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Anal pre-cancer test for HIV+ men
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LOS ANGELES, March 22 (UPI) -- A type of anal-canal Pap smear has been found to detect precancerous changes in the anal canals of HIV-positive men, a U.S. study found.
The University of California at Los Angeles study found abnormal anal cytology -- anal-canal Pap smear -- was highly predictive of anal cell abnormalities that were subsequently confirmed by anal biopsy.
The study, published in the International Journal of STD & AIDS, was based on data from 244 patients at the UCLA CARE clinic who had anal cytology screenings between February 2002 and December 2004.
HIV-positive men who have sex with men are up to 90 times more likely than the general population to develop anal cancer, according to UCLA CARE clinic.
The UCLA CARE Center is one of a few U.S. clinics offering anal dysplasia screening, a procedure that has not yet entered standard practice.
"The prevalence, and predictive value, of abnormal anal cytology to diagnose anal dysplasia in a population of HIV-positive men who have sex with men"
R D Cranston*, S D Hart- J A Gornbein , S L Hirschowitz-, G Cortina- and A A Moe
*Department of General Internal Medicine; -Department of Pathology; Department of Biomathematics;
Department of Infectious Disease,
University of California, Los Angeles, CA, USA
To date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.
".......screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer....
... detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the
samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy.
Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.
....anal cytology underestimated the degree of anal dysplasia... While only 6% of the cytology results indicated high-grade lesions or possible high0grade lesions, the researchers found, 52% of biopsy specimens were either grades 2 or 3 anal intraepithelial neoplasia
...Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment....
....Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia....Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain..."
Summary: Due to the increasing incidence of anal cancer in HIV-positive men who have sex with men, and the potential to detect and treat high-grade anal dysplasia - the putative anal cancer precursor - we have introduced an anal cytology screening service. Patients with abnormal anal cytology have follow-up high-resolution anoscopy (HRA) with biopsy of lesions clinically suspicious for high-grade dysplasia. In total, 244 men were screened and 235 (96%) of the samples were adequate for cytological interpretation using the Bethesda 2001 system. One hundred and sixty-four (67%) men had abnormal anal cytology, and 93 of them had follow-up HRA and anal biopsy. The positive predictive value for any anal cytological abnormality to predict any degree of anal dysplasia was 95.772.1%, and for any anal cytological abnormality to predict high-grade anal dysplasia was 55.975.1%. Abnormal anal cytology was highly predicative of anal dysplasia on biopsy.
INTRODUCTION
Anal cancer is a rare malignancy accounting for only 1.5% of all gastrointestinal tumours.1 However, in certain groups, the incidence of anal cancer is increased in comparison to the general population. Prior to the HIV pandemic, the incidence of anal cancer in men who have sex with men (MSM) who practice receptive anal
intercourse (RAI) was approximately 35 per 100,000,2 equivalent to the incidence rate of cervical cancer prior to the introduction of cervical cytology screening in developed countries. Currently, the incidence of anal cancer in HIV-positive MSM is estimated to be between 70 and 80 per 100,000 based on studies in both Europe and the USA.3,4
The anal and cervical canal share a common embryological origin, are classified cytologically using the same 2001 Bethesda system, and both develop dysplasia in association with anogenital human papillomavirus (HPV) infection.5 HPV can be grouped phenotypically into high-risk and low-risk HPV related to its association with cervical cancer.6 High-risk HPV, most commonly HPV 16 or 18, is present in almost 100% of anal and cervical cancers,7,8 and is now considered essential for the development of cervical cancer in association with co-factors such as cigarette smoking.9
The presence of either HPV or anal dysplasia, unlike other HIV-related infections or tumours, does not appear to be significantly influenced by the introduction of highly active antiretroviral therapy (HAART).10,11 Moreover, reports from San Diego and San Francisco Counties have shown that the incidence of anal cancer in these regions has increased from the pre- to the
post-HAART era.12,13 While it is unlikely that HAART therapy per se increases the risk of anal dysplasia and anal cancer, this finding may be explained by the fact that individuals with HIV infection taking HAART are living longer and allowing the anal canal to have prolonged exposure to oncogenic HPV in the context of relative immunosuppression.14 In addition, there is in vitro evidence
that HIV tat protein interacts with the HPV genome to increase oncoprotein expression that leads to chromosomal dysregulation and the potential of malignant cellular transformation.15,16
Using the cervical paradigm, screening for anal cytological abnormality, defining the abnormality pathologically by anal biopsy, and subsequently treating potentially premalignant lesion(s) has been proposed as a management strategy for the anal canal to prevent the progression of high-grade dysplasia to anal cancer. Anal cytology screening has similar sensitivity to cervical cytology screening in HIV-positive MSM to detect the presence of
dysplastic cells.17,18 Liquid-based cytology collection methods are increasingly
being used for the cervix, and have the advantage that remnant liquid fixative may be tested for HPV, as occurs in the triage of cervical samples that show atypical squamous cells of undetermined significance (ASC-US). The liquid cytology method may additionally abrogate potential problems associated with hypocelluarity, air drying artefact and faecal contamination in anal samples.17,19
While no national or international guidelines exist for anal cytology screening, investigators from the largest natural history study at the University of California, San Francisco, have suggested the following screening algorithm in MSM:
-- Normal anal cytology is repeated in one year in an HIV-positive population and in two to three years in an HIV-negative population.
-- All abnormal anal cytology is referred for high-resolution anoscopy (HRA). At HRA a biopsy is taken of any lesion(s) suspicious for dysplasia based on standard colposcopic criteria.20 If no dysplasia is identified, the individual has routine anal cytology screening as above. Using this system, the aim of anal cytology testing is to detect either normal or abnormal results, as previous
studies have shown that anal cytology grade is poorly predictive of anal dysplasia grade following HRA and biopsy, and should not be relied upon without histological confirmation.21
-- Low-grade dysplasia on biopsy is followed up at six-monthly intervals with HRA due to the high rate of progression from low-grade to high-grade dysplasia.22
-- High-grade dysplasia on biopsy is treated, or followed-up depending on the size of the lesion.
To date, most of the information available on anal dysplasia is derived from a limited number of natural history studies. This current study reflects clinical practice in a HIV primary care setting and aims to (1) estimate the prevalence of anal cytologic abnormalities, (2) estimate the positive predictive value of anal cytology for any degree of dysplasia and for high-grade dysplasia.
METHODS
Subjects
All subjects in this clinical study were MSM who attend the University of California Los Angeles (UCLA) Center for AIDS Research and Education (CARE) clinic. Anal cytology specimens were collected sequentially at the discretion of the treating clinician.
Anal cytology collection
Primary care physicians received anal cytology collection training. The cytology specimens were taken using a water-moistened Dacront swab and ThinPrept collection method with the patient in the left lateral position. The Dacront swab was introduced two inches beyond the anal margin, and removed with lateral pressure and a spiral motion over 10 seconds. After removal, the swab was immediately immersed and agitated in ThinPrept solution to disgorge the cells. Anal cytology samples were read by a UCLA cytopathologist and reported as ASC-US, atypical squamous cells cannot rule out high-grade (ASC-H), lowgrade
squamous intraepithelial lesions (LSIL), or highgrade squamous intraepithelial lesions (HSIL) using Bethesda 2001 terminology.5
High-resolution anoscopy
One practitioner performed all HRA exams. All patients with abnormal anal cytology were referred for further evaluation using HRA. This procedure uses a high-resolution anoscope (colposcope) set at 16 magnification to examine the peri-anal area and anal canal after the application of 3% acetic acid.23 The acetic acid causes acetowhitening of dysplastic anal epithelium similar to the
effect on cervical squamous epithelium. Cervical colposcopic features of high-grade dysplasia such as coarse punctuation and mosiacism have been shown to similarly indicate high-grade disease in the anal canal.20 Abnormal acetowhite epithelium was biopsied using disposable Trilobites (ESCO medical Instruments, Stony Brook, NY, USA) endoscopic forceps with a 2.3mm non-serrated cup. The biopsy specimens were immediately fixed in 10% formalin. Haemostasis was achieved with Monsell's solution prior to the end of the procedure.
Biopsies were processed using standard paraffin processing and read following staining with haematoxylin and eosin.
Statistical analysis
Biopsy results are used as the gold standard in the statistical analysis. Since biopsies were performed only for patients with non-negative cytology, estimates of sensitivity, specificity or likelihood ratios based on sensitivity and specificity using this data are biased and uninformative. Negative predictive values (NPV) also cannot be computed since no negative patients were biopsied. The positive predictive value (PPV) is computed using those with AIN 1, 2 or 3 biopsy results as true positives and is also computed using only AIN 2 or 3 as true positive. The weighted kappa statistic is computed as a measure of agreement beyond chance between the ordered cytology versus biopsy results and the Spearman rank
correlation (rs) is computed as a measure of association between the ordinal cytology versus biopsy results. Computations were carried out using StatXact version 5.0 (Cytel Software Inc., Cambridge, MA, USA). Results are reported as estimate7standard error.
RESULTS
A total of 244 patients had anal cytology screening between February 2002 and December 2004. The average age of patients was 44.1 years (range of 22-71 years), and ethnic breakdown was African American 8% (19), Asian 4% (9), Caucasian 72% (176), and Latino 16% (39) and Others 0% (1) - consistent with the general clinic population. The mean CD4 count at screening cytology was 457 cells per mm3 (range 1-1408 cells/mm3).
Twenty-nine percent (71) of patients had normal anal cytology, 67% (164) had abnormal anal cytology and 4% (9) of samples were unsatisfactory for interpretation due to hypocellularity (5), bacterial excess (2) and a predominance
of anucleated squames (2).
Abnormal cytology was reported as
-- ASC-US in 48% (78) (atypical squamous cells of undetermined significance)
-- ASC-H in 3% (5) (atypical squamous cells-high grade)
-- LSIL in 46% (76) ( low-grade squamous intraepithelial lesions)
-- HSIL in 3% (5) (high-grade squamous intraepithelial lesions)
Of the 166 patients with abnormal anal cytology, 93 had follow-up HRA and anal biopsy (Table 2). Patients who did not have HRA had either elected not to have the procedure or have yet to make an appointment.
Anal cytology grade showed poor correlation with the grade of dysplasia detected by paired HRA-directed anal biopsy. Ninety-two percent of the abnormal anal cytology was ASC-US or LSIL, however anal pathology reports showed high-grade dysplasia (anal intraepithelial neoplasia] [AIN] 2 or 3) in 52% of specimens, indicating that anal cytology underestimated the degree of anal dysplasia. The weighted kappa statistic is 0.0370.06 (P1/40.6337) and the Spearman correlation is rs1/40.05670.106 (P1/40.5956),
confirming poor agreement and correlation within the group of positive tests.
The PPV for any grade of anal cytological abnormality to predict any grade of anal dysplasia (AIN 1, 2 or 3) on biopsy was 95.772.1%. The PPV for any grade of anal dysplasia to predict high-grade anal dysplasia (AIN 2 or 3) on biopsy was 55.975.1%.
No significant adverse events such as infection, haemorrhage or pain uncontrolled with simple analgesia were reported in the study.
DISCUSSION
The clinicians in this study received one short training session on how to take an adequate anal cytology specimen and were able to collect adequate anal cytology samples in the majority of cases similar to a previous study.24
However, compared with previous studies, the grade of cytology was predominantly ASC-US and LSIL with fewer samples showing HSIL.21 This may have been due to the technique employed by the sampling clinicians or may
reflect cytopathological reporting. Assuming this result is more likely to reflect anal cytological sampling technique, repeating sampling technique instruction may have resulted in specimens that more closely reflect the anal cellular environment.
This study corroborates the poor correlation between the cytological grade of anal dysplasia and the histopathological examination of matched anal biopsy collected during HRA.21 As no patients with normal anal cytology were referred for HRA, sensitivity, specificity or NPV could not be reported for this population. However, given the high- PPVs of abnormal anal cytology to detect any grade of anal dysplasia, clinicians may be confident that an abnormal cytology result is likely to indicate the presence of some grade of anal dysplasia.
Despite the poor correlation of anal cytology with biopsy, empirically abnormal anal cytology identified subjects that were then referred for HRA and biopsy with over half of these subjects subsequently diagnosed with high-grade disease and referred for treatment. Previous modalities used to treat high-grade dysplasia have included cold scalpel excision with electrofulguration that showed lower rates of treatment efficacy in an HIV-positive population.25 More recently, the use of infrared coagulation (IRC) to treat high-grade dysplasia has been associated with higher efficacy rates with reduced post procedure pain.26 This device is used in an outpatient setting and delivers infra red light in aliquots of 0.5-3 second intervals (1.5 seconds for anal dysplasia) to previously anesthetized anal epithelium producing a focal shallow burn that reflects the time setting in mm, i.e. setting the IRC at 1.5 seconds will deliver a burn depth of 1.5mm26,27 Early clinical reports indicate efficacy (with follow-up biopsies showing normal or low-grade dysplasia) of 72% at six months.27
If referral for HRA is not available, patients with abnormal anal cytology should be informed about the risk of progression to anal cancer particularly with high-grade cytology results. Additionally, they should be made aware of common presenting symptoms of anal cancer such as pain, bleeding and the presence of a mass that would allow early investigation and referral for treatment.
The result of this study is likely to be reflective of other HIV primary care settings in the USA that have a predominance of Caucasian MSM over the age of 40 years. Thus, these clinics may also have a high burden of undiagnosed anal dysplasia.
In conclusion, detection of abnormal anal cytology is useful clinically in HIV-positive MSM to predict the presence of anal dysplasia. In this study, 96% of the
samples were adequate for cytological interpretation. The majority of abnormal cytology samples showed lower grades of dysplasia while more than half of these abnormal cytology specimens had high-grade dysplasia on biopsy.
Thus, any abnormality on anal cytology testing should prompt HRA follow-up to determine grade of dysplasia and allow consideration of treatment for high-grade disease.
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