World Journal of Colorectal Surgery Volume 6, Issue 5 2016 Article 1 High Resolution Anoscopy In A High Risk Population: A Retrospective Review Of 61 Patients Erich M. Wessel Mazin Al-Kasspooles Peter DiPasco Joseph Valentino Teresa Thomas John Ashcraft University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, ewessel@kumc.edu University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, mal-kasspooles@kumc.edu University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, pdipasco@kumc.edu University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, jvalentino@kumc.edu University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, tthomas9@kumc.edu University of Kansas Medical Center, Kansas City, Kansas, The United States Of America, jashcraft@kumc.edu Copyright c 2017 The Berkeley Electronic Press. All rights reserved.
High Resolution Anoscopy In A High Risk Population: A Retrospective Review Of 61 Patients Erich M. Wessel, Mazin Al-Kasspooles, Peter DiPasco, Joseph Valentino, Teresa Thomas, and John Ashcraft Abstract Background: Anal squamous cell carcinoma (ASCC) is rising in incidence throughout the United States. Many clinicians use High Resolution Anoscopy (HRA) for surveillance or as a means of directing aggressive treatment of premalignant lesions. However, expert recommendations for HRA are inconsistent. We report our experience using HRA to screen patients at high risk for ASCC. Methods: We retrospectively reviewed patients that underwent HRA between January 2011 and January 2016 noting the patient s pre/post procedure diagnosis and any subsequent changes in management or follow-up. Results: 61 patients underwent HRA between January 2011 and January 2016. HRA changed the diagnosis for 37 (59%) patients, overwhelmingly towards more advanced stages of dysplasia. However, we did not detect any invasive malignancies. 24 patients underwent chemo-ablative therapy. 16 of 19 patients that underwent treatment for HSIL, were only diagnosed after undergoing HRA. Two of the three patients that underwent treatment for LSIL were only given the diagnosis of LSIL after undergoing HRA. 62% of patients never followed up for surveillance anoscopy and only 11% followed up with repeat HRA. Conclusions: HRA is useful for stratifying patients at high risk for anal cancer. However, given the poor patient follow up in this population HRA should be reserved for patients who need additional information in order to make management decisions between surveillance or ablative therapy. Thorough discussions with patients at high-risk for anal cancer should occur prior to undergoing HRA to ensure that the procedure is only performed if management decisions hinge on the results. KEYWORDS: Anal Cancer, HRA, High Resolution Anoscopy, Anoscopy
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 1 Introduction Anal squamous cell carcinoma (ASCC) is rising in incidence throughout the United States 1,2,3,4,5 and other westernized countries. 6,7 Estimates expect there to be upwards of 8,000 new cases of ASCC in The United States in 2016 with deaths attributable to ASCC in excess of 1,000 during the same time. 8 As at other sites in the body, squamous cancers of the anal canal develop in the setting of chronic irritation, inflammation, and increased cell division that ultimately results in dysplasia and invasive malignancy. Anal squamous cell carcinoma appears to develop in an orderly fashion analogous to that of cervical cancer, with dysplasia progressing from mild to severe to overt malignancy. 2,3,5,9 The development of ASCC is associated with HPV 2,3,5,6,10,11, HIV 2,4,11, smoking 2, men who have sex with men 4,9 (MSM) and immunosuppression. 1,2,9 Prevalence studies estimate that the risk for ASCC among HIV-positive MSM is approximately double that of HIV-negative MSM. 5 Other studies have shown that the incidence of ASCC in HIV-positive MSM is almost 100 times greater than that of the general population. 5 The importance of screening for ASCC and its precursor lesions in this high risk population is underscored by the fact that neoplasia is a major cause of morbidity in patients with HIV 4,5 and ranks 2 nd among causes of mortality in patients with HIV. 7 In addition, early detection and treatment of ASCC has shown improved survival compared to those diagnosed with regional disease. 5 Despite the potential benefit, screening for anal cancer and its precursors presents several challenges. First, although the incidences of ASCC and its precursor lesions are rising, 12 their overall prevalence rates remain low, decreasing the potential yield of screening even in high risk populations. 2,3 In addition, lesions do not always progress from intraepithelial dysplasia to invasive malignancy, although HIV-positive patients are at an increased risk of progression of premalignant disease to a higher grade. 2,11 Research on the progression of anal intraepithelial neoplasia to invasive cancer is limited, and the true rate of conversion is unknown 9,11 with estimates ranging from 10-50%. 2,9,13 These inconsistencies have severely hindered the process of creating standard screening algorithms that can be applied to both the general public and high risk populations. The most recent guidelines from The American Society of Colon and Rectal Surgeons (ASCRS, 2012) recommend that patients with risk factors such as HPV, HIV, smoking, immunosuppression or pre malignant states such as low grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL), complete a screening disease-specific history and physical examination (level of evidence 1C) and anal cytology/papanicolaou smear (level of evidence 1C). 2 The reported sensitivity and specificity of these procedures varies widely in the literature. 1,2,5 To supplant the recommended screening, many Produced by The Berkeley Electronic Press, 2016
2 World Journal of Colorectal Surgery Vol. 6, Iss. 5 [2016], Art. 1 clinicians use High Resolution Anoscopy (HRA). This is generally performed by staining the squamocolumnar junction with acetic acid and/or Lugol iodine solution and examining the anal canal under magnification to identify abnormal areas for biopsy. Expert recommendations for HRA are inconsistent. The ASCRS notes that HRA can be used for surveillance (often in combination with digital rectal exam, and office anoscopy every 3-6 months) 2 or as a means of directing aggressive treatment of premalignant lesions. The success of either strategy largely depends on appropriate patient follow up and this is often underreported in the literature. Regardless of strategy, HRA can be uncomfortable for patients, time consuming, and currently without clear evidence of benefit. 11,12,14 We report our experience using HRA to screen a population at high risk for ASCC in a Midwestern city, including the clinical outcomes and patient follow up in hopes of better defining the role of HRA in the management of ASCC and its precursor lesions. Methods Our study was a retrospective review of patients treated at The University of Kansas Medical Center, a tertiary care center in Kansas City, Kansas, serving a metropolitan area of approximately 2 million people 15 and a large catchment population covering communities in Kansas and contiguous states. The study was approved by the University's Institutional Review Board prior to data collection. We used procedure codes to identify the records of all patients who underwent HRA in the five years between January 2011 and January 2016. All patients were 18 years of age or older and were referred to our clinic by infectious disease specialists at The University of Kansas Medical Center because of the presence of one or more risk factors for anal cancer i.e. history of anoreceptive intercourse, positivity for HIV and/or HPV, presence of perianal condylomata, or positive screening cytologic exams. High Resolution Anoscopy was performed with a metallic anoscope to visualize the entirety of the anal canal and squamocolumnar junction after the mucosa was exposed to a 3% acetic acid solution for a minimum of three minutes. Magnification devices were available for each procedure to aid in visualization. Cold forceps biopsies were taken of any areas within the anal canal that had palpable or visual abnormalities. Each chart was reviewed individually by a primary reviewer using an established protocol. The initial pathologic diagnosis (pre-hra) and the method by which it was determined were recorded and matched to the diagnosis post-hra for each patient. Any changes in diagnosis after HRA were noted. Additional data retrieved for each patient included treatment with chemoablation techniques, and http://services.bepress.com/wjcs/vol6/iss5/art1
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 3 the number of additional in-office anoscopic examinations and HRA procedures. Each chart was reviewed by a minimum of two members of the research team to validate data and improve accuracy. Microsoft Excel (Microsoft Corporation, Redmond WA) was used to generate descriptive statistics of the collective data. Results Sixty-one patients (53 males, 8 females) underwent HRA between January 2011 and January 2016. The average age was 47 (range 25-69). Initial Diagnosis and Diagnosis After HRA The presenting diagnoses and post HRA diagnoses for our patient cohort are shown in Table 1. The presenting diagnoses were based on the results of anal pap smear/cytology in 47 (77%) patients, colonoscopy in eight (13%) patients, and physical examination alone in six (10%) patients. High resolution anoscopy changed the diagnosis for 37 (59%) patients. These changes were overwhelmingly towards a more advanced stage of dysplasia and development of neoplasia (See Table 1). Thirty-one percent of our cohort (n=19) were ultimately diagnosed with LSIL and 47% of these patients (n=9) were only given the diagnosis of LSIL after undergoing HRA. In total, 56% of our cohort held the diagnosis of HSIL (n=34), but 74% percent of these patients were given the diagnosis of HSIL only after undergoing HRA. No patients were diagnosed with an invasive neoplasm during our study. Treatment Following screening, 24 patients underwent chemo-ablative therapy with either Imiquimod or topical 5-Flurouracil. The number of patients for each diagnosis that underwent treatment is shown in Table 2. Of the 19 patients that underwent treatment for HSIL, 84% of these patients (n=16) were diagnosed with HSIL only after undergoing HRA. Two of the three patients that underwent treatment for LSIL were only given the diagnosis of LSIL after undergoing HRA. Patients that chose surveillance over chemo-ablative therapy were asked to return for in-office anoscopy every 3-6 months. Follow up The number of patients who followed up with subsequent in-office anoscopy after HRA is shown in Figure 1. Sixty-two percent of patients never followed up in clinic for surveillance anoscopy after undergoing HRA. Produced by The Berkeley Electronic Press, 2016
4 World Journal of Colorectal Surgery Vol. 6, Iss. 5 [2016], Art. 1 The number of patients that underwent additional HRA after their initial HRA is shown in Figure 2. Eighty-nine percent of patients never had a repeat exam by HRA. Of the 11% of our cohort that underwent repeat HRA, none were noted to have a change in diagnosis or management. Of the 24 patients who underwent treatment, 54% (n=13) followed up in clinic with anoscopy and 29% (n=7) followed up with additional HRA. Within the group of 37 patients that chose not to have treatment, none underwent additional HRA and only 27% (n=10) followed up with anoscopy in clinic. Among the 15 patients with HSIL that elected to follow with surveillance and forego treatment, 53% (n=8) returned to clinic for repeat anoscopy. Nine of the patients with HSIL that opted for surveillance were diagnosed at the time of their initial HRA and only 55% (n=5) of these patients returned for anoscopy in clinic. Discussion Our retrospective review of patients at high risk for anal cancer who underwent HRA revealed several interesting trends regarding the recognition and management of pre-malignant lesions. First, cytologic screening exams such as anal pap smears and other diagnostic modalities, including colonoscopy, tend to underestimate the grade of squamous intraepithelial dysplasia. We found that 59% of patients had an upstage in their diagnosis after undergoing HRA. In fact, 25 of the 34 patients diagnosed with HSIL were only recognized after undergoing HRA. We also noted that approximately two thirds of patients who were initially diagnosed with LSIL actually had HSIL on HRA screening. Similar findings have been reported from other studies. 4,12 Possible explanations include the use of imprecise standard terminology for anal cytology 1 by pathologists or the variable sensitivity and specificity of anal cytology. Regardless of the cause, our findings suggest that HRA can determine the true extent of disease present within the anal canal and can facilitate patients in making informed decisions for disease management, i.e. whether to follow with a surveillance regime or to undergo curative therapies. For patients initially diagnosed with ASCUS, HRA offers an effective way of delineating their diagnosis from unknown significance as 80% of patients in our cohort initially diagnosed with ASCUS were found to have intraepithelial neoplasia at the time of HRA. Although nearly equivalent numbers of patients with HSIL pursued treatment as those that opted to follow with surveillance alone (19 vs 15 respectively), approximately 84% of patients undergoing treatment for HSIL were only given this diagnosis after their first HRA and only pursued treatment after being http://services.bepress.com/wjcs/vol6/iss5/art1
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 5 diagnosed with this higher grade of dysplasia. Similarly, 2 out of the 3 patients who underwent treatment for LSIL were only known to have a dysplastic lesion after undergoing HRA and they only pursued treatment after being given this diagnosis. These trends suggest that HRA has the greatest utility when the procedure can be used to clarify a patient s diagnosis and when results of the procedure will change the management decisions made by that patient. Current recommendations from the ASCRS state that patients at high risk for anal cancer or intraepithelial neoplasia may be managed with surveillance or curative therapy. 2 However, the overall rate of follow-up after HRA was less than half in our cohort. More importantly, only half of patients with HSIL that chose surveillance over therapy actually followed up in clinic for anoscopy. While there is no strong evidence demonstrating superiority of curative treatment over surveillance, the low follow-up rates observed in our cohort suggest that surveillance with anoscopy / HRA is a poor option for many patients and should only be reserved for patients who are likely to return for follow up. Interestingly, we noted that patients opting to forego treatment were also far less likely to follow up with surveillance exams compared to those who pursued therapy (27% vs 54%). This suggests that the treatment arm itself selects out patients who are more likely to follow up and supports the practice of aggressive treatment of lesions within this population rather than relying on patient follow up for surveillance. Our greatest limitations in performing this study were the relatively small size of our cohort and the retrospective nature of our research. Patient disease information and demographics were limited and prevented analysis of risk factors for disease progression. Future studies could incorporate this information and work towards testing the utility of HRA directly by comparing the survival and disease progression of patients that undergo HRA versus those that do not. Conclusion Our findings suggest that HRA is useful for stratifying patients at high risk for anal cancer as other screening examinations, such as cytology, appear to underestimate the grade of disease. However, given that no malignancies were detected in our cohort and that cytologic exams alone have a proven sensitivity for detecting pre-malignant lesions, our study suggests that HRA should be reserved for patients who need additional information in order to make management decisions between surveillance or ablative therapy. Thorough discussions with patients at high-risk for anal cancer should occur prior to undergoing HRA to ensure that the procedure is only performed if management Produced by The Berkeley Electronic Press, 2016
6 World Journal of Colorectal Surgery Vol. 6, Iss. 5 [2016], Art. 1 decisions hinge on the results. Finally, a strong unified approach is needed to ensure better long term follow up with this patient population. Acknowledgements We would like to acknowledge Dr. Anne Walling from The University of Kansas Medical Center in Wichita, Kansas for her help in preparing our manuscript. References 1. Albuquerque A. High-resolution anoscopy: unchartered territory for gastroenterologists? World J Gastrointest Endosc 2015; 7:1083-7 2. Coffey K, Beral V, Green J, Reeves G, Barnes I. Lifestyle and reproductive risk factors associated with anal cancer in women aged over 50 Years. Br J Cancer 2015; 112:1568-1574 3. Fox P. Anal Cancer Screening in Men Who Have Sex with Men. Curr Opin HIV AIDS. 2009:4: 64-67. 4. Gautier M, Brochard C, Lion A, et al. High-grade anal intraepithelial neoplasia: progression to invasive cancer Is not a certainty. Dig Liver Dis 2016; 48:806-11 5. Cosman B, Morris A, Santhat N, Madoff R. Anorectal Disorders. In: Greenfield's Surgery: Scientific Principles and Practice, Fifth Edition. Philadelphia, PA: Lippincott Williams & Wilkins, 2006. 6. Inkster MD, Wiland HO, Wu JS. Detection of anal dysplasia is enhanced by narrow band imaging and acetic acid. Colorectal Dis 2016; 18:17-21. 7. Mata-Marin JA, Hernandez-Figueroa J, Huerta-Garcia G, et al. Anal intraepithelial neoplasia among HIV-positive men who have sex with men. Sex Health 2015;12: 563 8. Long K, Menon R, Bastawrous A, Billingham R. Screening, Surveillance, and Treatment of Anal Intraepithelial Neoplasia. Clin Colon Rectal Surg 2016; 29:57-64. 9. Moscicki A, Darragha T, Berry-Lawhorn J, et al. Screening for anal cancer in women. J Low Genit Tract Dis 2015; 19:27-42 10. Sasaki, A. "Condyloma Acuminatum of the Anal Canal, Treated with Endoscopic Submucosal Dissection." World Journal of Gastroenterology WJG 22.8 (2016): 2636. Web. 11. Sendagorta E, Herranz P, Guadalajara H, et al. "Prevalence of abnormal anal cytology and high-grade squamous intraepithelial lesions among a cohort of http://services.bepress.com/wjcs/vol6/iss5/art1
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 7 HIV-infected men who have sex with men." Diseases of the Colon & Rectum 57.4 (2014): 475-81. Web. 12. Steele SR, Varma MG, Melton GB, Ross HM, Rafferty JF, Buie WD. Practice parameters for anal squamous neoplasms. Dis Colon Rectum 2012;55:.735-49. 13. Steinau M, Unger ER, Hernandez BY, et al. Human papillomavirus prevalence in invasive anal cancers in the United States before vaccine Introduction. J Low Genit Tract Dis 2013; 17:397-403. 14. Siegel R, Miller K, Jemal A. Cancer Statistics, 2016. CA: A Cancer Journal for Clinicians 2016; 66:7-30. 15. Loeff S, Mooji S, Richel O, de Vries H, Prins J. HPV and anal cancer in HIVinfected individuals: a review. Curr HIV/AIDS Rep. 2014, Sep;11(3):250-62 16. Salit I, Lytwyn A, Raboud J, Sano M, Chong S, Diong C, et. al. The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening; AIDS 2010; 24:1307-1313 17. Chiao E, Giordano T, Palefsky J, Tyring S, Serag H. Screening HIV-Infected Individuals for Anal Cancer Precursor Lesions: A Systematic Review; Clin Inf Dis 2006; 43:223-33. 18. "Kansas City Population 2016." - World Population Review. N.p., n.d. http://worldpopulationreview.com/us-cities/kansas-city-population/ Produced by The Berkeley Electronic Press, 2016
8 World Journal of Colorectal Surgery Vol. 6, Iss. 5 [2016], Art. 1 Table 1. Patient Diagnosis Before and After HRA. Within each presenting diagnosis, the number of patients that changed to a different diagnosis is shown. Note that there is a tendency for the severity of dysplasia to increase with HRA. However, no patients were noted to have an invasive malignancy. http://services.bepress.com/wjcs/vol6/iss5/art1
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 9 Table 2. Patients Decision for Ablative Therapy by Diagnosis. The relative percentage of patients within each diagnosis that chose therapy is shown. Note that relatively few patients with Low Grade Squamous Intraepithelial Lesions pursued therapy while nearly equivalent numbers of patients with High Grade Squamous Intraepithelial Lesions pursued therapy as those that did not. Produced by The Berkeley Electronic Press, 2016
10 World Journal of Colorectal Surgery Vol. 6, Iss. 5 [2016], Art. 1 Figure 1. Percentage of Patients Undergoing in-office Anoscopy after HRA. Note that an overwhelming majority of patients did not follow up for Anoscopy in clinic after their HRA. http://services.bepress.com/wjcs/vol6/iss5/art1
Wessel et al.: High Resolution Anoscopy In A High Risk Population: A Retrospecti 11 Figure 2. Percentage of Patients Receiving Repeat HRA. Note that very few patients underwent HRA after their initial procedure. Produced by The Berkeley Electronic Press, 2016