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Abnormal anal cytology risk in women with known genital squamous intraepithelial lesion.

Anal and cervical cancers have many similarities that include association with human papillomavirus (HPV) infection, occurrence in an epithelial transformation zone, and coexistence with high-grade squamous intraepithelial lesions. (1)

HPV has been observed in 99% of cervical cancers and 80-90% of anal cancers. (2-4) It is likely that the pathogenesis of anal cancer is similar to that of cervical cancer: that is, anal

HPV infection, in conjunction with other yet to be determined factors, leads to the development of high-grade anal intraepithelial neoplasia (HGAIN), which is a probable precursor to anal cancer. (4,5)

Considering that programmatic screening for cervical cancer with cytology has been associated with considerably decreased incidence and mortality rates of cervical cancer, (6) anal cytology has been assessed as a screening method for anal neoplasia in high-risk individuals in some countries such as the USA. (7)

Subjects with abnormal anal screening cytology are referred for a high-resolution anoscopy (HRA) or colposcopic evaluation of the anus. In cases diagnosed with HGAIN through directed biopsies, an ablation of HGAIN lesions must be done. (8)

Regardless of the extensive data on cervical neoplasia and HPV infection in women, there are limited data on anal neoplasia, anal HPV infection, and cytology. The purpose of this study was to assess the risk of abnormal anal cytology in women with known genital SIL.

This study, conducted at the LNRCC-Luis Antonio Hospital (hospital for cancer in Rio Grande do Norte, Brazil), assessed 200 HIV-seronegative women (using enzyme-linked immunosorbent assay [ELISA] and Western blot), 115 with and 85 without genital SIL. The first group of women had genital SIL diagnosed by cytology, genitoscopy, and biopsy, and the second group of women presenting for cervical cancer screening had no genital SIL, based on cytology (two negative Papanicolaou smears) and a negative genitoscopy. An expert pathologist reviewed the Papanicolaou tests and biopsies. Patients in use of immunosuppressive therapy, transplanted, and HIV-infected were excluded.

After obtaining written informed consent, each subject provided a detailed history of routine gynecologic healthcare and risk factors for the development of anal cytologic abnormalities. A standardized questionnaire inquired about history of anal intercourse; number of sexual partners; history of sexually transmitted diseases; cervical cytologic abnormalities; vulvar warts; cervical, vulvar, or vaginal cancers; solid organ transplantation; chronic corticosteroid use; history of cigarette smoking; and drug and alcohol use.

[FIGURE 1 OMITTED]

After administering the questionnaire and completing the patient history, a visual examination of the lower genital tract was performed, and samples were collected for cervical and anal cytology. The anal Pap smear was collected using a cytobrush, which was inserted 4 cm into the anal canal. The cytobrush was rotated 360[degrees] in a cone-shaped area and removed. The sample was then smeared onto a glass slide, immediately fixed in 95% ethyl alcohol and transported to the laboratory. Papanicolaou staining was used for cytopathologic diagnosis and any cytological finding from ASCUS was considered abnormal (Fig. 1).

Statistical analysis with 95% confidence intervals performed using descriptive and inferential statistics. A dichotomous variable of anal SIL was used to assess its association with the other nominal variables using Chi-square and Fisher exact test. A multiple logistic regression analysis (stepwise) was performed to identify predictors independently associated with anal SIL. Data were analyzed using the SPSS 20.0 program, and the level of significance was set at 5%. This study was approved by the Ethics Research Committee of the institution (CAAE 1 07769612.3.0000.5293).

The mean age for patients included in this study was 41.09 ([+ or -]12.64). Most were nonwhite (56%) and nonsmokers (91.5%), with up to eight years of school education (50.5%). Regarding the description of contextual variables, 55.5% used oral contraceptives, 9% used condoms, 80% had already been pregnant and of these 30% had had an abortion. The majority had up to three partners (73.5%) and had not contracted other (concomitant) sexually transmitted infection (STI), besides HPV (74%). More than half reported not practicing anal sex (75.5%), 91% had partners with no clinical evidence of HPV-induced lesions. 87.5% had not used drugs, and 96.5% denied bisexual relations. A large percentage of the women did not report any anal pathology (92%) or anal bleeding (68.5%). However, more than half had low genital intraepithelial lesions (57.5%), and a significant number developed abnormal anal cytology: 13% of the total sample and 17.4% among women with genital SIL. Concerning the association between anal SIL and the socioeconomic and contextual variables, a significant association was only observed between genital SIL and anal SIL (PR = 2.46; p = 0.03). There was no significant association between anal SIL and all other studied variables. In the logistic regression model, after adjusting for the variables age and partner with HPV, women with genital intraepithelial lesions presented more risk for abnormal anal Pap smear (aPR = 2.81; p = 0.02) (Table 1). Abnormal anal cytology was observed in 11 patients with cervical high squamous intraepithelial lesion (HSIL--NIC2 and 3), nine patients with cervical low squamous intraepithelial lesion (LSIL--NIC1), and in six women with inflammatory samples. However no differences were observed between the HSIL and LSIL groups. Vulvar lesions (genital warts) were found in four patients with LSIL--NIC1 cervical samples.

The anal Pap smear has been a beneficial tool for early detection of intra-anal dysplasia in patients at risk, such as HIV-infected men and women. (9,10)

In this study, there was no difference in the sociodemographic characteristics of women with genital lesions and women without HPV-associated genital lesions. Age and anal sex were not significantly associated with abnormal anal cytology or anal HPV-induced lesions in the study group, which is in contrast to past studies. (11,12)

Concerning prevalence, in this group we found abnormal anal cytology in 13% of the total sample and in 17.4% among women with genital SIL. Earlier, Jacyntho et al. (11) observed similar rates comparing 184 women with known genital SIL and 76 controls without genital SIL. Anal intraepithelial neoplasia was observed in 32 (17.4%) of the 184 women with genital SIL compared with two (2.6%) of the 76 controls without genital SIL. (11) Tatti et al.,13 studying 481 immunocompetent and immunosuppressed women with genital SIL, found a higher prevalence of abnormal anal cytology (27.8%), probably due to the inclusion of HIV-infected patients. (12) Several studies have reported that HIV-infected women have higher rates of abnormal anal cytology and histopathology results than HIV-uninfected women. (10,13,14) These results suggest that mainly in HIV-infected women, the presence of genital HPV-induced lesions could predict a probable abnormal anal cytology.

Considering that HPV infection is strongly linked with anal cancer and usually considered a field infection of the anogenital tract, it is possible that women with a history of genital SIL may be under a higher risk for anal cancer. Many large-scale cancer registry studies support robust associations between a history of genital SIL and cancers of the anus. (15-17) In a population-based cohort study, Edgren and Sparen (15) evaluated the risk of anal cancer in women with a later history of CIN3 by linking Swedish national registries with cancer registries. The incident rate ratio was 4.68 for women with prior high-grade cervical lesion when compared with those with no cervical lesion. The risk was substantially elevated five years after the diagnosis for all ages. (15)

A recent study examined women with high-grade disease (defined as in situ) or invasive cervical, vulvar, or vaginal cancer. The authors identified a significant association between previous genital SIL and invasive cancers of the cervix, vulva, vagina, and anus. (16)

A large study examined the long-term risk trend for a second cancer among 104,760 women with cervical cancer. Women with diagnosed cervical cancer had greater risk of developing anal cancer than women in the general population. (17)

In conclusion, there is powerful epidemiological evidence (18) showing a raised risk of anal cancer in women with a previous history of in situ and invasive cancers of the cervix, vagina, and vulva compared with the general population. In this study, we observed a higher risk for abnormal anal cytology in women with genital HPV-induced lesions, suggesting that these women must be more closely screened for anal cancer.

Article history:

Received 2 November 2015

Accepted 22 January 2016

Available online 29 March 2016

Conflicts of interest

The authors declare no conflicts of interest.

REFERENCES

(1.) 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; 43:223-33.

(2.) Daling JR, Madeleine MM, Johnson LG, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004; 101:270-80.

(3.) Madeleine MM, Franceschi S. Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis. Int J Cancer. 2008; 124:1626-36.

(4.) Walbloomers JMM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999; 189:12-9.

(5.) Devaraj B, Cosman BC. Expectant management of anal squamous dysplasia in patients with HIV. Dis Colon Rectum. 2006; 49:36-40.

(6.) Kitchener HC, Castle PE, Cox JT. Chapter 7: Achievements and limitations of cervical cytology screening. Vaccine. 2006; 24 Suppl. 3:63-70.

(7.) Palefsky J. Screening to prevent anal cancer: current thinking and future directions. Cancer Cytopathol. 2015; 123:509-10, http://dx.doi.org/10.1002/cncy.21571.

(8.) Palefsky J. Human papillomavirus-related tumors in HIV. Curr Opin Oncol. 2006; 18:463-8.

(9.) Arora R, Pandhi D, Mishra K, Bhattacharya SN, Yhome VA. Anal cytology and p16 immunostaining for screening anal intraepithelial neoplasia in HIV-positive and HIV-negative men who have sex with men: a cross-sectional study. Int J STD AIDS. 2014; 25:726-33.

(10.) Gingelmaier A, WeissenbacherT, Kost B, et al. Anal cytology as a screening tool for early detection of anal dysplasia in HIV-infected women. Anticancer Res. 2010; 30:1719-23.

(11.) Jacyntho CMA, Giraldo PC, Horta AA, et al. Association between genital intraepithelial lesions and anal squamous intraepithelial lesions in HIV negative women. Am J Obstet Gynecol. 2011; 205, 115.e1-1-5.

(12.) Giraldo P, Jacyntho C, Costa C, et al. Prevalence of anal squamous intra-epithelial lesion in women presenting genital squamous intra-epithelial lesion. Eur J Obstet Gynecol Reprod Biol. 2009; 142:73-5.

(13.) Tatti S, Suzuki V, Fleider L, et al. Anal intraepithelial lesions in women with human papillomavirus-related disease. J Low Genit Tract Dis. 2012; 16:454-9.

(14.) Chaves EB, Folgierini H, Capp E, et al. Prevalence of abnormal anal cytology in women infected with HIV J Med Virol. 2012; 84:1335-9.

(15.) Tandon R, Baranoski AS, Huang F et al. Abnormal anal cytology in HIV-infected women. Am J Obstet Gynecol. 2010; 203:e21-6.

(16.) Edgren G, Sparen P.Risk of anogenital cancer after diagnosis of cervical intraepithelial neoplasia: a prospective population-based study. Lancet Oncol. 2007; 8:311-6.

(17.) Saleem AM, Paulus JK, Shapter AP, et al. Risk of anal cancer in a cohort with human papillomavirus-related gynecologic neoplasm. Obstet Gynecol. 2011; 117:643-9.

(18.) Chaturvedi AK, Engels EA, Gilbert ES, et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst. 2007; 99:1634-43.

Maria do Socorro Nobre (a), Claudia Marcia Jacyntho (b), Jose Eleuterio Jr (c), Paulo Cesar Giraldo (d), Ana Katherine Goncalves (a),*

(a) Health Post Graduation Program, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil

(b) Department of Obstetric and Gynecology, Faculdade de Medicina Souza Marques, Rio de Janeiro, RJ, Brazil

(c) Department of Obstetrics and Gynecology, Universidade Federal do Ceara, Fortaleza, CE, Brazil

(d) Department of Obstetric and Gynecology, Universidade Estadual de Campinas, Campinas, SP, Brazil

* Corresponding author.

E-mail addresses: anakatherine@ufrnet.br, anakatherine_ufrnet@yahoo.com.br (A.K. Goncalves). http://dx.doi.org/10.1016/j.bjid.2016.01.008
Table 1--The risk of anal SIL in women with genital HPV induced
lesions.

Variable      Category    Anal SIL                   PR     CI 95%
                          Yes (%)      No (%)

GSIL          Yes         20 (17.4%)   95 (82.6%)    2.46   1.03-5.87
              No          6 (7.1%)     79 (92.9%)
Age           Until 41    11 (11.3%)   86 (88.7%)    0.78   0.38-1.61
                years
              >41 years   15 (14.6%)   88 (85.4%)
Race          White       8 (9.1%)     80 (90.9%)    0.57   0.26-1.24
              Non White   18 (16.1%)   94 (83.9%)
Years of      <8 years    13 (12.9%)   88 (87.1%)    0.98   0.48-2.01
  study       >8 years    13 (13.1%)   86 (86.9%)
Smoking       Yes         1 (5.9%)     16 (94.1%)    0.43   0.06-2.98
              No          25 (13.7%)   158 (86.3%)
Contra-       Yes         16 (12.6%)   111 (87.4%)   0.92   0.44-1.92
ceptive       No          10 (13.7%)   63 (86.3%)
use
N. partner    >3          18 (12.2%)   129 (87.8%)   0.81   0.37-1.75
              >3          8 (15.1%)    45 (84.9%)
STD           Yes         6 (11.3%)    47 (88.7%)    0.83   0.35-1.96
              No          20 (13.6%)   127 (86.4%)
HPV partner   Yes         4 (22.2%)    14 (77.8%)    1.84   0.71-4.75
              No          22 (12.1%)   160 (87.9%)
Anal sex      Yes         8 (16.3%)    41 (83.7%)    1.37   0.63-2.95
              No          18 (11.9%)   133 (88.1%)
Drug user     Yes         1 (20.0%)    4 (80.0%)     1.56   0.26-9.35
              No          25 (12.8%)   170 (87.2%)
Anal          Yes         1 (6.3%)     15 (93.8%)    0.46   0.07-3.18
disease       No          25 (13.6%)   159 (86.4%)
Anal          Yes         5 (7.9%)     58 (92.1%)    0.52   0.20-1.31
bleeding      No          21 (15.3%)   116 (84.7%)

Variable      p          aPR (b)   aCI 95%     p (c)
                                               value

GSIL          0.03 (a)   2.81      1.16-6.79   0.02

Age           0.49

Race          0.14

Years of      0.95
  study
Smoking       0.362

Contra-       0.824
ceptive
use
N. partner    0.59

STD           0.67

HPV partner   0.22

Anal sex      0.42

Drug user     0.63

Anal          0.40
disease
Anal          0.149
bleeding

GSIL, genital squamous intraepithelial lesions; SIL, squamous
intraepithelial lesion; PR, prevalence ration; CI, confidence
interval; aPR, adjusted prevalence ration; aCI, adjusted confidence
interval; STD, sexually transmitted disease.

(a) Chi-square test.

(b) Association Pearson's chi-square.

(c) Logistic regression.
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Article Details
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Title Annotation:Brief Communication
Author:Nobre, Maria do Socorro; Jacyntho, Claudia Marcia; Eleuterio, Jose, Jr.; Giraldo, Paulo Cesar; Gonca
Publication:The Brazilian Journal of Infectious Diseases
Article Type:Report
Date:May 1, 2016
Words:2380
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