Techniques Received: June 21, 2010 Accepted: July 29, 2010 Published online: February 15, 2011
Acta Cytologica 2011;55:218–224 DOI: 10.1159/000320922
Agreement between Methods for Diagnosing HPV-Induced Anal Lesions in Women with Cervical Neoplasia Sandra de Andrade Heráclio a Alex Sandro Rolland de Souza c Fátima Regina Gomes Pinto a Melania Maria Ramos Amorim b Micheline de Lucena Oliveira d Paulo Roberto Eleutério de Souza e
a
Department of Lower Genital Tract Pathology, Women’s Healthcare Center, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) and Cytopathology Division of the Pernambuco Public Health Laboratory, b Maternal and Child Healthcare Department, and c Department of Obstetrics and Gynecology and Fetal Medicine, Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), d Pernambuco Women’s Specialized Clinical Analysis Laboratory (LACEN), and e Department of Biology, Federal University of Pernambuco, Recife, Brazil
Key Words Anal cancer ⴢ Anal intraepithelial neoplasia ⴢ Anoscopy ⴢ Cervical intraepithelial neoplasia ⴢ Cytology ⴢ Human papillomavirus
Abstract Objective: To evaluate agreement between 3 methods for screening anal intraepithelial lesions: anal cytology, anoscopy and human papillomavirus (HPV) detection by PCR. Study Design: This prospective, cross-sectional study screened 324 women with cervical neoplasia for anal neoplasia. Agreement between methods was calculated using the coefficient. Results: Of 324 anal cytologies performed, 31.5% (n = 102) were found to be abnormal: low-grade anal lesions were detected in 19.1% (n = 62) of cases, high-grade lesions in 3.1% (n = 10) and atypical squamous cells of undetermined significance in 9.3% (n = 30). With respect to the biopsies, 25.7% (n = 20) were positive, consisting of 7 cases of HPV infection, 5 anal intraepithelial neoplasia (AIN) grade 1, 6 AIN grade 2, and 2 AIN grade 3. Twenty-one samples (6.5%) were inadequate for HPV analysis. Of the 303 adequate samples, 84.2% (n = 255) tested positive for HPV. Agreement between cytol-
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ogy and anoscopy was fair ( = 0.31). Agreement between PCR for HPV and cytology was slight ( = 0.08) and no agreement was found between PCR for HPV and anoscopy ( = 0.00). Conclusion: Agreement between the different methods of diagnosing HPV-induced anal lesions is slight to fair; however, anal cytology permits identification of cases in which lesions are present, allowing them to be referred for anoscopy and biopsy. Copyright © 2011 S. Karger AG, Basel
Introduction
Although few studies have evaluated precursory lesions of anal cancer in women who are seronegative for HIV, results suggest a higher incidence of anal cancer and its precursors in women compared to men, particularly when cervical [1, 2] and vulvar [3] neoplasia are present or if the individual is infected by the human papillomavirus (HPV) [4, 5]. The exact pathogenesis of anal squamous cancer and its precursory lesions remains unknown. The similarity between the epithelium of the anal canal and that of the
Correspondence to: Dr. Sandra de Andrade Heráclio Av. Dr. Malaquias 195/2701, Graças Recife, PE 50070-550 (Brazil) Tel. +55 81 3426 0284, Fax +55 81 2122 4703 E-Mail sandra_heráclio @ hotmail.com
cervix suggests that the same factors that act in producing cervical cancer and its precursory lesions also act in the genesis of anal canal lesions [1]. There is a transformation zone characterized by immature and unstable metaplastic epithelium with intense mitotic activity that could be susceptible to HPV infection [6, 7]. Several authors believe that sufficient evidence already exists to implement screening by anal cytology in the so-called risk groups [8–10]. Studies have shown that the cost-effectiveness of anal cytology is good, and that it represents a simple method, with sensitivity ranging from 33 to 98% and specificity ranging from 32 to 96% [10–12]. The techniques used in anal cytology are the same as those applied in cervical cytology. Nevertheless, few studies have compared the findings of anal cytology with anoscopy, histopathology and PCR for HPV to ensure that the diagnostic criteria applied to HPV-induced lesions in cervical cytology are similarly applicable for the diagnosis of lesions of the anal canal. The objective of the present study was to evaluate anal cytology as a screening method for anal HPV-induced intraepithelial lesions and to compare anal cytology with anoscopy and the presence of viral DNA as determined by PCR and to describe histopathological findings.
Methods A cross-sectional study was performed in which 324 women with cervical intraepithelial neoplasia (CIN) and cervical cancer were included and submitted to screening for anal lesions. The study was developed in the Lower Genital Tract Pathology Clinic at the Women’s Healthcare Center of the Prof. Fernando Figueira Institute of Integrated Medicine between December 2008 and December 2009. The study protocol was previously approved by the institution’s internal review board (approval No. 1324). All the women admitted to the study voluntarily agreed to participate and gave their signed informed consent. At the time of first consultation, material was collected from all the participants for the identification of anal HPV by PCR and anal cytology. In addition, high resolution anoscopy and serology for HIV infection were performed. Biopsies were performed in patients who had any abnormality at cytology and/or more severe abnormalities at anoscopy. In cases of a histopathological diagnosis of anal intraepithelial neoplasia (AIN) grade 1 or 2, six-monthly follow-up was recommended, whereas women with a diagnosis of AIN 3 were submitted to resection of the affected area, performed under colposcopic visualization by a proctologist, and followed by 6-monthly follow-up visits. Material for cytology was collected by the investigator from the anus of the patient using a disposable silicone brush, which was inserted 4 cm into the anal canal and rotated 360°. The material was placed on a glass slide and stored in a recipient with 70%
Diagnosing HPV-Induced Anal Lesions in Women with Cervical Neoplasia
alcohol to be sent to the laboratory. Papanicolaou staining was performed. The nomenclature used in the cytopathology reports was that recommended in the Bethesda System [13]. High-resolution anoscopy was performed using the colposcope to evaluate the general characteristics of the mucosa and the vascular network and adding 5% acetic acid and Lugol’s solution. The colposcopic nomenclature used was that recommended in 2002 Barcelona consensus [14]. Biopsy of the anal canal lesion was performed when needed. Lesions situated on hemorrhoids or prolapsed mucosae were referred to a proctologist for biopsy. The nomenclature used was the histological classification defined by Kreuter [15]. Samples for HPV DNA testing were collected from the squamocolumnar junction of the anus by introducing approximately 4 cm of an endocervical brush into the anus and rotating it 360°. The material was transferred to a 5-cm-long tube containing 3 ml of saline solution [16]. DNA extraction was performed on 500 l of anal secretion using a commercial extraction kit (Wizard Genomic DNA Purification kit, Promega, Madison, Wisc., USA). Following extraction, the samples were treated with ribonuclease, heated to 50 ° C in a water bath for denaturation of this protein and then stored at a temperature of –20 ° C. HPV infection was diagnosed using 2 sets of consensus primers. Two reactions were performed for each patient, one using the MY09 and MY11 set of primers and the other with the GP05+ and GP06+ set. All the smears were examined separately by 2 blinded specialists. If there was disagreement between these 2 observers, the material was evaluated by a third specialist. In cases in which there was disagreement between the 3 observers, the final diagnosis was reached by consensus. The criterion for the diagnosis of an anal canal lesion was the presence of any abnormality in 2 of the 3 diagnostic methods evaluated: cytology, anoscopy and biopsy. HPV DNA was the method used to determine the presence or absence of the virus in the lesion. The publicly available software programs Epi-Info version 3.5.2 and OpenEpi version 2.3 were used for the statistical analysis. The coefficient was calculated to verify the agreement between anoscopy, cytology and PCR results, with values ranging from 0 to 1, where 1 expressed maximum agreement and 0 the absolute absence of any agreement [17].
Results
In the present study, 324 women were submitted to screening for an HPV-induced lesion of the anal canal: 8% (n = 26) had invasive cervical neoplasia, 62% (n = 201) had CIN 2 or 3, 29.9% (n = 97) had CIN 1 and 2.8% (n = 8) were HIV-positive. Ninety-five (29.3%) of whom were found to have anal lesions. A total of 324 anal cytologies was performed of which 6.2% (n = 20) were unsatisfactory, 62.3% (n = 202) were within normal limits and 31.5% (n = 102) were found to have some degree of squamous atypia: low-grade anal squamous intraepithelial lesions (low-grade ASIL) in 19.1% (n = 62), high-grade anal squamous intraepithelial Acta Cytologica 2011;55:218–224
219
Table 1. Methods used for the diagnosis of anal lesions
Diagnostic method
n
Anal cytology (n = 324) Unsatisfactory Within normal limits Squamous cell atypia Low-grade SIL High-grade SIL Anoscopy (n = 324) Normal Acetowhite epithelium Verruga Vascular mosaicism Vascular punctuation Association of images1 Histology (n = 78) HPV Simple hyperplasia of the malpighian epithelium Suggestive of HPV infection Inflammatory AIN grade 1 AIN grade 2 AIN grade 3 Normal
%
20 6.2 202 62.3 30 9.3 62 19.1 10 3.1 120 37 191 59 1 0.3 1 0.3 5 1.5 6 1.9 7 9.1 19 24.4 7 9.0 5 6.4 5 6.4 6 7.7 2 2.6 27 34.6
1
Epithelial acetowhitening + punctuation; mosaicism + punctuation; epithelial acetowhitening + punctuation + mosaicism.
Table 2. Agreement between anoscopy and anal cytology
Anoscopy
Positive Negative
Anal cytology positive
negative
n
n
%
92 46.9 10 9.3
95% CI
p value
%
104 53.1 98 90.7
0.31 0.22–0.40 0.00
p value determined by 2 test.
lesions (high-grade ASIL) in 3.1% (n = 10) and atypical squamous cells of undetermined significance in 9.3% of cases (n = 30). No cases of atypical glandular cells were found in the sample population. Anoscopy was performed in all patients, results being normal in 120 cases (37%). The principal abnormalities found were: 191 cases of acetowhite epithelium (59%), 5 cases of vascular punctuation (1.5%), 1 case of verruga (0.3%), 1 of vascular mosaicism and 6 cases of image as220
Acta Cytologica 2011;55:218–224
sociation (1.9%). Acetowhite epithelium, either found alone or in association with the other images, was the most common atypical zone encountered, comprising 60.9% of the findings. The women in whom anoscopy revealed major abnormalities were submitted to biopsy irrespective of whether cytology was abnormal or not. Overall, 78 biopsies were performed, 50 in women in whom both anoscopy and cytology findings were abnormal and 28 in women with abnormal anoscopy results and normal cytology. Of the biopsies performed, 25.7% of cases (n = 20) were positive, histology being compatible with HPV infection in 7 cases, AIN 1 in five cases, AIN 2 in six cases and AIN 3 in two cases (table 1). In 52 of the women with abnormal cytology biopsy could not be performed. In order to permit agreement analysis to be performed using the test, the cases of unsatisfactory anal cytology and negative for -globin in the PCR for HPV DNA were excluded from the database. This resulted in a final number of 100 cytology samples for comparison with PCR. When the results of anoscopy and cytology were compared after being separated into positive and negative cases, it was found that of the 108 negative anoscopy results, cytology was also negative in 98 of these cases (90.7%), resulting in a of 0.31 (p = 0.00, 95% CI 0.22– 0.40; table 2). DNA extraction and PCR for HPV identification were performed in all 324 women; however, in 21 patients (6.5%), DNA extraction of HPV was inadequate, leaving 303 women for analysis. Of these, 84.2% (n = 255) tested positive for HPV DNA. Of the 191 women who tested positive at anoscopy, 84.3% (n = 161) tested positive for HPV by PCR, and of the 100 who were positive at cytology, 91% (n = 91) tested positive for HPV by PCR. Nevertheless, of the 184 women who tested negative at cytology, HPV testing by PCR was positive in 147 cases (79.9%) and negative in only 37 cases (20.1%). Comparing anoscopy and cytology with HPV by PCR resulted in coefficients of 0.00 and 0.08, respectively (table 3).
Discussion
The present results suggest that a high percentage of women with cervical neoplasia have HPV-induced anal lesions and that cytology represents an effective tool for identifying these lesions; however, the agreement between cytology, anoscopy and PCR for HPV as measured by the coefficient was weak. Heráclio/Souza/Pinto/Amorim/Oliveira/ Souza
Table 3. Agreement of anal cytology and
anoscopy with PCR for HPV
Method
Positive anoscopy Negative anoscopy Positive cytology1 Negative cytology
PCR HPV positive
negative
n
%
n
%
161 94 91 147
84.3 83.9 91 79.9
30 18 9 37
15.7 16.1 9 20.1
95% CI
p value
0.00
–0.09 to 0.10
0.93
0.08
0.01 to 0.15
0.01
p values determined by 2 test. 1 Two abnormal cytologies were excluded because the material for PCR was inadequate.
Reviewing the Medline, Lilacs and Scielo databases using the key words agreement, anal cytology, high resolution anoscopy, anal intraepithelial neoplasia, cervical intraepithelial neoplasia and HPV in both English and Portuguese, 10 papers related to agreement were found. Of these, 3 dealt with interobserver agreement in the diagnosis of cytology and histology findings [18–20], 4 compared the findings of cytology, anoscopy and histology [21–24] and 3 compared cytology with HPV DNA [25– 27]. Nevertheless, no study was found in which women with cervical neoplasia were evaluated. To compare the findings of the various studies available in the literature on the topic of screening for anal lesions represents a challenge since there is no standardized technique for collecting samples for anal cytology and consequently there is no uniformity in the technique used for the procedure. Both brushes [23] and cotton swabs [20] have been used; the depth to which they are introduced into the canal varies from 2 cm [19] to 5 cm [20]; and the technique used to process the sample may be in a conventional [21] or liquid medium [20]. However, of all the aforementioned variables the one most commonly associated with unsatisfactory smears was the depth to which the sampling instrument is introduced into the anal canal, the greatest number of cases with unsatisfactory material being found in those samples collected at a depth of 1.5–2 cm. [11, 28]. In the present study, the material collected for anal cytology was unsatisfactory in 6.2% of smears, a similar percentage to that reported in a study using conventional medium [24] and in another using liquid medium [29]; however, it was higher than the percentages reported in a study on anal cytology in HIV-positive patients [23] and in another on genital neoplasia [30].
A high percentage of abnormalities were found in the present samples when compared to another study performed in women with vulvar and cervical neoplasia [30] in which abnormal cytology smears were found in only 9% of cases. This difference may have occurred as a result of the larger sample size in the present study and the selection criteria or the anal cytology sampling technique. This hypothesis is corroborated by a recent systematic review published in 2006 in which anal cancer screening was evaluated in HIV-infected individuals. Those authors reviewed 18 articles and reported that the percentage of abnormal anal cytology ranged from 14 to 97% [11]. This review drew attention to the fact that there was no uniformity with respect to the technique used for the procedure and that the sensitivity of the method ranged from 42 to 98%, with specificity ranging from 32 to 96% [10]. With respect to anoscopy, the acetic acid technique used to identify areas of acetowhitening under colposcopic visualization has gained popularity over the past 10 years. Nevertheless, just as colposcopy, this is a highly expensive procedure and an adequately trained professional is required to perform it. The present findings are in agreement with another study that evaluated anoscopy and reported a higher rate of areas of acetowhitening and a lower frequency of vascular mosaicism, as well as difficulty in analyzing the limits of the margins of lesions and the presence of thick vessels associated with lesions of greater severity [31]. Studies suggest that despite the similarity that exists between the cervix and the anal canal, certain peculiarities of the anal epithelium may contribute towards reducing agreement between the methods. In the anal canal, there is an extensive squamocolumnar junction associated with deep crypts that make it easier for cytology to identify lesions that remain imperceptible at high res-
Diagnosing HPV-Induced Anal Lesions in Women with Cervical Neoplasia
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olution anoscopy [24, 27], which therefore, may lead to false-negative results at anoscopy. On the other hand, keratinization, which is a normal process of the anal epithelium, may determine superficial shedding of keratinized cells, with the potential for underestimating the lesion or for obtaining false-negative results at cytology [21, 22]. Two studies conducted in women with genital neoplasia reported a frequency of anal neoplasia of approximately 19% [32, 33]. The former study was conducted in England and evaluated 152 women with CIN 3, in whom 11 cases of AIN 3 and 18 cases of AIN 1 and 2 were diagnosed [32]. In the latter study, 211 women with genital neoplasia evaluated by high resolution anoscopy and biopsy were included, the reported prevalence of AIN being 19.5% [33]. In the present study, a similar rate of AIN of 25.7% (n = 20) was found. A meta-analysis published in 2009 assessed the prevalence and distribution of HPV detected by PCR in cases of carcinoma and intraepithelial neoplasia of the vulva, vagina and anus. Twenty-nine published studies on HPV in anal neoplasia were found, showing a prevalence of HPV of 91.5% in 671 cases of AIN 1, 93% in 609 cases of AIN 2, 94% in 234 cases of AIN 3, and 84.3% in 955 cases of anal carcinoma. The frequency of HPV was higher in cases of anal carcinoma compared to vulvar (40.4%) or vaginal carcinoma (69.9%). Nevertheless, the majority of the studies included in the meta-analysis evaluated HIVpositive men and the data are restricted to countries of Europe and North America [34]. In the present study, the frequency of positive samples for anal HPV was 84.2% (n = 255). These findings are in agreement with recent studies that reported a high prevalence of anal HPV infection in women with a cervical infection [25, 35, 36]. This association between the presence of cervical and anal HPV was identified both by hybrid capture and by PCR. There is evidence that specificity is greater for the detection of the presence of DNA for HPV by PCR when the GP5+/6+ set of primers is used instead of the MY09/11 set [16]. In the present study, both sets of primers were used. The present findings of abnormal cytology and positive PCR for HPV are in agreement with a study in which 655 women were analyzed, 470 of whom were HIV-positive and 185 HIV-negative. In that cohort, a frequency of abnormal anal cytology of 31% was found in the HIVpositive women (10% atypical squamous cells, 12% with low-grade ASIL and 9% with high-grade ASIL). The prevalence of anal HPV infection was 80%, while the prevalence of cervical HPV infection was below 45%. Those 222
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authors suggest either that HPV is more common in the anal canal or that it is present at higher levels in this area, making it more easily detected in this risk group [25]. Nevertheless, both this study and ours have limitations, because biopsy was not performed in all cases of abnormal cytology; therefore, it is possible that the true prevalence of AIN may still have been underestimated. Analyzing the agreement between the various diagnostic methods for anal neoplasia, the results of the present study are similar to those mentioned by other investigators, who have also reported weak agreement between these methods [21–24]. Exceptions occur in interobserver studies in which moderate agreement has been found, particularly in the case of more severe lesions [18–20]. Some questions arose during the course of this study: is it possible to establish anoscopic criteria that would permit differentiation between metaplasia or low-grade lesions and high-grade lesions? What would be the ideal time interval for screening women with AIN? What are the rates of regression and progression of these lesions? Is there another screening method that is more precise than current ones? Answers to these questions require further studies to be carried out with other design models, which should be planned for the future. Another important question that remains unanswered is whether evaluation of the anal canal by cytology or by any other screening method should be recommended for all women with cervical neoplasia irrespective of their HIV status. Studies suggest that the prevalence of highgrade anal intraepithelial lesions is high in this group of patients compared to the general population [32, 33]. Moreover, in immunosuppressed women, AIN 3 lesions may progress to invasive carcinoma within a 5-year period [2]. In a cohort study that evaluated the effect of an anal cancer screening program in HIV-positive individuals, a decrease from 90.9 to 70.6% was found in the need for chemotherapy for invasive anal carcinoma [37]. Another aspect to be considered is the result achieved by cytology in cervical cancer screening programs, which confirms that an organized program is capable of reducing mortality from cancer by as much as 80% [38, 39]. In cervical cytology, sensitivity ranges from 30 to 70% and specificity from 86 to 100% [40]. Although the use of cytology for screening anal lesions is recent, sensitivity and specificity values are similar to those found for cervical cytology. A recent study showed that the technique of blind sampling for anal smears is better than anoscopydirected sampling, which makes the method even simpler than cervical sampling [29]. Likewise, a cost-benefit Heráclio/Souza/Pinto/Amorim/Oliveira/ Souza
analysis showed screening by anal cytology to be a viable option for use within the public healthcare service [41]. In conclusion, the agreement between the various methods of diagnosing HPV-induced anal lesions is weak; however, anal cytology enables identification of
cases with HPV-induced lesions, permitting their referral for anoscopy and biopsy. Further studies should be conducted before an anal screening program for HPV-induced lesions can be established in this specific risk group.
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