The incidence of anal cancer is elevated in human immunodeficiency virus (HIV)‐infected men‐who‐have‐sex‐with‐men (MSM) compared to the general population. Anal high‐grade squamous intraepithelial ...lesions (HSIL) are common in HIV‐infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV‐infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high‐resolution anoscopy (HRA) and HRA‐guided biopsy. Although treatment for HSIL and follow‐up were recommended, not all were treated and some were lost to follow‐up. Prevalent cancer was found in 66 men. Seventy‐two HIV‐infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy‐proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV‐infected MSM. Early diagnosis is facilitated by careful follow‐up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed.
What's new?
The elevated incidence of anal cancer seen among HIV‐infected men‐who‐have‐sex‐with‐men (MSM) is presumably linked to the common occurrence of anal high‐grade squamous intraepithelial lesions (HSIL) in this population. This study provides some of the first evidence for direct progression of the postulated HSIL precursors to anal cancer. MSM were followed for a period of more than 20 years with high‐resolution anoscopy and biopsy. The data provide conclusive evidence of the malignant potential of anal HSIL and underscore the potential to reduce anal cancer through targeted removal of anal HSIL.
The aim of this study was to systematically review the findings of publications addressing the epidemiology of anal human papillomavirus (HPV) infection, anal intraepithelial neoplasia, and anal ...cancer in women. We conducted a systematic review among publications published from Jan. 1, 1997, to Sept. 30, 2013, to limit to publications from the combined antiretroviral therapy era. Three searches were performed of the National Library of Medicine PubMed database using the following search terms: women and anal HPV, women anal intraepithelial neoplasia, and women and anal cancer. Publications were included in the review if they addressed any of the following outcomes: (1) prevalence, incidence, or clearance of anal HPV infection, (2) prevalence of anal cytological or histological neoplastic abnormalities, or (3) incidence or risk of anal cancer. Thirty-seven publications addressing anal HPV infection and anal cytology remained after applying selection criteria, and 23 anal cancer publications met the selection criteria. Among HIV-positive women, the prevalence of high-risk (HR)–HPV in the anus was 16–85%. Among HIV-negative women, the prevalence of anal HR-HPV infection ranged from 4% to 86%. The prevalence of anal HR-HPV in HIV-negative women with HPV-related pathology of the vulva, vagina, and cervix compared with women with no known HPV-related pathology, varied from 23% to 86% and from 5% to 22%, respectively. Histological anal high-grade squamous intraepithelial lesions (anal intraepithelial neoplasia 2 or greater) was found in 3–26% of the women living with HIV, 0–9% among women with lower genital tract pathology, and 0–3% for women who are HIV negative without known lower genital tract pathology. The incidence of anal cancer among HIV-infected women ranged from 3.9 to 30 per 100,000. Among women with a history of cervical cancer or cervical intraepithelial neoplasia 3, the incidence rates of anal cancer ranged from 0.8 to 63.8 per 100,000 person-years, and in the general population, the incidence rates ranged from 0.55 to 2.4 per 100,000 person-years. This review provides evidence that anal HPV infection and dysplasia are common in women, especially in those who are HIV positive or have a history of HPV-related lower genital tract pathology. The incidence of anal cancer continues to grow in all women, especially those living with HIV, despite the widespread use of combined antiretroviral therapy.
To assess the prevalence of and factors associated with squamous intraepithelial lesions and condyloma human papillomavirus (HPV)-related lesions) in HIV-infected patients.
A cross-sectional study in ...a tertiary-care university hospital conducted in 516 consecutive outpatients.
A systematic examination for macroscopic HPV-related lesions through anoscopy with histological confirmation, evaluation of dysplasia and HPV typing. Sexual behaviours were assessed using a semi-directive questionnaire.
Of 473 patients examined, (200 homosexual men, 123 heterosexual men, 150 women), 108 (23%) had histologically confirmed anal HPV-related lesions (36, 15 and 11% of the respective populations), including 51 (47%) with only endoanal localization. Among these 108 patients, histological dysplasia of grades I or II and grade III were noted in 59 and two patients, respectively, invasive endoanal cancer in one; three patients also had high-risk oncogenicity HPV without dysplasia. Independent identified associated factors of HPV-related condyloma were the number of incidents of sexual intercourse per month odds ratio (OR) 1.04; 95% confidence interval (CI) 1.01-1.06, CD4 cell count below 200 x 10 cells/l (OR 3.22; 95% CI 1.37-7.60), history of anal HPV lesion (OR 4.57; 95% CI 2.13-9.81), and receptive anal intercourse (OR 2.30; 95% CI 1.11-4.77). The two latter factors remained associated with histological dysplasia (OR 2.82; 95% CI 1.38-5.76 for history of anal condyloma, and OR 4.29; 95% CI 2.18-8.44 for receptive anal intercourse).
The high rate of condyloma and histological dysplasia seen argues for a systematic screening for these lesions in HIV-infected individuals.
Human papillomavirus (HPV) DNA and p16 status have both been reported as prognostic factors in anal cancer, but the prognostic relevance of combined detection and particularly HPV-/p16+ and HPV+/p16- ...signatures is unknown. We evaluated combined HPV DNA and p16 status as a prognostic factor of treatment response in anal cancer.
106 patients treated with radiochemotherapy (RCT+5-FU/MMC) with available paraffin-embedded tumor tissue specimens were evaluated regarding local control (LC) and overall survival (OS) at 5 years. In addition to HPV DNA/p16 status, the influence of age, gender, previous surgery, initial recurrence, T stage, N status, and tumor localization was analyzed.
63 patients were HPV+/p16+, 9 were HPV+/p16-, 11 were HPV-/p16+, and 23 were HPV-/p16-. In univariate analysis, LC was significantly better in patients with T1/2 stage, female gender, and HPV/p16 status. HPV+/p16+ was associated with significantly better LC (88.1%; 95% confidence interval CI: 78.89-97.31) compared with HPV-/p16+ (63.6%; 95% CI: 35.18-92.02; P=.021) and especially HPV-/p16- (55.8%; 95% CI: 33.46-78.14; P=.002) but not with HPV+/p16- (77.8%; 95% CI: 50.56-105.04; P=.270). OS was influenced by T stage and LC. HPV+/p16+ patients showed a trend toward better OS compared with HPV-/p16- patients (HPV+/p16+: 81.1%; 95% CI: 70.12-92.08 vs HPV-/p16-: 68.8%; 95%CI: 47.44-90.16; P=.138). On multivariate analysis, T3/4 stage and HPV/p16 status (HPV-/p16+, HPV-/p16- vs HPV+/p16+) predicted poorer LC (T3/4: 50.3% vs T1/2: 86.6%, hazard ratio HR 0.22; 95% CI: 0.09-0.53; P<.001; HPV+/p16+ vs HPV-/p16+: HR 4.73; 95% CI: 1.33-16.82; P=.016, and HPV+/p16+ vs HPV-/p16-: HR 6.40; 95% CI: 2.23-18.35; P<.001), whereas local relapse dramatically influenced OS.
Our data suggest that HPV/p16 signature determines prognosis. HPV+/p16+ patients had the best prognosis, and HPV-/p16+ and HPV-/p16- patients showed the worst outcome and therefore require therapy optimization, particularly given that LC is the most important factor for OS.
Carcinomas of the anal canal are strongly associated with the human papillomavirus (HPV). Expression of p16 is used as a surrogate marker of HPV infection. In a retrospective study, we evaluated HPV ...genotyping and p16 expression as prognostic markers of overall survival (OS) and disease-specific survival (DSS) in patients diagnosed with American Joint Committee on Cancer (AJCC) stages I to III carcinoma of the anal canal.
HPV genotyping polymerase chain reaction (high-risk subtypes 16, 18, 31, 33, 45, 52, and 58) and immunohistochemical expression of p16 were analyzed by using paraffin-embedded tumor biopsies from 143 anal carcinomas. The patients were treated with combined chemoradiotherapy or radiotherapy alone.
HPV16 was detected in 81.0% of the tumors, followed by HPV33 (5.1%), HPV18 (2.2%), and HPV58 (0.7%). p16 positivity was found in 92.9% of the tumors. In univariable survival analysis, HPV positivity was significantly correlated with improved OS (74% v 52%; P=.036) and DSS (84% v 52%; P=.002), and p16 positivity was significantly correlated with improved OS (76% v 30%; P<.001) and DSS (85% v 30%; P<.001). In multivariable COX analysis that included HPV status, p16 status, sex, T stage, N stage, and treatment, p16 positivity remained an independent prognostic factor for OS (hazard ratio HR, 0.07; 95% CI, 0.01 to 0.61; P=.016) and DSS (HR, 0.07; 95% CI, 0.01 to 0.53; P=.011).
p16 positivity is an independent prognostic factor for OS and DSS in patients with AJCC stages I to III carcinoma of the anal canal.
BACKGROUND:High-resolution anoscopy has been shown to improve identification of anal intraepithelial neoplasia but a reduction in progression to anal squamous-cell cancer has not been substantiated ...when serial high-resolution anoscopy is compared with traditional expectant management.
OBJECTIVE:The aim of this study was to compare high-resolution anoscopy versus expectant management for the surveillance of anal intraepithelial neoplasia and the prevention of anal cancer.
DESIGN:This is a retrospective review of all patients who presented with anal squamous dysplasia, positive anal Pap smears, or anal squamous-cell cancer from 2007 to 2013.
SETTING:This study was performed in the colorectal department of a university-affiliated, tertiary care hospital.
PATIENTS:Included patients had biopsy-proven anal intraepithelial neoplasia from 2007 to 2013.
INTERVENTIONS:Patients were treated with high-resolution anoscopy with ablation or standard anoscopy with ablation. Both groups were treated with imiquimod and followed every 6 months indefinitely.
MAIN OUTCOME MEASURES:The incidence of anal squamous-cell cancer in each group was the primary end point.
RESULTS:From 2007 to 2013, 424 patients with anal squamous dysplasia were seen in the clinic (high-resolution anoscopy, 220; expectant management, 204). Three patients (high-resolution anoscopy, 1; expectant management, 2) progressed to anal squamous-cell cancer; 2 were noncompliant with follow-up and with HIV treatment, and the third was allergic to imiquimod and refused to take topical 5-fluorouracil. The 5-year progression rate was 6.0% (95% CI, 1.5–24.6) for expectant management and 4.5% (95% CI, 0.7–30.8) for high-resolution anoscopy (p = 0.37).
LIMITATIONS:This was a retrospective review. There is potential for selection and referral bias. Because of the rarity of the outcome, the study may be underpowered.
CONCLUSIONS:Patients with squamous-cell dysplasia followed with expectant management or high-resolution anoscopy rarely develop squamous-cell cancer if they are compliant with the protocol. The cost, morbidity, and value of high-resolution anoscopy should be further evaluated in lieu of these findings.
Only 4 prospective randomized phase 3 trials have been reported for anal cancer. A prognostic factor analysis for anal cancer from a prospective database has been published from only 1 study (N = ...110). To confirm and uncover new prognostic factors, we analyzed the prospective database of intergroup RTOG 98-11.
Univariate and multivariate analyses of the baseline characteristics for 5-year overall survival (OS) and disease-free survival (DFS) were carried out. Various combinations of tumor diameter and clinically positive nodes (N(+)) were analyzed to identify subgroups.
A total of 644 were assessable and analyzed. Tumor diameter >5 cm was associated with poorer 5-year DFS (P = .0003) and poorer 5-year OS (P = .0031), and N(+) was associated with poorer 5-year DFS (P </= .0001) and poorer 5-year OS (P = </= .0001) in the multivariate analysis. In stratified analyses, N(+) had more adverse influence on DFS and OS than did tumor diameter. Patients with >5-cm tumor and N(+) had the worst DFS (only 30% at 3 years compared with 74% for the best group; <5 cm primary and N0) and OS (only 48% at 4 years compared with 81% for the best group; <5 cm primary and N0). Men had worse DFS (P = .02) and OS (P = .016). These factors maintained their influence in each treatment arm.
This prospective prognostic factor analysis establishes tumor diameter as an independent prognosticator of poorer 5-year DFS and OS and confirms N(+) and male sex as poor prognostic factors. This analysis also uncovers novel subgroups (derived from combining prognostic factors) with incremental worsening of DFS and OS.
Reply to Fang and Buchwald Jongen, Vita W; Steenbergen, Renske D M; Schim van der Loeff, Maarten F
The Journal of infectious diseases,
10/2021, Letnik:
224, Številka:
7
Journal Article
Purpose Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after sphincter-preserving definitive chemoradiation (CRT) and is typically ...associated with anogenital human papilloma virus infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus-associated oropharyngeal squamous cell carcinoma, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC. Methods Sixty-one patients with stage I to III SCCAC received CRT including cisplatin, fluorouracil, and radiation therapy to the primary tumor and regional lymph nodes (45 to 54 Gy) plus eight once-weekly doses of concurrent cetuximab. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided α, 0.10; power 90%), assuming a 35% LRF rate from historical data. Results Poor risk features included stage III disease in 64% and male sex in 20%. The 3-year LRF rate was 23% (95% CI, 13% to 36%; one-sided P = .03) by binomial proportional estimate using the prespecified end point and 21% (95% CI, 7% to 26%) by Kaplan-Meier estimate in a post hoc analysis using methods consistent with historical data. Three-year rates were 68% (95% CI, 55% to 79%) for progression-free survival and 83% (95% CI, 71% to 91%) for overall survival. Grade 4 toxicity occurred in 32%, and 5% had treatment-associated deaths. Conclusion Although the addition of cetuximab to chemoradiation for SCCAC was associated with lower LRF rates than historical data with CRT alone, toxicity was substantial, and LRF still occurs in approximately 20%, indicating the continued need for more effective and less toxic therapies.
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