ITT population. The quadrivalent HPV vaccine may be a useful measure to reduce the incidence of anal disease in at-risk populations.