- Email: [email protected]
Anal Intraepithelial Neoplasia Screening With Anal Pap Tests: Follow-up and Corresponding Histology
j o u r n a l o f s u r g i c a l r e s e a r c h d e c e m b e r 2 0 1 9 ( 2 4 4 ) 1 1 7 e1 2 1
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Anal Intraepithelial Neoplasia Screening With Anal Pap Tests: Follow-Up and Corresponding Histology Cristina B. Geltzeiler, MD,a,b,* Joohee Son, BS,a Evie H. Carchman, MD,a Elise H. Lawson, MD,a Bruce A. Harms, MD,a,b Rob Striker, MD,c Suzanne Selvaggi, MD,d and Corrine I. Voils, PhDa,b a
Division of Colon and Rectal Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin b Department of Surgery, W. S. Middleton Memorial Veteran’s Hospital, Madison, Wisconsin c Department of Medicine, W. S. Middleton Memorial Veteran’s Hospital, Madison, Wisconsin d Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
article info
abstract
Article history:
Background: Anal cytology is used as a screening tool in the detection of precancerous anal
Received 28 February 2019
squamous lesions. Follow-up clinical examination after abnormal anal cytology is rec-
Received in revised form
ommended. The objective of this study was to determine how often abnormal cytology was
18 April 2019
followed by a clinical examination at our institution and how often cytology predicted
Accepted 7 June 2019
histologic outcome.
Available online xxx
Materials and methods: A retrospective chart review was performed (2008-2018) on patients with anal cytology, demonstrating either low-grade or high-grade squamous intraepithelial
Keywords:
lesion. Clinical examination within 1 y (digital rectal examination, anoscopy, or high-
Anal cytology
resolution anoscopy) was recorded. The probability of anal intraepithelial neoplasm on
Anal dysplasia
biopsy after dysplasia on cytology was calculated, and McNemar’s test was used to
HIV
determine if there was correspondence between cytology and histology.
HPV
Results: A total of 327 anal cytology results demonstrated dysplasia (75% low grade and 25%
Anal intraepithelial neoplasia
high grade) in 182 patients. Seventy-five percent of dysplastic anal cytology were followed
Anal Pap test
by clinical examination within 1 y, and 50% were biopsied. The probability of dysplasia on histology after dysplasia on cytology was 72% (95% confidence interval: 64%-78.5%). Twenty-eight percent of low-grade cytology results were upgraded to advanced disease (high-grade or invasive cancer) on histology. A low-grade cytology result was unable to preclude high-grade histology in our population. Conclusions: There is room for improvement at our institution to consistently follow-up with clinical examination after abnormal anal cytology. Our data suggest this is especially important considering anal cytology is an imperfect predictor of histologic anal intraepithelial neoplasia and invasive disease. Clinical examination is a critical component of anal dysplasia screening and follow-up. Published by Elsevier Inc.
This work was presented at the Academic Surgical Congress, Oral Quick Shot presentation February 6, 2019. * Corresponding author. University of Wisconsin Hospital and Clinics, K3/704 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375. Tel.: þ1 608 263 2521; fax: þ1 608 252 0950. E-mail address: [email protected] (C.B. Geltzeiler). 0022-4804/$ e see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.jss.2019.06.029
118
j o u r n a l o f s u r g i c a l r e s e a r c h d e c e m b e r 2 0 1 9 ( 2 4 4 ) 1 1 7 e1 2 1
Introduction The incidence of anal cancer has been incrementally increasing over the last 4 decades in the United States.1 Anal dysplasia, an anal cancer precursor, is a growing health concern for high-risk populations, such as human immunodeficiency virus (HIV)-positive individuals and those who engage in anal-receptive intercourse.2-4 Anal dysplasia is caused by infection with human papillomavirus (HPV) and can be screened using anal ThinPrep Papanicolaou (Pap) testing with cytologic analysis.5,6 Recent data have determined that cytology is an imperfect indicator of dysplasia presence and grade when compared with histology.7 Although recommendations on the type (cytology versus pathology) and frequency of surveillance are controversial, most practitioners recommend follow-up clinical examination for patients with an abnormal anal Pap.8-11 Clinical examination can consist of high-resolution anoscopy (HRA), standard anoscopy, or, at a minimum, physical examination with digital rectal examination (DRE).11 Clinical examination is used to confirm diagnosis and/or treat dysplastic and cancerous lesions. Although a follow-up examination is recommended, it often involves referral to clinicians who specialize in these techniques, such as colorectal surgeons.11 Furthermore, it involves invasive and procedural examinations that may not be acceptable to patients. Little is known on the rate and outcomes of follow-up clinical examination after abnormal anal Pap tests. The objective of this study was to determine how often an abnormal anal Pap test was followed by clinical examination at our institution and how often cytology was associated with histologic anal intraepithelial neoplasm (AIN) and types of AIN.
Materials and methods We identified all patients who underwent anal ThinPrep Pap testing at a single academic medical center between 2008 and 2018. Patients were identified via pathology repository of all anal cytology records. Retrospective chart review was performed for patients with anal cytology results demonstrating dysplasia defined as low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL). We did not examine patients with Pap test resulting in atypical squamous cells of undetermined significance because of controversy in follow-up recommendations (clinical examination versus repeat Pap test) in the literature.7,12,13 Patient variables of interest included demographics and pertinent medical history. Age was recorded at the time of the patient’s first abnormal anal cytology result. Medical history of interest included HIV status, antiretroviral therapy, and pre-exposure prophylaxis (PrEP) use. Smoking history was defined as currently smoking or a history of tobacco use documented in the medical chart. Anal receptive intercourse history was recorded if indicated in the patient chart. History of other nonHPV-related sexually transmitted diseases (gonorrhea, chlamydia, hepatitis C, hepatitis B, syphilis, and genital
herpes) and reported clinical history of anal condyloma was also noted. Data were recorded for any subsequent clinical follow-up within 12 mo after the patient’s abnormal anal cytology result. Clinical follow-up was defined as HRA, standard anoscopy, or DRE alone. These data were obtained by electronic medical record review of all clinic and procedure notes related to AIN diagnosis. All pathology results in the timeframe were reviewed, and if anal tissue was sampled, histologic results of these biopsies were recorded. Low-grade lesions on biopsy were described as “low-grade” or AIN1. High-grade lesions on biopsy were those described as “high-grade,” AIN 2/3, or squamous cell carcinoma in situ. The probability of AIN on biopsy after AIN on cytology was calculated using 2 2 contingency tables. The marginal homogeneity between the two tests (cytology and biopsy results) was examined using McNemar’s chi-squared test. This study was approved by the University of Wisconsin Institutional Review Board.
Results A total of 1361 anal ThinPrep Pap tests from 557 patients were analyzed from 2008 to 2018. There were 327 reports resulting as LSIL or HSIL from 182 patients, of which 167 (92%) were male, 12 (6%) female, and 3 (2%) identified as transgender, biologically male. Median age was 53 y with an interquartile range of 19-81. The majority of the patients were White (78%), and 65% were current or former smokers. About 45% of the patients had a history of nonHPV-related sexually transmitted infections other than HIV, and 53% had a reported clinical history of anal condyloma. There were 73% of patients with a documented history of anal receptive intercourse (Table 1). Most patients (97%) had a documented HIV diagnosis, and all patients with HIV were on antiretroviral therapy. There were six HIV-negative patients with abnormal anal Pap tests. Each of these patients underwent cytology testing because of other risk factors: documented history of anal-receptive intercourse (n ¼ 1), use of PrEP therapy because of high-risk sexual behavior and reported history of anal condyloma (n ¼ 2), and history of high-grade AIN on biopsy of a clinically evident lesion (n ¼ 3; Table 1). Of the abnormal cytologic results, 75% (n ¼ 246) were lowgrade dysplasia and 25% (n ¼ 81) were high-grade dysplasia. Most abnormal Pap tests were obtained in the infectious disease clinic (n ¼ 319), with the remaining obtained by colorectal surgery (n ¼ 5) and gastroenterology (n ¼ 3). Follow-up clinical examination within 1 y of abnormal testing was performed following 75% (n ¼ 245) of abnormal Pap tests. Many patients had multiple abnormal Pap tests. Follow-up clinical examination did not occur in 31% (n ¼ 56) of patients on least one occasion following abnormal Pap test, and 14% (n ¼ 26) of patients never had a clinical examination after abnormal Pap. A minority of patients did not follow-up at our institution at all within 1 y of their anal Pap test (5% [n ¼ 9]). Clinical examination was more likely to occur after a high-grade Pap test result (86% [n ¼ 70]) compared with a low-grade Pap test result (71% [n ¼ 175]). The majority of patients with a follow-up
119
geltzeiler et al anal dysplasia follow-up
Table 1 e Patient factors. Total number of patients (n ¼ 182) Gender, n (%) Male
167 (92)
Female
12 (6)
Transgender
3 (2)
Age (y)*
43 (19-81)
followed by biopsy, 28% (n ¼ 12) were negative for AIN, 33% (n ¼ 14) were downgraded to low-grade disease, and 39% (n ¼ 17) confirmed high-grade disease on histology. None demonstrated invasive disease (Table 3). The probability of AIN on histology after an abnormal Pap test was 72% with a 95% confidence interval of 64%-78.5%. When evaluating if low- and high-grade cytology correspond with low- and high-grade histology, there was not reliable agreement between the two tests, P ¼ 0.006.
Race, n (%) White
142 (78)
African American
20 (11)
Native American
2 (1)
Hispanic
Discussion
12 (7)
Asian
6 (3)
HIV status, n (%) Yes
176 (97)
No
6 (3)
Antiretroviral therapy
176 (97)
PrEP therapy
2 (1)
Anal receptive intercourse, n (%) Yes
133 (73)
No
22 (12)
Unknown
27 (15)
Smoking history, n (%)
118 (65)
STI other than HPV, n (%)
82 (45)
Anal condyloma, n (%)
97 (53)
STI ¼ sexually transmitted infection. * Age in median with interquartile range in parentheses.
examination underwent HRA, 75% (n ¼ 183), or standard anoscopy, 21% (n ¼ 53). DRE alone was performed for 4% of patients (n ¼ 9; Table 2). Anal biopsies were performed 50% (n ¼ 163) of the time after a dysplastic Pap result. Of the 120 LSIL Pap tests followed by biopsy, 28% (n ¼ 34) were negative for AIN, 44% (n ¼ 53) confirmed low-grade disease, 25% (n ¼ 30) were upgraded to high-grade disease, and 3% (n ¼ 3) demonstrated invasive cancer on histology. In all of the invasive cancer cases, a clinically evident lesion was present at the time of office examination by a colorectal surgeon. Of the 43 HSIL Pap tests
In this single-center study, only 75% of abnormal anal Pap test results were followed up with clinical examination within 1 y, and 50% were biopsied for histologic confirmation. When biopsied, only 72% of abnormal Pap tests demonstrated AIN or invasive disease on histologic examination, and 28% were upgraded to advanced disease (high-grade or invasion) after low-grade cytology. These advanced lesions would not have been detected without clinical examination following cytology. There is room for improvement in our institution, and likely others, to consistently follow-up with clinical examination after abnormal anal cytology. Our data suggest this is especially important considering anal cytology is an imperfect predictor of histologic AIN and invasive disease. Clinical examination is a critical component of anal dysplasia screening. Screening for AIN in high-risk patients has been recommended by most clinicians with the goal of identifying and treating patients with precancerous or cancerous lesions.14 Screening is important, as many patients with disease are asymptomatic.15 Collection of anal Pap tests for cytologic analysis is an invasive test. Often clinicians who collect specimens for cytology are not trained in anorectal examination or anoscopy, which are recommended as follow-up examination after abnormal screening results. Anoscopy, and especially HRA, is a specialized examination requiring procedural expertise and usually referral to a specialist to be performed.11,16 At our
Table 3 e Comparison of anal cytology and histology by type of anoscopy. LSIL with biopsies (n ¼ 120), n (%)
HSIL with biopsies (n ¼ 43), n (%)
Histology
Table 2 e Anal cytology and clinical follow-up after 12 mo.
No clinical examination Clinical examination HRA Anoscopy Digital rectal examination
LSIL (n ¼ 246), n (%)
HSIL (n ¼ 81), n (%)
Follow-up within 12 mo
Follow-up within 12 mo
71 (29)
11 (14)
175 (71)
70 (86)
131 (75)
52 (75)
36 (21)
17 (24)
8 (4)
1 (1)
Negative
34 (28)
12 (28)
HRA
33 (97)
12 (100)
1 (3)
0
Anoscopy Low grade HRA Anoscopy High grade HRA Anoscopy Invasive cancer
53 (44)
14 (33)
47 (89)
12 (86)
6 (11)
2 (14)
30 (25)
17 (39)
26 (87)
17 (100)
4 (13)
0
3 (3)
0
HRA
2 (67)
0
Anoscopy
1 (33)
0
120
j o u r n a l o f s u r g i c a l r e s e a r c h d e c e m b e r 2 0 1 9 ( 2 4 4 ) 1 1 7 e1 2 1
institution, only 75% of the abnormal test results were referred for and received recommended specialized follow-up examination despite 5-8 providers (depending on the year) available to provide the service over the study period. Morency et al. recently evaluated a similar number of abnormal Pap tests. Their group had an even lower rate of biopsy after dysplastic cytology (43% versus 50% in our cohort), suggesting that other institutions also struggle to consistently follow-up on abnormal Pap tests.7 Reasons for lack of follow-up in our study were not completely ascertained from chart review but may be multifactorial, with contributions by the patient, health care system, and provider. Advanced disease would have been missed in 28% of our patient population without follow-up clinical examination and/or histologic examination. This emphasizes the importance of education on the part of all providers and also the patient as to the recommendation of clinical examination after an abnormal anal Pap test. There is no current national benchmark or standard for compliance rates with clinical follow-up after abnormal Pap test. We do believe, however, that patients should be counseled as to the standard follow-up practice before Pap test. If clinical examination is not acceptable to the patient, a Pap test alone is not an adequate substitute, as demonstrated by our data. A patient’s care often involves infectious disease providers, primary care providers, gastroenterologists, dermatologists, and colorectal surgeons. It is not always clear which clinician on the HIV-positive patient’s multidisciplinary care team should take ownership of this portion of their care. In our study, we have demonstrated poor agreement with grade of disease when comparing cytology to histology. We have also demonstrated that 28% of the low-grade cytology, when
actually biopsied, were upgraded to advanced disease (highgrade or invasive disease). This emphasizes the critical importance of clinical examination and referral for specialized services. It may be reasonable for a clinical examination to occur at the time of initial screening. This proposition presents its own challenges, as many providers rely on registered nurses or other midlevel providers to collect anorectal samples, some of whom have little to no experience or comfort with anorectal examination.17 Other authors have demonstrated similarly low accuracy of cytology for dysplasia presence and type.6,18,19 Sensitivity and specificity of anal Pap tests compared with histology have been variably reported but sensitivities reported as low as 42% and specificity as low as 26%.6,7,18-20 Because of risks of procedure, at our institution, we do not perform biopsies after negative cytology result and, therefore, could not determine sensitivity or specificity. We did, however, demonstrate poor correspondence between cytologic and histologic results. Other authors’ findings converge with our results to suggest that anal cytology alone is inadequate and requires follow-up clinical examination. Cases of high-grade cytology that were downgraded to lowgrade or normal on histology in our study may be related to sampling error. Siegenbeek van Heukelom et al.16 have demonstrated that increased number of biopsies correlates with increasing detection of high-grade disease on histology. Although intriguing, each biopsy has resultant potential risks of bleeding and discomfort. We also believe that most clinically relevant high-grade lesions will be visually evident on HRA and, because of possible risk, do not blindly biopsy in our practice. Sambursky et al.13 have recently demonstrated HPV
Fig e University of Wisconsin Protocol for follow-up after anal Pap tests. (Color version of figure is available online.)
geltzeiler et al anal dysplasia follow-up
testing to be more sensitive and specific in demonstrating dysplasia than cytology typing. At our institution, HPV typing is not performed because of increased cost and almost universal positivity in high-risk patient populations. This practice may need to be revisited based on others’ results for more accurate prediction of high-grade disease. This study has important limitations. This is a retrospective analysis at a single institution. We are unable to determine if better correspondence between cytology and histology would have occurred in a lower-risk patient population. We are also limited by the data available in the medical record. If a patient received follow-up at another institution, we might have missing data as to their clinical examination. We are not able to determine reasons why there was no clinical examination after abnormal cytology results. These findings of inconsistent clinical follow-up, however, have prompted a multidisciplinary education of clinicians involved in the care of these patients and development of a robust and welldefined protocol for clinical follow-up and care of these patients (Figure).
Conclusions In conclusion, we have demonstrated that anal cytology is an imperfect predictor of anal intraepithelial neoplasia when compared with histology. Cytology is a screening tool to detect disease. Clinical examination is a critical component of care for these high-risk patients for early disease detection.
Acknowledgment The authors would like to acknowledge Yiwei Xu, MHS, for statistical assistance and Erek Kucher for acquisition of pathology data. Authors’ contributions: C.G., J.S., R.S., S.S., and C.V. contributed to conception and design; C.G., J.S., E.C., E.L., B.H., R.S., S.S., and C.V. analyzed and interpreted the data; C.G., J.S., E.C., E.L., B.H., R.S., and C.V. drafted and revised the article. Dr C.I.V. was supported by a Research Career Scientist award from the Department of Veterans Affairs Health Services Research and Development Service, United States (RCS 14-443).
Disclosure No author of this publication has any disclosure or conflict of interest to report.
references
1. National Cancer Institute. Cancer stat facts: anal cancer. Available at: https://seer.cancer.gov/statfacts/html/anus. html. Accessed February 28, 2019. 2. Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19:1407e1414.
121
3. Fazendin EA, Crean AJ, Fazendin JM, et al. Condyloma acuminatum, anal intraepithelial neoplasia, and anal cancer in the setting of HIV: do we really understand the risk? Dis Colon Rectum. 2017;60:1078e1082. 4. Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and metaanalysis. Lancet Oncol. 2012;13:487e500. 5. Factor SH, Cooperstein A, Pereira GA, Goldstone SE. Are colon and rectal surgeons ready to screen for anal dysplasia? Results of a survey on attitudes and practice. Sex Transm Dis. 2014;41:246e253. 6. Goncalves JCN, Macedo ACL, Madeira K, et al. Accuracy of anal cytology for diagnostic of precursor lesions of anal cancer: systematic review and meta-analysis. Dis Colon Rectum. 2019;62:112e120. 7. Morency EG, Harbert T, Fatima N, Samolcyzk J, Maniar KP, Nayar R. Anal cytology: institutional statistics, correlation with histology, and development of multidisciplinary screening program with review of the current literature. Arch Pathol Lab Med. 2019;143:23e29. 8. Cajas-Monson LC, Ramamoorthy SL, Cosman BC. Expectant management of high-grade anal dysplasia in people with HIV: long-term data. Dis Colon Rectum. 2018;61:1357e1363. 9. Crawshaw BP, Russ AJ, Stein SL, et al. High-resolution anoscopy or expectant management for anal intraepithelial neoplasia for the prevention of anal cancer: is there really a difference? Dis Colon Rectum. 2015;58:53e59. 10. Leeds IL, Fang SH. Anal cancer and intraepithelial neoplasia screening: a review. World J Gastrointest Surg. 2016;8:41e51. 11. Stewart DB, Gaertner WB, Glasgow SC, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for anal squamous cell cancers (revised 2018). Dis Colon Rectum. 2018;61:755e774. 12. Chin-Hong PV, Palefsky JM. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect Dis. 2002;35:1127e1134. 13. Sambursky JA, Terlizzi JP, Goldstone SE. Testing for human papillomavirus strains 16 and 18 helps predict the presence of anal high-grade squamous intraepithelial lesions. Dis Colon Rectum. 2018;61:1364e1371. 14. Swedish KA, Lee EQ, Goldstone SE. The changing picture of high-grade anal intraepithelial neoplasia in men who have sex with men: the effects of 10 years of experience performing high-resolution anoscopy. Dis Colon Rectum. 2011;54:1003e1007. 15. Hicks CW, Wick EC, Leeds IL, et al. Patient symptomatology in anal dysplasia. JAMA Surg. 2015;150:563e569. 16. Siegenbeek van Heukelom ML, Marra E, Cairo I, et al. Detection rate of high-grade squamous intraepithelial lesions as a quality assurance metric for high-resolution anoscopy in HIV-positive men. Dis Colon Rectum. 2018;61:780e786. 17. Rosa-Cunha I, Degennaro VA, Hartmann R, et al. Description of a pilot anal pap smear screening program among individuals attending a veteran’s affairs HIV clinic. AIDS Patient Care STDS. 2011;25:213e219. 18. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis. 2006;43:223e233. 19. Silva M, Peixoto A, Sarmento JA, Coelho R, Macedo G. Anal cytology, histopathology and anoscopy in an anal dysplasia screening program: is anal cytology enough? Rev Esp Enferm Dig. 2018;110:109e114. 20. Papaconstantinou HT, Lee AJ, Simmang CL, et al. Screening methods for high-grade dysplasia in patients with anal condyloma. J Surg Res. 2005;127:8e13.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Anal Intraepithelial Neoplasia Screening With Anal Pap Tests: Follow-Up and Corresponding Histology Cristina B. Geltzeiler, MD,a,b,* Joohee Son, BS,a Evie H. Carchman, MD,a Elise H. Lawson, MD,a Bruce A. Harms, MD,a,b Rob Striker, MD,c Suzanne Selvaggi, MD,d and Corrine I. Voils, PhDa,b a
Division of Colon and Rectal Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin b Department of Surgery, W. S. Middleton Memorial Veteran’s Hospital, Madison, Wisconsin c Department of Medicine, W. S. Middleton Memorial Veteran’s Hospital, Madison, Wisconsin d Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
article info
abstract
Article history:
Background: Anal cytology is used as a screening tool in the detection of precancerous anal
Received 28 February 2019
squamous lesions. Follow-up clinical examination after abnormal anal cytology is rec-
Received in revised form
ommended. The objective of this study was to determine how often abnormal cytology was
18 April 2019
followed by a clinical examination at our institution and how often cytology predicted
Accepted 7 June 2019
histologic outcome.
Available online xxx
Materials and methods: A retrospective chart review was performed (2008-2018) on patients with anal cytology, demonstrating either low-grade or high-grade squamous intraepithelial
Keywords:
lesion. Clinical examination within 1 y (digital rectal examination, anoscopy, or high-
Anal cytology
resolution anoscopy) was recorded. The probability of anal intraepithelial neoplasm on
Anal dysplasia
biopsy after dysplasia on cytology was calculated, and McNemar’s test was used to
HIV
determine if there was correspondence between cytology and histology.
HPV
Results: A total of 327 anal cytology results demonstrated dysplasia (75% low grade and 25%
Anal intraepithelial neoplasia
high grade) in 182 patients. Seventy-five percent of dysplastic anal cytology were followed
Anal Pap test
by clinical examination within 1 y, and 50% were biopsied. The probability of dysplasia on histology after dysplasia on cytology was 72% (95% confidence interval: 64%-78.5%). Twenty-eight percent of low-grade cytology results were upgraded to advanced disease (high-grade or invasive cancer) on histology. A low-grade cytology result was unable to preclude high-grade histology in our population. Conclusions: There is room for improvement at our institution to consistently follow-up with clinical examination after abnormal anal cytology. Our data suggest this is especially important considering anal cytology is an imperfect predictor of histologic anal intraepithelial neoplasia and invasive disease. Clinical examination is a critical component of anal dysplasia screening and follow-up. Published by Elsevier Inc.
This work was presented at the Academic Surgical Congress, Oral Quick Shot presentation February 6, 2019. * Corresponding author. University of Wisconsin Hospital and Clinics, K3/704 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375. Tel.: þ1 608 263 2521; fax: þ1 608 252 0950. E-mail address: [email protected] (C.B. Geltzeiler). 0022-4804/$ e see front matter Published by Elsevier Inc. https://doi.org/10.1016/j.jss.2019.06.029
118
j o u r n a l o f s u r g i c a l r e s e a r c h d e c e m b e r 2 0 1 9 ( 2 4 4 ) 1 1 7 e1 2 1
Introduction The incidence of anal cancer has been incrementally increasing over the last 4 decades in the United States.1 Anal dysplasia, an anal cancer precursor, is a growing health concern for high-risk populations, such as human immunodeficiency virus (HIV)-positive individuals and those who engage in anal-receptive intercourse.2-4 Anal dysplasia is caused by infection with human papillomavirus (HPV) and can be screened using anal ThinPrep Papanicolaou (Pap) testing with cytologic analysis.5,6 Recent data have determined that cytology is an imperfect indicator of dysplasia presence and grade when compared with histology.7 Although recommendations on the type (cytology versus pathology) and frequency of surveillance are controversial, most practitioners recommend follow-up clinical examination for patients with an abnormal anal Pap.8-11 Clinical examination can consist of high-resolution anoscopy (HRA), standard anoscopy, or, at a minimum, physical examination with digital rectal examination (DRE).11 Clinical examination is used to confirm diagnosis and/or treat dysplastic and cancerous lesions. Although a follow-up examination is recommended, it often involves referral to clinicians who specialize in these techniques, such as colorectal surgeons.11 Furthermore, it involves invasive and procedural examinations that may not be acceptable to patients. Little is known on the rate and outcomes of follow-up clinical examination after abnormal anal Pap tests. The objective of this study was to determine how often an abnormal anal Pap test was followed by clinical examination at our institution and how often cytology was associated with histologic anal intraepithelial neoplasm (AIN) and types of AIN.
Materials and methods We identified all patients who underwent anal ThinPrep Pap testing at a single academic medical center between 2008 and 2018. Patients were identified via pathology repository of all anal cytology records. Retrospective chart review was performed for patients with anal cytology results demonstrating dysplasia defined as low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL). We did not examine patients with Pap test resulting in atypical squamous cells of undetermined significance because of controversy in follow-up recommendations (clinical examination versus repeat Pap test) in the literature.7,12,13 Patient variables of interest included demographics and pertinent medical history. Age was recorded at the time of the patient’s first abnormal anal cytology result. Medical history of interest included HIV status, antiretroviral therapy, and pre-exposure prophylaxis (PrEP) use. Smoking history was defined as currently smoking or a history of tobacco use documented in the medical chart. Anal receptive intercourse history was recorded if indicated in the patient chart. History of other nonHPV-related sexually transmitted diseases (gonorrhea, chlamydia, hepatitis C, hepatitis B, syphilis, and genital
herpes) and reported clinical history of anal condyloma was also noted. Data were recorded for any subsequent clinical follow-up within 12 mo after the patient’s abnormal anal cytology result. Clinical follow-up was defined as HRA, standard anoscopy, or DRE alone. These data were obtained by electronic medical record review of all clinic and procedure notes related to AIN diagnosis. All pathology results in the timeframe were reviewed, and if anal tissue was sampled, histologic results of these biopsies were recorded. Low-grade lesions on biopsy were described as “low-grade” or AIN1. High-grade lesions on biopsy were those described as “high-grade,” AIN 2/3, or squamous cell carcinoma in situ. The probability of AIN on biopsy after AIN on cytology was calculated using 2 2 contingency tables. The marginal homogeneity between the two tests (cytology and biopsy results) was examined using McNemar’s chi-squared test. This study was approved by the University of Wisconsin Institutional Review Board.
Results A total of 1361 anal ThinPrep Pap tests from 557 patients were analyzed from 2008 to 2018. There were 327 reports resulting as LSIL or HSIL from 182 patients, of which 167 (92%) were male, 12 (6%) female, and 3 (2%) identified as transgender, biologically male. Median age was 53 y with an interquartile range of 19-81. The majority of the patients were White (78%), and 65% were current or former smokers. About 45% of the patients had a history of nonHPV-related sexually transmitted infections other than HIV, and 53% had a reported clinical history of anal condyloma. There were 73% of patients with a documented history of anal receptive intercourse (Table 1). Most patients (97%) had a documented HIV diagnosis, and all patients with HIV were on antiretroviral therapy. There were six HIV-negative patients with abnormal anal Pap tests. Each of these patients underwent cytology testing because of other risk factors: documented history of anal-receptive intercourse (n ¼ 1), use of PrEP therapy because of high-risk sexual behavior and reported history of anal condyloma (n ¼ 2), and history of high-grade AIN on biopsy of a clinically evident lesion (n ¼ 3; Table 1). Of the abnormal cytologic results, 75% (n ¼ 246) were lowgrade dysplasia and 25% (n ¼ 81) were high-grade dysplasia. Most abnormal Pap tests were obtained in the infectious disease clinic (n ¼ 319), with the remaining obtained by colorectal surgery (n ¼ 5) and gastroenterology (n ¼ 3). Follow-up clinical examination within 1 y of abnormal testing was performed following 75% (n ¼ 245) of abnormal Pap tests. Many patients had multiple abnormal Pap tests. Follow-up clinical examination did not occur in 31% (n ¼ 56) of patients on least one occasion following abnormal Pap test, and 14% (n ¼ 26) of patients never had a clinical examination after abnormal Pap. A minority of patients did not follow-up at our institution at all within 1 y of their anal Pap test (5% [n ¼ 9]). Clinical examination was more likely to occur after a high-grade Pap test result (86% [n ¼ 70]) compared with a low-grade Pap test result (71% [n ¼ 175]). The majority of patients with a follow-up
119
geltzeiler et al anal dysplasia follow-up
Table 1 e Patient factors. Total number of patients (n ¼ 182) Gender, n (%) Male
167 (92)
Female
12 (6)
Transgender
3 (2)
Age (y)*
43 (19-81)
followed by biopsy, 28% (n ¼ 12) were negative for AIN, 33% (n ¼ 14) were downgraded to low-grade disease, and 39% (n ¼ 17) confirmed high-grade disease on histology. None demonstrated invasive disease (Table 3). The probability of AIN on histology after an abnormal Pap test was 72% with a 95% confidence interval of 64%-78.5%. When evaluating if low- and high-grade cytology correspond with low- and high-grade histology, there was not reliable agreement between the two tests, P ¼ 0.006.
Race, n (%) White
142 (78)
African American
20 (11)
Native American
2 (1)
Hispanic
Discussion
12 (7)
Asian
6 (3)
HIV status, n (%) Yes
176 (97)
No
6 (3)
Antiretroviral therapy
176 (97)
PrEP therapy
2 (1)
Anal receptive intercourse, n (%) Yes
133 (73)
No
22 (12)
Unknown
27 (15)
Smoking history, n (%)
118 (65)
STI other than HPV, n (%)
82 (45)
Anal condyloma, n (%)
97 (53)
STI ¼ sexually transmitted infection. * Age in median with interquartile range in parentheses.
examination underwent HRA, 75% (n ¼ 183), or standard anoscopy, 21% (n ¼ 53). DRE alone was performed for 4% of patients (n ¼ 9; Table 2). Anal biopsies were performed 50% (n ¼ 163) of the time after a dysplastic Pap result. Of the 120 LSIL Pap tests followed by biopsy, 28% (n ¼ 34) were negative for AIN, 44% (n ¼ 53) confirmed low-grade disease, 25% (n ¼ 30) were upgraded to high-grade disease, and 3% (n ¼ 3) demonstrated invasive cancer on histology. In all of the invasive cancer cases, a clinically evident lesion was present at the time of office examination by a colorectal surgeon. Of the 43 HSIL Pap tests
In this single-center study, only 75% of abnormal anal Pap test results were followed up with clinical examination within 1 y, and 50% were biopsied for histologic confirmation. When biopsied, only 72% of abnormal Pap tests demonstrated AIN or invasive disease on histologic examination, and 28% were upgraded to advanced disease (high-grade or invasion) after low-grade cytology. These advanced lesions would not have been detected without clinical examination following cytology. There is room for improvement in our institution, and likely others, to consistently follow-up with clinical examination after abnormal anal cytology. Our data suggest this is especially important considering anal cytology is an imperfect predictor of histologic AIN and invasive disease. Clinical examination is a critical component of anal dysplasia screening. Screening for AIN in high-risk patients has been recommended by most clinicians with the goal of identifying and treating patients with precancerous or cancerous lesions.14 Screening is important, as many patients with disease are asymptomatic.15 Collection of anal Pap tests for cytologic analysis is an invasive test. Often clinicians who collect specimens for cytology are not trained in anorectal examination or anoscopy, which are recommended as follow-up examination after abnormal screening results. Anoscopy, and especially HRA, is a specialized examination requiring procedural expertise and usually referral to a specialist to be performed.11,16 At our
Table 3 e Comparison of anal cytology and histology by type of anoscopy. LSIL with biopsies (n ¼ 120), n (%)
HSIL with biopsies (n ¼ 43), n (%)
Histology
Table 2 e Anal cytology and clinical follow-up after 12 mo.
No clinical examination Clinical examination HRA Anoscopy Digital rectal examination
LSIL (n ¼ 246), n (%)
HSIL (n ¼ 81), n (%)
Follow-up within 12 mo
Follow-up within 12 mo
71 (29)
11 (14)
175 (71)
70 (86)
131 (75)
52 (75)
36 (21)
17 (24)
8 (4)
1 (1)
Negative
34 (28)
12 (28)
HRA
33 (97)
12 (100)
1 (3)
0
Anoscopy Low grade HRA Anoscopy High grade HRA Anoscopy Invasive cancer
53 (44)
14 (33)
47 (89)
12 (86)
6 (11)
2 (14)
30 (25)
17 (39)
26 (87)
17 (100)
4 (13)
0
3 (3)
0
HRA
2 (67)
0
Anoscopy
1 (33)
0
120
j o u r n a l o f s u r g i c a l r e s e a r c h d e c e m b e r 2 0 1 9 ( 2 4 4 ) 1 1 7 e1 2 1
institution, only 75% of the abnormal test results were referred for and received recommended specialized follow-up examination despite 5-8 providers (depending on the year) available to provide the service over the study period. Morency et al. recently evaluated a similar number of abnormal Pap tests. Their group had an even lower rate of biopsy after dysplastic cytology (43% versus 50% in our cohort), suggesting that other institutions also struggle to consistently follow-up on abnormal Pap tests.7 Reasons for lack of follow-up in our study were not completely ascertained from chart review but may be multifactorial, with contributions by the patient, health care system, and provider. Advanced disease would have been missed in 28% of our patient population without follow-up clinical examination and/or histologic examination. This emphasizes the importance of education on the part of all providers and also the patient as to the recommendation of clinical examination after an abnormal anal Pap test. There is no current national benchmark or standard for compliance rates with clinical follow-up after abnormal Pap test. We do believe, however, that patients should be counseled as to the standard follow-up practice before Pap test. If clinical examination is not acceptable to the patient, a Pap test alone is not an adequate substitute, as demonstrated by our data. A patient’s care often involves infectious disease providers, primary care providers, gastroenterologists, dermatologists, and colorectal surgeons. It is not always clear which clinician on the HIV-positive patient’s multidisciplinary care team should take ownership of this portion of their care. In our study, we have demonstrated poor agreement with grade of disease when comparing cytology to histology. We have also demonstrated that 28% of the low-grade cytology, when
actually biopsied, were upgraded to advanced disease (highgrade or invasive disease). This emphasizes the critical importance of clinical examination and referral for specialized services. It may be reasonable for a clinical examination to occur at the time of initial screening. This proposition presents its own challenges, as many providers rely on registered nurses or other midlevel providers to collect anorectal samples, some of whom have little to no experience or comfort with anorectal examination.17 Other authors have demonstrated similarly low accuracy of cytology for dysplasia presence and type.6,18,19 Sensitivity and specificity of anal Pap tests compared with histology have been variably reported but sensitivities reported as low as 42% and specificity as low as 26%.6,7,18-20 Because of risks of procedure, at our institution, we do not perform biopsies after negative cytology result and, therefore, could not determine sensitivity or specificity. We did, however, demonstrate poor correspondence between cytologic and histologic results. Other authors’ findings converge with our results to suggest that anal cytology alone is inadequate and requires follow-up clinical examination. Cases of high-grade cytology that were downgraded to lowgrade or normal on histology in our study may be related to sampling error. Siegenbeek van Heukelom et al.16 have demonstrated that increased number of biopsies correlates with increasing detection of high-grade disease on histology. Although intriguing, each biopsy has resultant potential risks of bleeding and discomfort. We also believe that most clinically relevant high-grade lesions will be visually evident on HRA and, because of possible risk, do not blindly biopsy in our practice. Sambursky et al.13 have recently demonstrated HPV
Fig e University of Wisconsin Protocol for follow-up after anal Pap tests. (Color version of figure is available online.)
geltzeiler et al anal dysplasia follow-up
testing to be more sensitive and specific in demonstrating dysplasia than cytology typing. At our institution, HPV typing is not performed because of increased cost and almost universal positivity in high-risk patient populations. This practice may need to be revisited based on others’ results for more accurate prediction of high-grade disease. This study has important limitations. This is a retrospective analysis at a single institution. We are unable to determine if better correspondence between cytology and histology would have occurred in a lower-risk patient population. We are also limited by the data available in the medical record. If a patient received follow-up at another institution, we might have missing data as to their clinical examination. We are not able to determine reasons why there was no clinical examination after abnormal cytology results. These findings of inconsistent clinical follow-up, however, have prompted a multidisciplinary education of clinicians involved in the care of these patients and development of a robust and welldefined protocol for clinical follow-up and care of these patients (Figure).
Conclusions In conclusion, we have demonstrated that anal cytology is an imperfect predictor of anal intraepithelial neoplasia when compared with histology. Cytology is a screening tool to detect disease. Clinical examination is a critical component of care for these high-risk patients for early disease detection.
Acknowledgment The authors would like to acknowledge Yiwei Xu, MHS, for statistical assistance and Erek Kucher for acquisition of pathology data. Authors’ contributions: C.G., J.S., R.S., S.S., and C.V. contributed to conception and design; C.G., J.S., E.C., E.L., B.H., R.S., S.S., and C.V. analyzed and interpreted the data; C.G., J.S., E.C., E.L., B.H., R.S., and C.V. drafted and revised the article. Dr C.I.V. was supported by a Research Career Scientist award from the Department of Veterans Affairs Health Services Research and Development Service, United States (RCS 14-443).
Disclosure No author of this publication has any disclosure or conflict of interest to report.
references
1. National Cancer Institute. Cancer stat facts: anal cancer. Available at: https://seer.cancer.gov/statfacts/html/anus. html. Accessed February 28, 2019. 2. Palefsky JM, Holly EA, Efirdc JT, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005;19:1407e1414.
121
3. Fazendin EA, Crean AJ, Fazendin JM, et al. Condyloma acuminatum, anal intraepithelial neoplasia, and anal cancer in the setting of HIV: do we really understand the risk? Dis Colon Rectum. 2017;60:1078e1082. 4. Machalek DA, Poynten M, Jin F, et al. Anal human papillomavirus infection and associated neoplastic lesions in men who have sex with men: a systematic review and metaanalysis. Lancet Oncol. 2012;13:487e500. 5. Factor SH, Cooperstein A, Pereira GA, Goldstone SE. Are colon and rectal surgeons ready to screen for anal dysplasia? Results of a survey on attitudes and practice. Sex Transm Dis. 2014;41:246e253. 6. Goncalves JCN, Macedo ACL, Madeira K, et al. Accuracy of anal cytology for diagnostic of precursor lesions of anal cancer: systematic review and meta-analysis. Dis Colon Rectum. 2019;62:112e120. 7. Morency EG, Harbert T, Fatima N, Samolcyzk J, Maniar KP, Nayar R. Anal cytology: institutional statistics, correlation with histology, and development of multidisciplinary screening program with review of the current literature. Arch Pathol Lab Med. 2019;143:23e29. 8. Cajas-Monson LC, Ramamoorthy SL, Cosman BC. Expectant management of high-grade anal dysplasia in people with HIV: long-term data. Dis Colon Rectum. 2018;61:1357e1363. 9. Crawshaw BP, Russ AJ, Stein SL, et al. High-resolution anoscopy or expectant management for anal intraepithelial neoplasia for the prevention of anal cancer: is there really a difference? Dis Colon Rectum. 2015;58:53e59. 10. Leeds IL, Fang SH. Anal cancer and intraepithelial neoplasia screening: a review. World J Gastrointest Surg. 2016;8:41e51. 11. Stewart DB, Gaertner WB, Glasgow SC, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for anal squamous cell cancers (revised 2018). Dis Colon Rectum. 2018;61:755e774. 12. Chin-Hong PV, Palefsky JM. Natural history and clinical management of anal human papillomavirus disease in men and women infected with human immunodeficiency virus. Clin Infect Dis. 2002;35:1127e1134. 13. Sambursky JA, Terlizzi JP, Goldstone SE. Testing for human papillomavirus strains 16 and 18 helps predict the presence of anal high-grade squamous intraepithelial lesions. Dis Colon Rectum. 2018;61:1364e1371. 14. Swedish KA, Lee EQ, Goldstone SE. The changing picture of high-grade anal intraepithelial neoplasia in men who have sex with men: the effects of 10 years of experience performing high-resolution anoscopy. Dis Colon Rectum. 2011;54:1003e1007. 15. Hicks CW, Wick EC, Leeds IL, et al. Patient symptomatology in anal dysplasia. JAMA Surg. 2015;150:563e569. 16. Siegenbeek van Heukelom ML, Marra E, Cairo I, et al. Detection rate of high-grade squamous intraepithelial lesions as a quality assurance metric for high-resolution anoscopy in HIV-positive men. Dis Colon Rectum. 2018;61:780e786. 17. Rosa-Cunha I, Degennaro VA, Hartmann R, et al. Description of a pilot anal pap smear screening program among individuals attending a veteran’s affairs HIV clinic. AIDS Patient Care STDS. 2011;25:213e219. 18. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis. 2006;43:223e233. 19. Silva M, Peixoto A, Sarmento JA, Coelho R, Macedo G. Anal cytology, histopathology and anoscopy in an anal dysplasia screening program: is anal cytology enough? Rev Esp Enferm Dig. 2018;110:109e114. 20. Papaconstantinou HT, Lee AJ, Simmang CL, et al. Screening methods for high-grade dysplasia in patients with anal condyloma. J Surg Res. 2005;127:8e13.