Correlating Pap Smear Results and Colposcopy-Directed Large Loop Excision of the Transformation Zone Histopathology in HIV-Infected and HIV-Uninfected Women: A Case-Control Study in South Africa
Background. In low-resource settings (LRS) with high HIV/AIDS and cervical cancer rates, new screening strategies face many logistic hurdles. Since cytology is there to stay, at least in the median-term future, it is important to assess to what extent HIV-HPV coinfection impacts the accuracy of screening methods and strategies. Methods. We audited the correlation between cytological diagnosis of minimal abnormality ( CIN1), CIN2+, or cancer and the histological diagnosis of colposcopy-directed large loop excision of the transformation zone of 399 HIV-uninfected controls and 389 HIV-infected cases. Results. The average age at diagnosis of CIN2+ of the cases was 4.2 years younger than controls ( ). The endpoint used to assess the accuracy of cytology was minimal cytological abnormality (≤CIN1/LGSIL). The sensitivity, specificity, and negative and positive predictive values were 92.7, 18.5, 45.1, and 77.9%, respectively. The overall ratio of discordance/concordance between cytology and histology was similar in both groups. Conclusion. In LRS, where rapid-HPV testing is not yet part of screening algorithms, a cytological diagnosis of minimal abnormality requires visual inspection and treatment of visualized lesions especially in HIV-infected women aged 30 years. The cytological endpoint of accuracy should be set low to avoid false negative smears. 1. Introduction It is often stated that more stringent follow-up by means of Pap smears is warranted in HIV-infected than uninfected women [1–3]. The rationale is based on the assumption that cervical cancer is an AIDS-defining illness [4]. However, this assumption is debatable since there is no convincing evidence indicating that the incidence of cervical cancer increased with the spread of HIV/AIDS, be it in the developing or the developed world [5–8]. This being said, the question remains whether preventative strategies should be tailor-made for HIV-infected women. The prevention of cervical cancer encompasses primary (HPV vaccination and life style) and secondary (screening) measures. In low-resource settings (LRS), HPV vaccination is not yet practiced because of a wide array of logistical hurdles, and cytological screening is mostly either absent or limited to opportunistic testing [9, 10]. Cervical cytology has been the mainstay of prevention for many decades. Because of its wide range of sensitivity and specificity and the availability of low-cost/low-technology HPV-DNA test kits, there is a slowly growing paradigm shift favoring alternatives based on cytology, rapid-HPV testing, visual inspection,
References
[1]
P. Lehtovirta, J. Paavonen, and O. Heikinheimo, “Risk factors, diagnosis and prognosis of cervical intraepithelial neoplasia among HIV-infected women,” International Journal of STD and AIDS, vol. 19, no. 1, pp. 37–41, 2008.
[2]
D. N. Dames, C. Ragin, A. Griffith-Bowe, P. Gomez, and R. Butler, “The prevalence of cervical cytology abnormalities and human papillomavirus in women infected with the human immunodeficiency virus,” Infectious Agents and Cancer, vol. 4, no. 1, article S8, 2009.
[3]
L. S. Massad, G. D’Souza, F. Tian, H. Minkhoff, M. Cohen, R. L. Wright, et al., “Negative predictive value of pap testing: implications for screening intervals for women with human immunodeficiency virus,” Obstetrics & Gynecology, vol. 120, no. 4, pp. 791–797, 2012.
[4]
Centers for Disease Control and Prevention, “1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults,” Morbidity Mortality Weekly Report Recommendation Report, vol. 41, pp. 1–19, 1992.
[5]
W. K. Sekirime and R. Gray, “HIV infection among Uganda women with cervical cancer: a retrospective study,” Gynecologic and Obstetric Investigation, vol. 63, no. 4, pp. 222–228, 2007.
[6]
J. R. Moodley, M. Hoffman, H. Carrara et al., “HIV and pre-neoplastic and neoplastic lesions of the cervix in South Africa: a case-control study,” BMC Cancer, vol. 6, article 135, 2006.
[7]
A. K. Chaturvedi, M. M. Madeleine, R. J. Biggar, and E. A. Engels, “Risk of human papillomavirus-associated cancers among persons with AIDS,” Journal of the National Cancer Institute, vol. 101, no. 16, pp. 1120–1130, 2009.
[8]
M. Bower, D. Mazhar, and J. Stebbing, “Should cervical cancer be an acquired immunodeficiency syndrome-defining cancer?” Journal of Clinical Oncology, vol. 24, no. 16, pp. 2417–2419, 2006.
[9]
L.-J. Van Bogaert and D. C. Knapp, “Opportunistic testing of medically underserved women for cervical cancer in south africa,” Acta Cytologica, vol. 45, no. 3, pp. 313–316, 2001.
[10]
M. Hoffman, D. Cooper, H. Carrara et al., “Limited Pap screening associated with reduced risk of cervical cancer in South Africa,” International Journal of Epidemiology, vol. 32, no. 4, pp. 573–577, 2003.
[11]
M. Arbyn, R. Sankaranarayanan, R. Muwonge et al., “Pooled analysis of the accuracy of five cervical cancer screening tests assessed in eleven studies in Africa and India,” International Journal of Cancer, vol. 123, no. 1, pp. 153–160, 2008.
[12]
J. Cuzick, M. Arbyn, R. Sankaranarayanan et al., “Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries,” Vaccine, vol. 26, no. 10, pp. K29–K41, 2008.
[13]
I. M. C. M. De Kok, J. Van Rosmalen, J. Dillner et al., “Primary screening for human papillomavirus compared with cytology screening for cervical cancer in European settings: cost effectiveness analysis based on a Dutch microsimulation model,” British Medical Journal, vol. 344, no. 7847, article e670, 2012.
[14]
L. Kuhn, C. Wang, W.-Y. Tsai, T. C. Wright, and L. Denny, “Efficacy of human papillomavirus-based screen-and-treat for cervical cancer prevention among HIV-infected womens,” AIDS, vol. 24, no. 16, pp. 2553–2561, 2010.
[15]
L. J. van Bogaert, “Cervical cancer prevention in resource-limited settings with special emphasis on areas of high cervical cancer and human immunodeficiency virus endemicity,” in Human Papillomavirus: Prevalence, Detection and Management, H. B. Smith, Ed., Novapublishers, New York, NY, USA, 2013.
[16]
G. Ronco, P. Giorgi-Rossi, F. Carozzi et al., “Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test,” Journal of the National Cancer Institute, vol. 100, no. 7, pp. 492–501, 2008.
[17]
P. Naucler, W. Ryd, S. T?rnberg et al., “Efficacy of HPV DNA testing with cytology triage and/or repeat HPV DNA testing in primary cervical cancer screening,” Journal of the National Cancer Institute, vol. 101, no. 2, pp. 88–99, 2009.
[18]
S. H. van der Burg and J. M. Palefsky, “Human immunodeficiency virus and human papilloma virus—why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful,” Journal of Translational Medicine, vol. 7, p. 108, 2009.
[19]
T. M. Darragh, T. J. Colgan, T. Cox, D. Heller, M. Henry, R. Luff, et al., “The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology,” International Journal of Gynecological Pathology, vol. 32, no. 1, pp. 76–115, 2013.
[20]
V. V. Sahasrabuddhe, R. A. Bhosale, A. N. Kavatkar et al., “Comparison of visual inspection with acetic acid and cervical cytology to detect high-grade cervical neoplasia among HIV-infected women in India,” International Journal of Cancer, vol. 130, no. 1, pp. 234–240, 2012.
[21]
K. Nanda, D. C. McCrory, E. R. Myers et al., “Accuracy of the papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review,” Annals of Internal Medicine, vol. 132, no. 10, pp. 810–819, 2000.
[22]
M. Branca, E. Rossi, M. Alderisio et al., “Performance of cytology and colposcopy in diagnosis of cervical intraepithelial neoplasia (CIN) in HIV-positive and HIV-negative women,” Cytopathology, vol. 12, no. 2, pp. 84–93, 2001.
[23]
R. Sankaranarayanan, A. M. Budukh, and R. Rajkumar, “Effective screening programmes for cervical cancer in low- and middle-income developing countries,” Bulletin of the World Health Organization, vol. 79, no. 10, pp. 954–962, 2001.
[24]
M.-H. Mayrand, E. Duarte-Franco, I. Rodrigues et al., “Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer,” The New England Journal of Medicine, vol. 357, no. 16, pp. 1579–1588, 2007.
[25]
P. E. Gravitt, P. Paul, H. A. Katki et al., “Effectiveness of VIA, pap, and HPV DNA testing in a cervical cancer screening program in a Peri-Urban community in Andhra Pradesh, India,” PLoS ONE, vol. 5, no. 10, Article ID e13711, 2010.
[26]
South African HPV advisory board, “Cervical cancer and human papillomavirus: South African guidelines for screening and testing,” Southern African Journal of Gynaecologic Oncology, vol. 2, no. 1, pp. 23–26, 2010.
[27]
S. O. Albert, O. A. Oguntayo, and M. O. A. Samaila, “Comparative study of visual inspection of the cervix using acetic acid (VIA) and Papanicolaou (Pap) smears for cervical cancer screening,” Ecancer, vol. 6, article 262.
[28]
C. Firnhaber, N. Mayisela, S. Williams, A. Swarts, M. Faesen, S. Levin, et al., “Validation of cervical screening methods in HIV positive women from Johannesburg South Africa,” Plos ONE, vol. 8, no. 1, Article ID e53494, 2013.
[29]
P. E. Castle, M. H. Stoler, T. C. Wright, A. Sharma, T. L. Wright, and C. M. Behrens, “Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study,” The Lancet Oncology, vol. 12, no. 9, pp. 880–890, 2011.
[30]
N. Khuakoonratt, S. Tangjitgamol, S. Manusirivithaya et al., “Prevalence of high grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer in patients with low grade squamous intraepithelial lesion (LSIL) at cervical pap smear,” Asian Pacific Journal of Cancer Prevention, vol. 9, no. 2, pp. 253–258, 2008.
[31]
R. Kiatiyosnusorn, P. Suprasert, J. Srisomboon, S. Siriaree, S. Khunamornpong, and C. Kietpeerakool, “High-grade histologic lesions in women with low-grade squamous intraepithelial lesion cytology from a region of Thailand with a high incidence of cervical cancer,” International Journal of Gynecology and Obstetrics, vol. 110, no. 2, pp. 133–136, 2010.
[32]
P. A. de Lemos, M. T. Garcia-Zapata, and S. B. Tavares, “Cervical cytopathology in a population of HIV-positive and HIV-negative women,” Journal of Tropical Medicine, vol. 2012, Article ID 869758, 4 pages, 2012.
[33]
J. Atashili, W. C. Miller, J. S. Smithy, P. M. Ndumbe, G. M. Ikomey, J. Eron, et al., “Age trends in the prevalence of cervical squamous intraepithelial lesions among HIV-positive women in Cameroon: a cross-sectional study,” BMC Research Notes, vol. 5, article 590, 2012.
[34]
J. R. Anderson, P. Paramsothy, C. Heilig, D. J. Jamieson, K. Shah, and A. Duerr, “Accuracy of Papanicolaou test among HIV-infected women,” Clinical Infectious Diseases, vol. 42, no. 4, pp. 562–568, 2006.
[35]
C. L. Curry, Y. H. Sage, O. Vragovic, and E. A. Stier, “Minimally abnormal pap testing and cervical histology in hiv-infected women,” Journal of Women's Health, vol. 21, no. 1, pp. 87–91, 2012.
[36]
A. Duerr, P. Paramsothy, D. J. Jamieson et al., “Effect of HIV infection on atypical squamous cells of undetermined significance,” Clinical Infectious Diseases, vol. 42, no. 6, pp. 855–861, 2006.
[37]
L. A. Boardman, K. Cotter, C. Raker, and S. Cu-Uvin, “Cervical intraepithelial neoplasia grade 2 or worse in human immunodeficiency virus-infected women with mildly abnormal cervical cytology,” Obstetrics and Gynecology, vol. 112, no. 2, pp. 238–243, 2008.
[38]
M. T. Galgano, P. E. Castle, K. A. Atkins, W. K. Brix, S. R. Nassau, and M. H. Stoler, “Using Biomarkers as objective standards in the diagnosis of cervical biopsies,” American Journal of Surgical Pathology, vol. 34, no. 8, pp. 1077–1087, 2010.
[39]
L. Nappi, C. Carriero, S. Bettocchi, J. Herrero, A. Vimercati, and G. Putignano, “Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 121, no. 2, pp. 226–232, 2005.
[40]
M. Zeier, M. H. Botha, F. H. van der Merwe et al., “Progression and persistence of low-grade cervical squamous intraepithelial lesions in women living with human immunodeficiency virus,” Journal of Lower Genital Tract Disease, 2012.
[41]
M. Alsharif, K. Kjeldahl, C. Curran, S. Miller, H. E. Gulbahce, and S. E. Pambuccian, “Clinical significance of the diagnosis of low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion,” Cancer Cytopathology, vol. 117, no. 2, pp. 92–100, 2009.
[42]
M. J. Thrall, D. A. Smith, and D. R. Mody, “Women ≥30 years of age with low grade squamous intraepithelial lesion (LSIL) have low positivity rates when cotested for high-risk human papillomavirus: should we reconsider HPV triage for LSIL in older women?” Diagnostic Cytopathology, vol. 38, no. 6, pp. 407–412, 2010.
[43]
“National Department of Health, South Africa “ National Guideline on Cervical Cancer Screening Programme” , Pretoria,” 2003.