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Distribution of Cervical Intraepithelial Neoplasia on the Cervix in Chinese Women: Pooled Analysis of 19 Population Based Screening Studies Yu-Qian Zhao1, Irene J

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Distribution of Cervical Intraepithelial Neoplasia on the Cervix in Chinese Women: Pooled Analysis of 19 Population Based Screening Studies Yu-Qian Zhao1, Irene J Zhao et al. BMC Cancer (2015) 15:485 DOI 10.1186/s12885-015-1494-4 RESEARCH ARTICLE Open Access Distribution of cervical intraepithelial neoplasia on the cervix in Chinese women: pooled analysis of 19 population based screening studies Yu-qian Zhao1, Irene J. Chang1,2, Fang-hui Zhao1, Shang-ying Hu1, Jennifer S. Smith3, Xun Zhang4, Shu-min Li5, Ping Bai5, Wen-hua Zhang5 and You-lin Qiao1* Abstract Background: Controversy remains whether a pattern of cervical intraepithelial neoplasia exists on the cervix. Our study aims at determining if the prevalence of histologically proven lesions differs by cervical four-quadrant location or by 12 o'clock surface locations of diagnosis. Methods: We conducted a retrospective, histopathological study of 19 different population based cervical cancer screening studies from 1999 to 2010 by Cancer Hospital of Chinese Academy of Medical Sciences. The Institutional Review Board for human research subjects at CHCAMS approved all of the studies. During the colposcopy procedure, participant received either 4-quadrant biopsy or directed biopsy with/without endocervical curettage. Data of all samples were stratified by the methods of sampling. Kruskal-Wallis test was used to determine overall distribution of normal/CIN1, CIN2 and CIN3+ on the cervix. Results: In total, 53,088 cervical samples were included in distribution analysis. 66.9 % samples were obtained by random biopsy, 16.1 % were by directed biopsy, and 17.0 % were by endocervical curettage. 95.9%of the biopsied samples were diagnosed as normal/CIN1, 2.0 % were CIN2, and 2.1 % were CIN3 + . CIN2 and CIN3+ were most 2 often found in quadrants 2 and 3 (χKW = 46.6540, p < 0.0001) and at the 4- and 7-o'clock positions by directed biopsy (ORCIN2 = 2.572, 1.689, ORCIN3+ = 3.481, 1.678, respectively), and at the 5-, 6-, 7-, 9- and 12-o’clock positions by random biopsy. CIN3+ was least often found at the 11-o’clock position by directed biopsy (OR = 0.608). Conclusions: Our results suggest a predisposition of specific locations on the cervix to CIN occurrence. Quadrants 2 and 3, especially the 4- and 7-o’clock positions should be preferentially targeted during biopsy. The decision for random biopsy should be reconsidered in future studies. Keywords: Colposcopy, Cervical intraepithelial neoplasia, Lesion location, Biopsy, Cervical cancer Background within the transformation zone of the cervix, where Persistent infection with high risk human papillomavirus primary screening methods such as the Papanicolaou (hr-HPV) has been established as the major etiological (Pap) smear detect early cytological abnormalities [4, 6]. factor for cervical intraepithelial neoplasia (CIN) [1–3]. Definitive diagnosis of CIN is obtained through colpos- Early detection of precursor lesions is imperative be- copy with biopsy and histopathology [7–10]. cause without treatment, all grades of CIN may progress Colposcopy with directed biopsy is the current gold to invasive cervical cancer, although CIN 1 lesions standard for diagnosis of pre-invasive cervical cancer, progress less frequently [4, 5]. Carcinogenesis occurs with sensitivity up to 84.8 % for high-grade squamous intraepithelial lesions or worse (HSIL+) [11]. Despite its * Correspondence: [email protected] high accuracy and concordance with histology, colpos- 1 Department of Cancer Epidemiology, Cancer Hospital Chinese Academy of copy technique remains largely operator-dependent with Medical Sciences and Peking Union Medical College, 17 South Panjiayuan Lane, PO Box 2258, 100021 Beijing, China no standardized guidelines [12–14]. To address the Full list of author information is available at the end of the article © 2015 Zhao et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhao et al. BMC Cancer (2015) 15:485 Page 2 of 8 practitioner-dependent limitations of colposcopically di- Technologies to Advance Rapid Testing(START) 2003, rected biopsy, colposcopists are recommended to obtain 2004, 2005, 2006, 2007, Screening Technologies to additional random biopsies from distinct locations, and Advance Rapid Testing—Utility and Program Planning to perform endocervical curettage (ECC) in women with (START-UP) 2010, cooperative screening studies with ambiguous pap smears or women over 45 years old with International Agency for Research on Cancer(IARC) I, II suspected high-grade lesions [15–17]. and III, FastHPV trial (2007), Prevalence survey (2008), Controversy exists in literature on whether there is a and Hybrid Capture (HC) 2 trial (2008)). The Institutional topographical pattern of CIN on the cervix that could be Review Board for human research subjects at CHCAMS targeted by colposcopy [18–24]. The cervix is often approved all these studies prior to commencing. Written identified by clockwise, using the o’clock position with informed consent was obtained from all women. Study the 12 o’clock and the 6 o’clock position being located at procedures and methodology have been described previ- the midpoint of the anterior and posterior lip of the ously [25, 26]. cervix, the 3 o’clock and 9 o’clock position located at the Participants who were biopsied in all studies were midpoint of the right and left side, respectively. Some between 19 to 65 years old, not pregnant, and had no researchers reported a predilection of histologically history of pelvic surgery or irradiation. In colposcopy, confirmed CIN loci for the anterior and posterior cer- the surface of the cervix divided by perpendicular lines vical os [18–21]. He et al. suggests that CIN lesions are drawn from 12- to 6- o’clock and from 3- to 9-o’clock. not randomly distributed, but concentrated in the 12-, The four cervical quadrants are labeled clockwise, with 8-, and 7-o’clock sites on the cervix [18]. Allard et al and quadrant 1 from 12 to 3 o’clock, quadrant 2 from 3 to 6 Heatley M reported a predilection for the locations on o’clock, quadrant 3 from 6 to 9 o’clock, and quadrant 4 anterior and posterior lips of the cervix [19, 20]. Richart from 9 to 12 o’clock. Screened women included in our claimed CIN occurs more frequently on the anterior lip analysis had at least one positive result on various of the cervix than on the posterior [21]. However, Yang cervical cancer screening tests (Additional file 1), except HP et al have not found preferential sites on the cervix for women in the SPOCCS I trial which all participants for CIN3 [22]. Besides, there are also some studies re- underwent 4-quadrant biopsy and ECC regardless of port heterogeneity in CIN occurrence across the cervix, their screening results and in START-UP study that but claiming the evidence maybe confounded by some 10 % of all primary screening negative women under- factors, such as a tendency of the anterior and posterior went colposcopy and 4-quadrant random biopsy and lips to look more acetowhite, the inherent imprecision ECC. After being referred to colposcopy, according to of colposcopy and operator bias for anterior-posterior the proposals (SPOCCS II, SPOCCS III, START 2003- cervical sampling due to mechanical ease [23, 24]. Clini- 2007), participants received colposcopically directed cians were recommend to take multiple random biopsies biopsy in any abnormal-appearing area and random bi- during colposcopy in all cervical quadrants even without opsy in other negative quadrants at the squamocolumnar visible lesions to avoid missing CIN invisible to the junction around 2-, 4-, 8-, and 10-o’clock so that partici- naked eye [15, 16], a possible existing predilection distri- pants in these studies referred to colposcopy had a mini- bution of CINs on the cervix may help the clinicians to mum of 4 quadrants biopsies. In other studies (Prevalence make decisions while performing random biopsy. Since study, HC2 trial, FastHPV trial and IARC 1-3), partici- controversy still remains, our study aims to determine if pants received directed biopsy at the positive colpscopy the prevalence of histologically proven CIN lesions quadrant only or 4-quadrant biopsy were performed at differs by cervical 4-quadrant location or by 12-o’clock the squamocolumnar junction if the colposcopy diagnosis location of diagnosis on the cervix. These findings may were negative. ECC was subsequently performed accord- help in the development of colposcopy guidelines. ing to study protocols. The indications for colposcopically directed biopsies were the same across the studies that Method any abnormal-appearing areas should be targeted, includ- Population ing suspicious HPV infection or low-grade lesions. The We conducted a retrospective, pooled data analysis of 19 quadrants and/or o’clock location were required to be re- different population based screening studies conducted corded by the operators. Only participants with complete by the Cancer Hospital, Chinese Academy of Medical biopsy records and pathological diagnoses were included. Sciences (CHCAMS) in Beijing, China. We determined Samples with incomplete data, unsatisfactory biopsies, the distribution of CIN 2+ lesions among 38,633 women and biopsies with ambiguous diagnoses or non-specific participating in studies from 1999 to 2010 listed in labeling of location of origin (e.g., “close to 6 o’clock”, Additional file 1 a (i.e, Shanxi Province Cervical “between 2 and 3 o’clock”) were excluded. Cases with only Cancer Screening Study(SPOCCS) I (1999), SPOCCS II quadrant but no o’clock data were included in the 4- (2001-2002), SPOCCS III-1-5 (2006-2007), Screening quadrant analysis and excluded from the 12 o’clock Zhao et al. BMC Cancer (2015) 15:485 Page 3 of 8 location analysis.
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