Obstetrics & Gynecology:
Anal Intraepithelial Neoplasia in Women With Genital Intraepithelial Neoplasia
Santoso, Joseph T. MD; Long, Mary MD; Crigger, Mary RN, OCN; Wan, Jim Y. PhD; Haefner, Hope K. MD
From the Department of Obstetrics & Gynecology, University of Tennessee-West Clinic, Memphis, Tennessee; the Department of Obstetrics and Gynecology, University of Tennessee-University of Tennessee Health Science Center, Memphis, Tennessee; the Division of Gynecologic Oncology, West Clinic, Memphis, Tennessee; the Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; and the Department of Obstetrics and Gynecology, The University of Michigan Hospitals, Ann Arbor, Michigan.
See related editorial on page 566.
Corresponding author: Joseph T. Santoso, MD, Department of Obstetrics & Gynecology, University of Tennessee-West Clinic, 1588 Union Avenue, Memphis, TN 38104; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors did not report any potential conflicts of interest.
OBJECTIVE: To estimate the prevalence of anal intraepithelial neoplasia in heterosexual women with genital intraepithelial neoplasia, and to compare anal cytology with colposcopy for their effectiveness in anal intraepithelial neoplasia screening.
METHODS: Women with confirmed intraepithelial neoplasia on the cervix, vagina, or vulva were referred for gynecologic oncology care. All patients underwent anal cytology and high-resolution anoscopy. Any lesion detected on anoscopy was biopsied. Wilson score method was used to estimate 95% confidence interval for prevalence. McNemar's test compared the two screening methods.
RESULTS: Women with average age of 39.6 years (range 14 to 83 years) underwent anal cytology and anoscopy (N=205). Of the 205 patients with genital intraepithelial neoplasia, 25 patients (12.2%) had biopsy-proven anal intraepithelial neoplasia. Twelve patients (5.9%) had abnormal anal cytology (nine with atypical squamous cells of undetermined significance [ASC-US], three with low-grade squamous intraepithelial lesions [LSIL]). None of the nine patients with anal ASC-US had biopsy-proven anal intraepithelial neoplasia. Of the three patients with anal LSIL, two had anal intraepithelial neoplasia II and one had condyloma on biopsy. However, 78 patients (38%) had abnormal anoscopy findings that resulted in 25 biopsy-proven anal intraepithelial neoplasias (8 anal intraepithelial neoplasia I, 5 anal intraepithelial neoplasia II, 12 anal intraepithelial neoplasia III)), condylomas (n=11), and hyperkeratosis (n=8). Anoscopy identified 32% (25 patients) with anal intraepithelial neoplasia out of 78 abnormal anoscopic examinations. In diagnosing anal intraepithelial neoplasia, anoscopy has 100% sensitivity and 71% specificity; anal cytology has 8% sensitivity and 94% specificity.
CONCLUSION: Patients with cervical, vulvar, and vaginal intraepithelial neoplasia have 12.2% prevalence of anal intraepithelial neoplasia and should be screened with high-resolution anoscopy. In anal intraepithelial neoplasia screening, anoscopy is more sensitive but less specific than anal cytology.
LEVEL OF EVIDENCE: II
Human papilloma virus (HPV) is well known to cause cervical, vulvar, and vaginal intraepithelial neoplasia. Cervical intraepithelial neoplasia and its association with HPV have been well studied. Because the cervix and anus share similar embryologic and anatomic characteristics, HPV has been thought to contribute to the development of anal intraepithelial neoplasia.1–3 A study by Hampl et al4 documented that 89% of anal intraepithelial neoplasia contained HPV. Several risk factors contribute to the development of anal intraepithelial neoplasia. The most significant risk factors are anal HPV infection, receptive anal intercourse, and human immunodeficiency virus (HIV) infection.
As with cervical intraepithelial neoplasia, anal intraepithelial neoplasia may be further subdivided into low-grade squamous intraepithelial lesions (anal intraepithelial neoplasia I) and high-grade squamous intraepithelial lesions (anal intraepithelial neoplasia II and III) based on the progression or regression rates. Anal intraepithelial neoplasia, especially high-grade, is believed to be the main precursor of anal cancer.5 Thus, prevention and treatment of anal intraepithelial neoplasia may reduce the risk of developing anal cancer.
The majority of anal intraepithelial neoplasia studies have been done in men having sex with men,6–8 which refers to men who engage in sexual activity with other men, regardless of how they identify themselves sexually (heterosexual, bisexual, or homosexual). Few studies in women with anal intraepithelial neoplasia have been done, and most have focused on HIV-infected women.9–11 The prevalence of anal intraepithelial neoplasia in U.S. heterosexual women is largely unknown. In a study by Stier et al,11 eight women infected with HIV and with cervical intraepithelial neoplasia were found to have anal intraepithelial neoplasia. In a population-based study, Swedish women with cervical intraepithelial neoplasia had a higher risk of developing anal cancer than vulvar cancer.12 Another study in England revealed that 19% of women with cervical intraepithelial neoplasia had anal intraepithelial neoplasia.13
There are no clear data on how to screen for anal intraepithelial neoplasia. Although formal guidelines recommending anal Pap test screening have not been adopted by the U.S. Public Health Service, some specialists recommend anal cytologic screening for HIV-infected men and women.14 Some investigators recommended anal cytology as the screening method for anal intraepithelial neoplasia with high-resolution anoscopy to follow for abnormal anal cytology.1 This recommendation, however, has not been tested in a research setting nor accepted completely by others.15 Other studies suggest anoscopy as a better method to diagnose anal intraepithelial neoplasia than anal cytology.16,17 Additionally, there is no formal consensus on how to treat anal intraepithelial neoplasia. Many health care providers treat anal intraepithelial neoplasia as they do cervical intraepithelial neoplasia, with ablative therapy (infrared coagulation, tricholoroacetic acid) or surgical excision.
Our study has two objectives. The first objective is to estimate the prevalence of anal intraepithelial neoplasia in heterosexual women with genital intraepithelial neoplasia. The second objective is to compare anal cytology with anal colposcopy for their effectiveness in screening for anal intraepithelial neoplasia.
The study consisted of 205 consecutive patients with genital (vulvar, vaginal, or cervical) intraepithelial neoplasia referred to the University of Tennessee-West Clinic gynecologic oncology division between June 2006 and December 2009. The study was approved by our University Hospital's institutional review board.
Patients were included in the study if they had a confirmed diagnosis of genital intraepithelial neoplasia (using biopsies of the vulva, vagina, or cervix). Patients were excluded if they had a history of anal intraepithelial neoplasia, any anogenital cancer (cervix, vulva, vagina, anus, rectum), or absence of a rectum. All patients were evaluated as part of our clinical practice with anal cytology and anoscopy by one gynecologic oncologist who was trained in high-resolution anoscopy. Medical history and demographic data, such as age, and sexual history were also collected from the chart. Any unique identifiers were deleted to protect patients' privacy. Anonymous data were reviewed in detail.
Vulvar, vaginal, and cervical examinations were done in the usual dorsolithomy position. Three-percent acetic acid was applied, and the patients were carefully evaluated with a colposcope. Then, an anal smear was obtained using a plastic cotton swab soaked in normal saline then gently inserted until resistance from the wall of the rectum was met (approximately 4.5 cm). The swab was withdrawn with lateral pressure, using a spiral motion, and was applied to sample the entire circumference of the anal canal. The swab was processed using the ThinPrep (Hologic, Inc, Marlborough, MA) technique. Next, high-resolution anoscopic examination was performed by inserting a plastic disposable anoscope into the anus and 3% acetic acid was sprayed into the mucosa. A cotton swab soaked in 3% acetic acid was then applied evenly to the deeper anal canal before visualization. Anoscopic examination with 16× magnification was performed. Any abnormalities (acetowhite changes, raised lesions, discolorations) were biopsied. A local anesthetic (lidocaine 1% without epinephrine) was injected before biopsy of lesion distal to the dentate line. Digital vaginal and rectal examinations were also performed.
The sample size was estimated according to the first objective of the study. The prevalence of anal intraepithelial neoplasia in the study population was assumed to be around 10%. This prevalence was estimated with a 95% confidence interval (CI) with a precision of 5% on each side of the estimate. A probability of 80% was desired to have the CI with such precision. Using the SAS POWER procedure (SAS Institute, Cary, NC), the required sample size was found to be a minimum of 180 participants. Sensitivity, specificity, and positive and negative predictive values are reported along with exact 95% CIs using the Wilson score method. McNemar's test was used to compare anal cytology and anoscopy.
Table 1 describes the demographic characteristics of the study population. A total of 209 consecutive heterosexual women with an average age of 39.6 years (range 14 to 83 years) underwent anal cytology and anoscopy. The cytology and anoscopy were completed regardless of the patients' colorectal screening status. Four patients did not have complete pair data of anal cytology and anoscopy because patients declined anal cytology or anoscopy, resulting in a study group of 205 patients. During the study, 131 patients (64%) were currently sexually active and 74 (36%) were not sexually active. Ten patients were HIV positive as revealed by their medical history.
Of 205 patients with genital intraepithelial neoplasia, 25 patients (12.2%, 95% CI 8–17%) had anal intraepithelial neoplasia. Twelve patients (5.9%, 95% CI 3–10%) had an abnormal anal smear (nine ASC-US, three LSIL). None of the nine anal ASC-US results were determined to be biopsy-proven anal intraepithelial neoplasia. The three anal LSIL resulted in two anal intraepithelial neoplasia II and one condyloma. However, 78 patients (38%, 95% CI 31–45%) had abnormal anoscopy findings that resulted in 25 biopsy-proven anal intraepithelial neoplasia (8 anal intraepithelial neoplasia I, 5 anal intraepithelial neoplasia II, 12 anal intraepithelial neoplasia III) and 11 condylomas. Eight patients had hyperkeratosis. Anoscopy identified 32% with anal intraepithelial neoplasia (25 of 78 abnormal anoscopic examinations).
In diagnosing anal intraepithelial neoplasia (using biopsy-proven anal intraepithelial neoplasia as the gold standard), anoscopy has 100% sensitivity (95% CI 87–100%) and 71% specificity (95% CI 64–77%) with a positive predictive value 25/(25+52)=32% (95% CI 24–44%) and negative predictive value 127/(127+0)=100% (95% CI 97–100%). Anal smear has 8% sensitivity (95% CI 2–24%) and 94% specificity (95% CI 89–97%) with positive predictive value 15% (95% CI 4–42%) and negative predictive value 88% (95% CI 82–91%). The number of patients with positive anal cytology and anoscopy for anal intraepithelial neoplasia are shown in Tables 2 and 3. Positive predictive values vary with prevalence. With anal intraepithelial neoplasia prevalence of 12.2% in this sample, the positive predictive values were low, as was expected.
McNemar's test showed that the two screening methods are statistically different (P<.001). Because a better screening method is the test with higher sensitivity, anoscopy (100% sensitivity) is a better screening test for anal intraepithelial neoplasia than anal cytology (8% sensitivity).
The prevalence of anal intraepithelial neoplasia in the general population is unknown. The prevalence of anal intraepithelial neoplasia in women in the general population with genital intraepithelial neoplasia and the methods of screening for anal intraepithelial neoplasia has not been studied extensively. We found a significant rate of anal intraepithelial neoplasia in women with intraepithelial neoplasia of the cervix, vulva, or vagina. It was expected that anal intraepithelial neoplasia would be present in these women considering that human papilloma virus infects all of these locations. However, we did not expect that greater than 10% of women with genital intraepithelial neoplasia also suffer from anal intraepithelial neoplasia. These findings suggest that women with cervical, vulvar, or vaginal intraepithelial neoplasia should be screened with high-resolution anoscopy for anal intraepithelial neoplasia. This is an important finding because the care of women with lower genital tract intraepithelial neoplasia has traditionally been followed by health care providers who have not been trained in high-resolution anoscopy. Collaboration between specialties that provide care for women (gynecologists, family medicine physicians, colorectal surgeons, internists, advanced practice clinicians, etc) is needed to optimize anal intraepithelial neoplasia screening.11,18
Our study suggests that anal cytology is not a completely effective screening tool. Anoscopy, which is considered the gold standard for diagnosing anal intraepithelial neoplasia, is also the best screening method available. If anoscopy does not uncover the abnormality, it is very unlikely that anal intraepithelial neoplasia will be found. A Brazilian study in HIV-infected patients also found that anoscopy is a more sensitive screening test than anal cytology.19 Another study that included 153 men having sex with men (100 of whom were HIV positive) showed a sensitivity of anal cytology that was only 47% for anal intraepithelial neoplasia detection.17 A more recent study in 102 U.S. women screened with anal cytology, then followed with anoscopy, found only 9 of 102 patients (9%) with abnormal cytology, and 7 patients underwent biopsy (all anal intraepithelial neoplasia I).15 We could only speculate that our anal smear, despite using liquid-based cytology, may be contaminated with stool. The contamination may make it more difficult to visualize anal dysplastic cells. Another potential explanation is lack of cellularity in the anal smear sample.
One may ask about the role of HPV testing in diagnosing anal intraepithelial neoplasia. We did not carry out this part of the study. The role of HPV testing in anal intraepithelial neoplasia is probably minimal. Although sexually active women are commonly infected by HPV in the anus,15 the majority of anal HPV infections resolve in a relatively short time to have relevant therapeutic implications. In a study by Shvetsov et al,20 the median clearance times for HPV-16 and HPV-18, the predominant types associated with anal cancer and intraepithelial neoplasia, were 132 days and 212 days, respectively. Thus, HPV infection in healthy women is cleared rapidly, suggesting a limited efficacy of HPV testing as an anal cancer screening tool. Indeed, a British study looking specifically into HPV genotyping found it to be ineffective in screening for anal intraepithelial neoplasia.21
Our study has several limitations. First, the study population and screening procedures were done by one gynecologic oncologist, which may limit the application of the result to other populations and practices. Because a single operator completed all the testing, our study results are confounded with the skill level of this individual. However, homogeneity arising from a single gynecologic oncologist conducting all of the smears and anoscopies may reduce interobserver variability. Furthermore, the patients' risk factors for anal intraepithelial neoplasia, such as penetrative anal intercourse, were not much different than the rate obtained nationally by the Centers for Disease Control and Prevention, whose large study found that 35% of U.S. women engage in anal sex compared with our rate of 32%.22 Another significant risk factor for anal intraepithelial neoplasia is having the diagnosis of HIV. In contrast to most studies that concentrated on HIV population, our cohort had only 10 patients (4.8%) with HIV. Second, we could not control to which laboratories the anal cytology and anoscopic biopsy specimens were sent, as these decisions are dependent on the patients' types of insurance. Third, the potential interpathologist discrepancy was not evaluated. Fourth, the high rate of anal intraepithelial neoplasia in our study may not be a good representation of general population of patients because we are a referral center for genital intraepithelial neoplasia. Finally, our total number of 26 patients with the diagnosis of anal intraepithelial neoplasia is still inadequate to evaluate the role of HIV, sexual practice, number of sexual partners, smoking, and other factors that may contribute to the development of anal intraepithelial neoplasia. With increases in anal sexual practice, we may see an increase in anal intraepithelial neoplasia and anorectal cancer. However, with the introduction of HPV vaccines, the spread of HPV and anal intraepithelial neoplasia may be reduced. It is unclear which factors would become more dominant in influencing the rate of anal intraepithelial neoplasia in the future. Further studies are needed to clarify factors that may contribute to the development of anal intraepithelial neoplasia and confirm a better screening method for anal intraepithelial neoplasia.
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