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transformation zone component in conventional cervical Papanicolaou smears
Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 81e84
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Clinical parameters associated with absence of endocervical/transformation zone component in conventional cervical Papanicolaou smears Lou Sun a, Peng-Hui Wang b, c, d, Chen-Hui Lee e, Tsai-Feng Fu f, Min-Min Chou a, Sheau-Feng Hwang a, Yu-Min Ke a, Shih-Tien Hsu a, g, Chien-Hsing Lu a, c, e, h, i, * a
Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan d Department of Medical Research, China Medical University Hospital, Taichung, Taiwan e Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan f Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou County, Taiwan g School of Medicine, China Medical University, Taichung, Taiwan h Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan i Rong-Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 17 March 2014
Objective: To study clinical factors predicting the absence of endocervical/transformation zone (EC/TZ) components of conventional cervical Papanicolaou (Pap) smears. Materials and methods: The medical charts of patients who received Pap smears between March 2006 and August 2006 in the hospital were reviewed. The results of their Pap smears were retrieved while their demographic and clinical information were obtained from the medical charts. After excluding 378 cases with incomplete demographic data and 1397 cases with a history of pelvic irradiation, pelvic malignancy, and hysterectomy, 5662 cases were enrolled for data analysis. The relationship between clinical parameters and the absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests. Results: The incidence of satisfactory but absence of EC/TZ component was 8.7% (491/5662). Pregnancy increased the absence of EC/TZ component [odds ratio (OR}: 2.84, 95% confidence interval (CI): 2.14e3.77, p < 0.0001]. Postpartum status and endocervical polyps decreased incidence (OR: 0.61, 95% CI: 0.38e0.98, p ¼ 0.043 and OR: 0.33, 95% CI: 0.25e0.44, p < 0.0001, respectively). Conclusions: Pregnancy is the only clinical factor associated with increased incidence of absence of EC/TZ cells. For these pregnant women undergoing a Pap smear, a more effective strategy may be needed to get a satisfactory smear with adequate EC/TZ components. Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Keywords: endocervical cell endocervical polyp Papanicolaou smear transformation zone
Introduction In the 1988 Bethesda System, specimen adequacy of a Papanicolaou (Pap) smear includes one category called less than optimal, which indicates that the smear provides useful diagnostic * Corresponding author. Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, 160 Chung-Kang Road Section 3, Taichung City 40705, Taiwan. E-mail address: [email protected] (C.-H. Lu).
information but is less than optimal due to obscurity caused by inflammation, absence of endocervical cells, endocervical mucus, or squamous metaplastic cells [1]. The terminology has since been revised to satisfactory for evaluation but limited by in the 1991 Bethesda system [2]. In the 2001 Bethesda system, the terminology is eliminated and replaced by presence or absence of endocervical or transformation zone [EC/TZ] components or other quality indicators such as partially obscuring blood or inflammation [3]. From the report of the Cervical Cancer Screening Registration System of the Health Promotion Administration, Ministry of Health and Welfare,
http://dx.doi.org/10.1016/j.tjog.2014.03.015 1028-4559/Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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L. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 81e84
Taiwan, 25.6% of all Pap smears were less than satisfactory [4], including 35.9% that were due to the absence of EC/TZ cells. This means that 9.2% of all Pap smears are satisfactory but without EC/TZ cells. Thus, this issue has a significant impact on a large portion of the population who receive Pap smear examinations and to physicians who take the smears. The absence of EC/TZ components was initially found to decrease the sensitivity of detecting epithelial abnormalities and even cervical cancers [5e8]. Later studies that used better study designs and even larger populations failed to establish an association between the lack of endocervical cells and the increased incidence of high-grade diseases or cervical cancers [9,10]. There are currently no randomized trials or meta-analyses on this issue [11]. For patients with a negative smear and absence of EC/TZ components, the American Society for Colposcopy and Cervical Pathology suggests repeat Pap smear in 12 months. In cases with a history of minor cervical abnormalities or inadequate smear history or procedures, repeat smear within 6 months is beneficial [12]. The impact of the absence of endocervical cells is immense to both patients and doctors. However, the clinical conditions associated with absence of EC/TZ cells have never been studied. Therefore, this retrospective study was designed to explore the clinical conditions associated with absence of EC/TZ cells. Materials and methods The materials and methods used here had been published in previous studies [13,14]. The Institutional Review Board of Taichung Veterans General Hospital approved the study. Patients who received conventional Pap smears between March 2006 and August 2006 were enrolled. The results of their Pap smear were retrieved from the Department of Pathology and Laboratory Medicine. Their demographic and clinical information were obtained from their medical charts, as recorded by the attending physicians who took the Pap smears. In terms of the whole procedure of Pap smear examination, the cervical smears were taken with Ayre's spatulas, endocervical cytobrushes, or a combination with attempts to scrub the whole transformation zone. Findings of pelvic examination were also recorded. The smears were fixed in separate bottles of 95% alcohol for fixation, stained using the Papanicolaou technique, screened by qualified cytotechnologists under light microscopy, and then rescreened by a cytopathologist before the formal reports. In the study period, 7437 Pap smears were taken. After excluding 378 cases due to incomplete demographic data, 7059 cases were included. Their data on history of pelvic malignancy (excluding microinvasive carcinoma of cervix), systemic chemotherapy, pelvic irradiation, cervical conization (including cold knife cone, loop electro-surgical excision procedure, and needle cone), hysterectomy (total abdominal hysterectomy, total vaginal hysterectomy, laparoscopic-assisted vaginal hysterectomy, modified radical hysterectomy, and radical hysterectomy), pregnancy, within 3 months postpartum (>20 gestational weeks), vaginal bleeding or spotting, abnormal vaginal discharge (suggestive of infection or foreign body reaction), intrauterine device, and endocervical polyps were obtained. After further excluding 1397 cases with a history of either pelvic irradiation, systemic chemotherapy, pelvic malignancy, or hysterectomy [13], 5662 cases were enrolled for data analysis. The relationship between clinical parameters with satisfactory but absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests for significance analysis. Statistical significance was set at p 0.05. Data were analyzed using SPSS software (SPSS for Windows, version 12.0; SPSS Inc., Chicago, IL, USA).
Results Some detailed demographic characteristics and quality and results of the Pap smears of the cohort were published before and the parts relevant to this study summarized [13,14]. The median age of the cohort was 44.5 years (range, 15e93 years). Median gravidity was 2.7 (range, 0e15), and median parity was 1.9 (range, 0e12). Of the 5662 patients enrolled in final analysis, specimen adequacy was satisfactory in 4919 (86.9%), satisfactory but absence of EC/TZ component in 491 (8.7%), and unsatisfactory for evaluation in 252 (4.5%). The incidence of abnormal Pap smears equals to or greater than atypical cells was 4.53%. On an attempt to explore the clinical factors by univariate analysis, only pregnancy was associated with increased incidence of satisfactory but absence of EC/TZ component (Table 1). Among the 304 pregnant women who received Pap smears in the hospital, 78 (25.6%) had satisfactory but absence of EC/TZ component. By contrast, age > 50 years and menopause were associated with lower incidence of absence of EC/TZ component. When these parameters were further analyzed by multivariate binary logistic regression test, pregnancy was found to be significantly associated with more satisfactory but absence of EC/TZ component [odds ratio (OR): 2.84, 95% confidence interval (CI): 2.143.77, p < 0.0001; Table 2]. However, within 3 months postpartum and the presence of endocervical polyps were associated with a lower incidence (OR: 0.61, 95% CI: 0.38e0.98, p ¼ 0.043; and OR: 0.33, 95% CI: 0.25e0.44, p < 0.0001, respectively; Table 2). Discussion Given the proportion of absence of EC/TZ component in a large population receiving Pap smears, correct management must be reemphasized [4]. According to the American Society for Colposcopy and Cervical Pathology guidelines [15], women with a routine Pap Table 1 Predictive factors for satisfactory but absence of endocervical/transformation component by univariate analysis. Variables Age 50 y < 50 y Menopause Yes No S/p Conization Yes No Pregnancy Yes No Within 3 mo PP Yes No Vaginal bleeding Yes No Abnormal discharge Yes No IUD insertion Yes No Endocervical polyps Yes No
Absence (n)
Reference (n)
64 (3.8) 427 (11.5)
1618 (96.2) 3301 (88.5)
37 (2.6) 454 (11.4)
1397 (97.4) 3522 (88.6)
26 (6.5) 465 (9.3)
371 (93.5) 4548 (90.7)
78 (25.7) 413 (8.1)
226 (74.3) 4693 (91.9)
19 (7.0) 472 (9.2)
254 (93.0) 4665 (90.8)
32 (10.1) 459 (9.0)
286 (89.9) 4633 (91.0)
36 (8.1) 455 (9.2)
408 (91.9) 4511 (90.8)
16 (9.8) 75 (9.1)
148 (90.2) 4771 (90.9)
4 (3.8) 487 (9.2)
102 (96.2) 4817 (90.8)
p < 0.0001
< 0.0001
0.084
< 0.0001
0.254
0.595
0.513
0.865
0.080
PP ¼ postpartum; Absence ¼ satisfactory Pap smear but absence of endocervical/ transformation zone component; N ¼ number; Reference ¼ satisfactory Pap smear, including clear demonstration of endocervical/transformation zone component.
L. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 81e84 Table 2 Relationship between clinical factors with satisfactory but absence of endocervical/ transformation zone component, by multivariate binary analysis. Variables
OR (95% CI)
p
Age 50 y S/p conization Pregnancy Within 3-month postpartum Vaginal bleeding Abnormal discharge IUD insertion Endocervical polyps
0.42 0.71 2.84 0.61 1.09 0.84 1.05 0.33
0.090 0.103 < 0.0001 0.043 0.652 0.340 0.858 < 0.0001
(0.15e1.15) (0.47e1.07) (2.14e3.77) (0.38e0.98) (0.74e1.61) (0.59e1.20) (0.62e1.79) (0.25e0.44)
95% CI ¼ 95% confidence interval; IUD ¼ intrauterine device; OR ¼ odds ratio; S/p ¼ post status.
smear with absence of EC/TZ component should have yearly followup. Early follow-up at 6-month intervals may be beneficial to women with certain conditions, which include previous abnormal squamous or glandular abnormalities, positive high-risk human papilloma virus tests, inadequate screening history and sampling process, and repeated, obscuring factors causing the absence of EZ/TZ components. Although recent retrospective studies reveal no association between the lack of EC/TZ components and increased incidence of high-grade disease or cervical cancer [9,10], whether this condition will cause false negatives in the screening for glandular dysplasia or adenocarcinoma is another concern [16]. In a longitudinal analysis of Pap smear results using statewide database at 36-month intervals in Australia, Mitchell [10] found six cases of adenocarcinoma or adenocarcinoma in situ in the cohort with two Pap smear both with presence of EC/TZ cells and four cases of adenocarcinoma or adenocarcinoma in situ in the cohort with absence and presence of EC/TZ. One case of adenocarcinoma was diagnosed in the presence/ absence cohort, but none in the absence/absence cohort. Although there was insufficient statistical power due to the scarcity of cases in the cohort, there was a trend that the presence of EC/TZ cells helped screen out glandular abnormalities. Most glandular lesions arise from the columnar (endocervical) portion of the cervical epithelium. Theoretically, the inability to collect EC/TZ cells may decrease the sensitivity for detecting glandular abnormalities. This may be a potential loophole in population screening programs for cervical cancer prevention. From data of countries that provide population screening, the incidence of squamous cell carcinoma of the cervix is decreased by nearly 70% after 30e50 years of cervical cytology screening [17e20]. However, from reports of different countries, the incidence of adenocarcinoma and adenosquamous carcinoma has reached a plateau or is still increasing [20e23]. This disparity may be partly due to the lower sensitivity in detecting glandular abnormalities than squamous abnormalities [24]. Failure to collect EC/TZ cells due to technical or instrument problems may also play a role in lowering sensitivity. From this viewpoint, collecting EC/TZ cells during cervical sampling is still strongly recommended. Under the influence of large amounts of estrogen and progesterone during pregnancy, the cervix undergoes numerous and variable physiologic changes. However, tissue edema, copious mucus production, frequent inflammation, and confusing decidual cells often complicate the sampling and interpretation of cytology in pregnancy [25]. Although pregnancy induces cervical ectropion that represents eversion of the squamocolumnar junction, pregnancy is associated with the lack of endocervical cells on cervicovaginal cytology. Kruger et al reported that endocervical cell recovery rate was lower during pregnancy than during nonpregnancy (60e65% vs. 85%) [26]. Kost et al had similar findings [27]. Thus, strategies should be developed to collect more endocervical cells during Pap smears in pregnant women.
83
Paraiso et al. reported increased endocervical yield with both the cytobrush and modified Ayers spatula (90.7%) and the CervexBrush (83.3%) methods, compared to the cotton swab and modified Ayre's spatula (70.8%) in pregnant women [28]. Stillson and Knight also found that cytobrushespatula yielded more endocervical cell during pregnancy [29]. The explanation for the lower EC/TZ component collection during pregnancy is the thick tenacious cervical mucus barriers during pregnancy. Another explanation is the lesser cytobrush use, with the assumption that the collection device will increase the rate of premature rupture of membrane and the spatula itself is enough for cervical epithelial cell collection. Based on the characteristics of the retrospective study, all of them need further confirmation and the strategy can be used to increase EC/TZ component collection in the satisfactory Pap smear. After placental expulsion and hormonal withdrawal, the cervical ectropion is usually not regressed, but the cervical mucosa is atropic [30]. The relationship between specimen adequacy and postpartum status has not been previously studied. The absence of EC/TZ component occurs significantly less among postpartum women in this study, which can be explained by the grossly ectropic cervix but no coating mucus as seen in pregnancy. This facilitates EC/TZ cell collection. Endocervical polyps are a focal hyperplasia of the glandular epithelium of the endocervix that contains a glandular structure with a fibrous core [31]. The relationship between endocervical polyps and the adequacy of Pap smear has not been previously studied. This study shows that the presence of endocervical polyp(s) significantly decreases the incidence of absence of EC/TZ cells (relative risk 0.33). This can be explained by the nature and causes of endocervical polyps, which are hyperplasia of endocervical glands. Thus, obtaining endocervical cells is easier. Aging and conization may both cause synechiae and even cervical stenosis. It may be expected that these conditions will increase the incidence of absence of EC/TZ component [32,33]. However, from this research, age 50 years and conization are both associated with less absence of EC/TZ component, although this was not statistically significant. This may be due to the retrospective data analysis. The sampling devices used are chosen by the attending physicians for the purpose to collect cervical cytology with the best quality. These well-trained specialists are more familiar with the anatomic limitations of the cervix and will preferentially use a cytobrush instead of a spatula in cervical cell sampling. Thus, the incidence of absence of EC/TZ component is decreased compared to the entire cohort. This study is limited by the relatively low incidence of satisfactory but absence of EC/TZ component smears. This limitation can be compensated by the use of multivariate logistic regression test. The bias of tertiary medical center-based study may also be counteracted by the methods of analysis. Limitations also come from the nature of retrospective cross-sectional studies. Potential bias may come from collection devices used and judgment of vaginal discharge and vaginal bleeding. Medical chart record as the source of data is another potential cause of bias. Such biases can be partially attenuated by the fact that Pap smears are routinely taken by experienced attending physicians, who also made the medical records. Conflicts of interest All authors have no conflicts of interest to declare. Acknowledgments Biostatistics Task Force of Taichung Veterans General Hospital.
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Funding This study was supported by the grants from TCVGH-1016402B, TCVGH- NCNU1027906 (to CH Lu), NSC 102-2314-B-010-032, Taipei VGH- V103A-016; Taipei VGH-V103C-112, and Taipei VGH-V103E4003 (to PH Wang). References [1] The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 1989;262:931e4. [2] Broder S. Rapid Communication - The Bethesda System for Reporting Cervical/ Vaginal Cytologic Diagnoses - Report of the 1991 Bethesda Workshop. JAMA 1892;1992:267. [3] Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114e9. [4] Cervical Cancer Screening Registration System. 2010. http://www.hpa.gov.tw/ BHPNet/Web/Stat/StatisticsShow.aspx?No¼201003110001 [Accessed Jan. 19 2014]. [5] Woodman CB, Williams D, Yates M, Tomlinson K, Ward K. Indicators of effective cytological sampling of the uterine cervix. Lancet 1989;334:88e90. [6] Mauney M, Eide D, Sotham J. Rates of condyloma and dysplasia in Papanicolaou smears with and without endocervical cells. Diagn Cytopathol 1990;6:18e21. [7] Robertson JH, Woodend B. Negative cytology preceding cervical cancer: causes and prevention. J Clin Pathol 1993;46:700e2. [8] Ribeiro AA, Santos Sdo C, de Souza e Silva SRR, Nascimento MA, FonsechiCarvasan GA, Carneiro MA, et al. Endocervical component in conventional cervical smears: influence on detection of squamous cytologic abnormalities. Diagn Cytopathol 2007;35:209e12. [9] Mitchell H, Medley G. Longitudinal study of women with negative cervical smears according to endocervical status. Lancet 1991;337:265e7. [10] Mitchell H. Longitudinal analysis of histologic high-grade disease after negative cervical cytology according to endocervical status. Cancer 2001;93:237e40. [11] Elumir-Tanner LM, Doraty M, Southern Alberta Primary Care Research Network (SAPCReN). Management of Papanicolaou test results that lack endocervical cells. CMAJ 2011;183:563e8. [12] Davey DD, Austin RM, Birdsong G, Buck HW, Cox JT, Darragh TM, et al. ASCCP patient management guidelines: Pap test specimen adequacy and quality indicators. Am J Clin Path 2002;118:714e8. [13] Lu CH, Chang CC, Ho ES, Chen SJ, Lin SJ, Fu TF, et al. Should adequacy criteria in cervico-vaginal cytology be modified after radiotherapy, chemotherapy, or hysterectomy? Cancer Cytopathol 2010;118:474e81. [14] Lu CH, Chang CC, Chang MC, Chen SJ, Jan YJ, Fu TF, et al. Clinical parameters associated with unsatisfactory specimens of conventional cervical smears. Diagn Cytopathol 2011;39:87e91. [15] Davey DD, Cox JT, Austin RM, Birdsong G, Colgan TJ, Howell LP, et al. Cervical cytology specimen adequacy: patient management guidelines and optimizing specimen collection. J Low Genit Tract Dis 2008;12:71e81.
[16] Birdsong GG. Pap smear adequacy: is our understanding satisfactory... or limited? Diagn Cytopathol 2001;24:79e81. [17] Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. BMJ 1999;318:904e8. [18] Willoughby BJ, Faulkner K, Stamp EC, Whitaker CJ. A descriptive study of the decline in cervical screening coverage rates in the North East and Yorkshire and the Humber Regions of the UK from 1995 to 2005. J Public Health 2006;28:355e60. [19] SEER Stat Fact Sheets: Cervix Uteri Cancer. 1992e2010. http://seer.cancer.gov/ statfacts/html/cervix.html [Accessed Feb. 5th, 2014]. [20] Cancer registration annual report, Taiwan. 2010. http://www.hpa.gov.tw/ BHPNet/Portal/File/StatisticsFile/201305061037065219/99%e5%b9%b4%e7%99% 8c%e7%97%87%e7%99%bb%e8%a8%98%e5%a0%b1%e5%91%8a.pdf [Accessed Feb. 3rd, 2014]. ~ oz N, Barros-Dios XM, Parkin DM. In[21] Vizcaino AP, Moreno V, Bosch FX, Mun ternational trends in the incidence of cervical cancer: I. Adenocarcinoma and adeno-squamous cell carcinomas. Int J Cancer 1998;75:536e45. [22] Oh CM, Jung KW, Won YJ, Shin A, Kong HJ, Jun JK, et al. Trends in the incidence of in situ and invasive cervical cancer by age group and histological type in Korea from 1993 to 2009. PLoS One 2013;8:e72012. [23] Kjaer SK, Brinton LA. Adenocarcinomas of the uterine cervix: the epidemiology of an increasing problem. Epidemiol Rev 1993;15:486e98. [24] Ruba S, Schoolland M, Allpress GS, Sterrett G. Adenocarcinoma in situ of the uterine cervix: screening and diagnostic errors in Papanicolaou smears. Cancer 2004;102:280e7. [25] Michael CW, Esfahani FM. Pregnancy-related changes: a retrospective review of 278 cervical smears. Diagn Cytopathol 1997;17:99e107. [26] Kruger J, Dunton CJ, Sewell EC, Cardonick E. Randomized pilot study comparing rates of endocervical cell recovery between conventional pap smears and liquid-based cytology in a pregnant population. J Low Genit Tract Dis 2003;7:101e3. [27] Kost ER, Snyder RR, Schwartz LE, Hankins GD. The “less than optimal” cytology: importance in obstetric patients and in a routine gynecologic population. Obstet Gynecol 1993;81:127e30. [28] Paraiso MF, Brady K, Helmchen R, Roat TW. Evaluation of the endocervical Cytobrush and Cervex-Brush in pregnant women. Obstet Gynecol 1994;84: 539e43. [29] Stillson T, Knight AL, Elswick Jr RK. The effectiveness and safety of two cervical cytologic techniques during pregnancy. J Fam Pract 1997;45:159e63. [30] Tambouret RH, Wilbur DC. The many faces of atrophy in gynecologic cytology. Clin Lab Med 2003;23:659e79. [31] Stamatellos I, Stamatopoulos P, Bontis J. The role of hysteroscopy in the current management of the cervical polyps. Arch Gynecol Obstet 2007;276: 299e303. [32] Dunn TS, Landry E, Ring C, Martin C. Absent endocervical cells on pap smears after loop electrosurgical excision procedure. J Low Genit Tract Dis 2007;11: 138e40. [33] Boulanger JC, Gondry J, Verhoest P, Capsie C, Najas S. Treatment of CIN after menopause. Eur J Obstet Gynecol Reprod Biol 2001;95:175e80.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Clinical parameters associated with absence of endocervical/transformation zone component in conventional cervical Papanicolaou smears Lou Sun a, Peng-Hui Wang b, c, d, Chen-Hui Lee e, Tsai-Feng Fu f, Min-Min Chou a, Sheau-Feng Hwang a, Yu-Min Ke a, Shih-Tien Hsu a, g, Chien-Hsing Lu a, c, e, h, i, * a
Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, Taichung, Taiwan Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan Department of Obstetrics and Gynecology, National Yang-Ming University School of Medicine, Taipei, Taiwan d Department of Medical Research, China Medical University Hospital, Taichung, Taiwan e Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan f Graduate Institute of Biomedicine and Biomedical Technology, National Chi Nan University, Nantou County, Taiwan g School of Medicine, China Medical University, Taichung, Taiwan h Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan i Rong-Hsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan b c
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 17 March 2014
Objective: To study clinical factors predicting the absence of endocervical/transformation zone (EC/TZ) components of conventional cervical Papanicolaou (Pap) smears. Materials and methods: The medical charts of patients who received Pap smears between March 2006 and August 2006 in the hospital were reviewed. The results of their Pap smears were retrieved while their demographic and clinical information were obtained from the medical charts. After excluding 378 cases with incomplete demographic data and 1397 cases with a history of pelvic irradiation, pelvic malignancy, and hysterectomy, 5662 cases were enrolled for data analysis. The relationship between clinical parameters and the absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests. Results: The incidence of satisfactory but absence of EC/TZ component was 8.7% (491/5662). Pregnancy increased the absence of EC/TZ component [odds ratio (OR}: 2.84, 95% confidence interval (CI): 2.14e3.77, p < 0.0001]. Postpartum status and endocervical polyps decreased incidence (OR: 0.61, 95% CI: 0.38e0.98, p ¼ 0.043 and OR: 0.33, 95% CI: 0.25e0.44, p < 0.0001, respectively). Conclusions: Pregnancy is the only clinical factor associated with increased incidence of absence of EC/TZ cells. For these pregnant women undergoing a Pap smear, a more effective strategy may be needed to get a satisfactory smear with adequate EC/TZ components. Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).
Keywords: endocervical cell endocervical polyp Papanicolaou smear transformation zone
Introduction In the 1988 Bethesda System, specimen adequacy of a Papanicolaou (Pap) smear includes one category called less than optimal, which indicates that the smear provides useful diagnostic * Corresponding author. Department of Obstetrics and Gynecology, Taichung Veterans General Hospital, 160 Chung-Kang Road Section 3, Taichung City 40705, Taiwan. E-mail address: [email protected] (C.-H. Lu).
information but is less than optimal due to obscurity caused by inflammation, absence of endocervical cells, endocervical mucus, or squamous metaplastic cells [1]. The terminology has since been revised to satisfactory for evaluation but limited by in the 1991 Bethesda system [2]. In the 2001 Bethesda system, the terminology is eliminated and replaced by presence or absence of endocervical or transformation zone [EC/TZ] components or other quality indicators such as partially obscuring blood or inflammation [3]. From the report of the Cervical Cancer Screening Registration System of the Health Promotion Administration, Ministry of Health and Welfare,
http://dx.doi.org/10.1016/j.tjog.2014.03.015 1028-4559/Copyright © 2016, Taiwan Association of Obstetrics & Gynecology. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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L. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 81e84
Taiwan, 25.6% of all Pap smears were less than satisfactory [4], including 35.9% that were due to the absence of EC/TZ cells. This means that 9.2% of all Pap smears are satisfactory but without EC/TZ cells. Thus, this issue has a significant impact on a large portion of the population who receive Pap smear examinations and to physicians who take the smears. The absence of EC/TZ components was initially found to decrease the sensitivity of detecting epithelial abnormalities and even cervical cancers [5e8]. Later studies that used better study designs and even larger populations failed to establish an association between the lack of endocervical cells and the increased incidence of high-grade diseases or cervical cancers [9,10]. There are currently no randomized trials or meta-analyses on this issue [11]. For patients with a negative smear and absence of EC/TZ components, the American Society for Colposcopy and Cervical Pathology suggests repeat Pap smear in 12 months. In cases with a history of minor cervical abnormalities or inadequate smear history or procedures, repeat smear within 6 months is beneficial [12]. The impact of the absence of endocervical cells is immense to both patients and doctors. However, the clinical conditions associated with absence of EC/TZ cells have never been studied. Therefore, this retrospective study was designed to explore the clinical conditions associated with absence of EC/TZ cells. Materials and methods The materials and methods used here had been published in previous studies [13,14]. The Institutional Review Board of Taichung Veterans General Hospital approved the study. Patients who received conventional Pap smears between March 2006 and August 2006 were enrolled. The results of their Pap smear were retrieved from the Department of Pathology and Laboratory Medicine. Their demographic and clinical information were obtained from their medical charts, as recorded by the attending physicians who took the Pap smears. In terms of the whole procedure of Pap smear examination, the cervical smears were taken with Ayre's spatulas, endocervical cytobrushes, or a combination with attempts to scrub the whole transformation zone. Findings of pelvic examination were also recorded. The smears were fixed in separate bottles of 95% alcohol for fixation, stained using the Papanicolaou technique, screened by qualified cytotechnologists under light microscopy, and then rescreened by a cytopathologist before the formal reports. In the study period, 7437 Pap smears were taken. After excluding 378 cases due to incomplete demographic data, 7059 cases were included. Their data on history of pelvic malignancy (excluding microinvasive carcinoma of cervix), systemic chemotherapy, pelvic irradiation, cervical conization (including cold knife cone, loop electro-surgical excision procedure, and needle cone), hysterectomy (total abdominal hysterectomy, total vaginal hysterectomy, laparoscopic-assisted vaginal hysterectomy, modified radical hysterectomy, and radical hysterectomy), pregnancy, within 3 months postpartum (>20 gestational weeks), vaginal bleeding or spotting, abnormal vaginal discharge (suggestive of infection or foreign body reaction), intrauterine device, and endocervical polyps were obtained. After further excluding 1397 cases with a history of either pelvic irradiation, systemic chemotherapy, pelvic malignancy, or hysterectomy [13], 5662 cases were enrolled for data analysis. The relationship between clinical parameters with satisfactory but absence of EC/TZ component was analyzed by Pearson Chi-square tests with Yates continuity correction and binary logistic regression tests for significance analysis. Statistical significance was set at p 0.05. Data were analyzed using SPSS software (SPSS for Windows, version 12.0; SPSS Inc., Chicago, IL, USA).
Results Some detailed demographic characteristics and quality and results of the Pap smears of the cohort were published before and the parts relevant to this study summarized [13,14]. The median age of the cohort was 44.5 years (range, 15e93 years). Median gravidity was 2.7 (range, 0e15), and median parity was 1.9 (range, 0e12). Of the 5662 patients enrolled in final analysis, specimen adequacy was satisfactory in 4919 (86.9%), satisfactory but absence of EC/TZ component in 491 (8.7%), and unsatisfactory for evaluation in 252 (4.5%). The incidence of abnormal Pap smears equals to or greater than atypical cells was 4.53%. On an attempt to explore the clinical factors by univariate analysis, only pregnancy was associated with increased incidence of satisfactory but absence of EC/TZ component (Table 1). Among the 304 pregnant women who received Pap smears in the hospital, 78 (25.6%) had satisfactory but absence of EC/TZ component. By contrast, age > 50 years and menopause were associated with lower incidence of absence of EC/TZ component. When these parameters were further analyzed by multivariate binary logistic regression test, pregnancy was found to be significantly associated with more satisfactory but absence of EC/TZ component [odds ratio (OR): 2.84, 95% confidence interval (CI): 2.143.77, p < 0.0001; Table 2]. However, within 3 months postpartum and the presence of endocervical polyps were associated with a lower incidence (OR: 0.61, 95% CI: 0.38e0.98, p ¼ 0.043; and OR: 0.33, 95% CI: 0.25e0.44, p < 0.0001, respectively; Table 2). Discussion Given the proportion of absence of EC/TZ component in a large population receiving Pap smears, correct management must be reemphasized [4]. According to the American Society for Colposcopy and Cervical Pathology guidelines [15], women with a routine Pap Table 1 Predictive factors for satisfactory but absence of endocervical/transformation component by univariate analysis. Variables Age 50 y < 50 y Menopause Yes No S/p Conization Yes No Pregnancy Yes No Within 3 mo PP Yes No Vaginal bleeding Yes No Abnormal discharge Yes No IUD insertion Yes No Endocervical polyps Yes No
Absence (n)
Reference (n)
64 (3.8) 427 (11.5)
1618 (96.2) 3301 (88.5)
37 (2.6) 454 (11.4)
1397 (97.4) 3522 (88.6)
26 (6.5) 465 (9.3)
371 (93.5) 4548 (90.7)
78 (25.7) 413 (8.1)
226 (74.3) 4693 (91.9)
19 (7.0) 472 (9.2)
254 (93.0) 4665 (90.8)
32 (10.1) 459 (9.0)
286 (89.9) 4633 (91.0)
36 (8.1) 455 (9.2)
408 (91.9) 4511 (90.8)
16 (9.8) 75 (9.1)
148 (90.2) 4771 (90.9)
4 (3.8) 487 (9.2)
102 (96.2) 4817 (90.8)
p < 0.0001
< 0.0001
0.084
< 0.0001
0.254
0.595
0.513
0.865
0.080
PP ¼ postpartum; Absence ¼ satisfactory Pap smear but absence of endocervical/ transformation zone component; N ¼ number; Reference ¼ satisfactory Pap smear, including clear demonstration of endocervical/transformation zone component.
L. Sun et al. / Taiwanese Journal of Obstetrics & Gynecology 55 (2016) 81e84 Table 2 Relationship between clinical factors with satisfactory but absence of endocervical/ transformation zone component, by multivariate binary analysis. Variables
OR (95% CI)
p
Age 50 y S/p conization Pregnancy Within 3-month postpartum Vaginal bleeding Abnormal discharge IUD insertion Endocervical polyps
0.42 0.71 2.84 0.61 1.09 0.84 1.05 0.33
0.090 0.103 < 0.0001 0.043 0.652 0.340 0.858 < 0.0001
(0.15e1.15) (0.47e1.07) (2.14e3.77) (0.38e0.98) (0.74e1.61) (0.59e1.20) (0.62e1.79) (0.25e0.44)
95% CI ¼ 95% confidence interval; IUD ¼ intrauterine device; OR ¼ odds ratio; S/p ¼ post status.
smear with absence of EC/TZ component should have yearly followup. Early follow-up at 6-month intervals may be beneficial to women with certain conditions, which include previous abnormal squamous or glandular abnormalities, positive high-risk human papilloma virus tests, inadequate screening history and sampling process, and repeated, obscuring factors causing the absence of EZ/TZ components. Although recent retrospective studies reveal no association between the lack of EC/TZ components and increased incidence of high-grade disease or cervical cancer [9,10], whether this condition will cause false negatives in the screening for glandular dysplasia or adenocarcinoma is another concern [16]. In a longitudinal analysis of Pap smear results using statewide database at 36-month intervals in Australia, Mitchell [10] found six cases of adenocarcinoma or adenocarcinoma in situ in the cohort with two Pap smear both with presence of EC/TZ cells and four cases of adenocarcinoma or adenocarcinoma in situ in the cohort with absence and presence of EC/TZ. One case of adenocarcinoma was diagnosed in the presence/ absence cohort, but none in the absence/absence cohort. Although there was insufficient statistical power due to the scarcity of cases in the cohort, there was a trend that the presence of EC/TZ cells helped screen out glandular abnormalities. Most glandular lesions arise from the columnar (endocervical) portion of the cervical epithelium. Theoretically, the inability to collect EC/TZ cells may decrease the sensitivity for detecting glandular abnormalities. This may be a potential loophole in population screening programs for cervical cancer prevention. From data of countries that provide population screening, the incidence of squamous cell carcinoma of the cervix is decreased by nearly 70% after 30e50 years of cervical cytology screening [17e20]. However, from reports of different countries, the incidence of adenocarcinoma and adenosquamous carcinoma has reached a plateau or is still increasing [20e23]. This disparity may be partly due to the lower sensitivity in detecting glandular abnormalities than squamous abnormalities [24]. Failure to collect EC/TZ cells due to technical or instrument problems may also play a role in lowering sensitivity. From this viewpoint, collecting EC/TZ cells during cervical sampling is still strongly recommended. Under the influence of large amounts of estrogen and progesterone during pregnancy, the cervix undergoes numerous and variable physiologic changes. However, tissue edema, copious mucus production, frequent inflammation, and confusing decidual cells often complicate the sampling and interpretation of cytology in pregnancy [25]. Although pregnancy induces cervical ectropion that represents eversion of the squamocolumnar junction, pregnancy is associated with the lack of endocervical cells on cervicovaginal cytology. Kruger et al reported that endocervical cell recovery rate was lower during pregnancy than during nonpregnancy (60e65% vs. 85%) [26]. Kost et al had similar findings [27]. Thus, strategies should be developed to collect more endocervical cells during Pap smears in pregnant women.
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Paraiso et al. reported increased endocervical yield with both the cytobrush and modified Ayers spatula (90.7%) and the CervexBrush (83.3%) methods, compared to the cotton swab and modified Ayre's spatula (70.8%) in pregnant women [28]. Stillson and Knight also found that cytobrushespatula yielded more endocervical cell during pregnancy [29]. The explanation for the lower EC/TZ component collection during pregnancy is the thick tenacious cervical mucus barriers during pregnancy. Another explanation is the lesser cytobrush use, with the assumption that the collection device will increase the rate of premature rupture of membrane and the spatula itself is enough for cervical epithelial cell collection. Based on the characteristics of the retrospective study, all of them need further confirmation and the strategy can be used to increase EC/TZ component collection in the satisfactory Pap smear. After placental expulsion and hormonal withdrawal, the cervical ectropion is usually not regressed, but the cervical mucosa is atropic [30]. The relationship between specimen adequacy and postpartum status has not been previously studied. The absence of EC/TZ component occurs significantly less among postpartum women in this study, which can be explained by the grossly ectropic cervix but no coating mucus as seen in pregnancy. This facilitates EC/TZ cell collection. Endocervical polyps are a focal hyperplasia of the glandular epithelium of the endocervix that contains a glandular structure with a fibrous core [31]. The relationship between endocervical polyps and the adequacy of Pap smear has not been previously studied. This study shows that the presence of endocervical polyp(s) significantly decreases the incidence of absence of EC/TZ cells (relative risk 0.33). This can be explained by the nature and causes of endocervical polyps, which are hyperplasia of endocervical glands. Thus, obtaining endocervical cells is easier. Aging and conization may both cause synechiae and even cervical stenosis. It may be expected that these conditions will increase the incidence of absence of EC/TZ component [32,33]. However, from this research, age 50 years and conization are both associated with less absence of EC/TZ component, although this was not statistically significant. This may be due to the retrospective data analysis. The sampling devices used are chosen by the attending physicians for the purpose to collect cervical cytology with the best quality. These well-trained specialists are more familiar with the anatomic limitations of the cervix and will preferentially use a cytobrush instead of a spatula in cervical cell sampling. Thus, the incidence of absence of EC/TZ component is decreased compared to the entire cohort. This study is limited by the relatively low incidence of satisfactory but absence of EC/TZ component smears. This limitation can be compensated by the use of multivariate logistic regression test. The bias of tertiary medical center-based study may also be counteracted by the methods of analysis. Limitations also come from the nature of retrospective cross-sectional studies. Potential bias may come from collection devices used and judgment of vaginal discharge and vaginal bleeding. Medical chart record as the source of data is another potential cause of bias. Such biases can be partially attenuated by the fact that Pap smears are routinely taken by experienced attending physicians, who also made the medical records. Conflicts of interest All authors have no conflicts of interest to declare. Acknowledgments Biostatistics Task Force of Taichung Veterans General Hospital.
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Funding This study was supported by the grants from TCVGH-1016402B, TCVGH- NCNU1027906 (to CH Lu), NSC 102-2314-B-010-032, Taipei VGH- V103A-016; Taipei VGH-V103C-112, and Taipei VGH-V103E4003 (to PH Wang). References [1] The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 1989;262:931e4. [2] Broder S. Rapid Communication - The Bethesda System for Reporting Cervical/ Vaginal Cytologic Diagnoses - Report of the 1991 Bethesda Workshop. JAMA 1892;1992:267. [3] Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002;287:2114e9. [4] Cervical Cancer Screening Registration System. 2010. http://www.hpa.gov.tw/ BHPNet/Web/Stat/StatisticsShow.aspx?No¼201003110001 [Accessed Jan. 19 2014]. [5] Woodman CB, Williams D, Yates M, Tomlinson K, Ward K. Indicators of effective cytological sampling of the uterine cervix. Lancet 1989;334:88e90. [6] Mauney M, Eide D, Sotham J. Rates of condyloma and dysplasia in Papanicolaou smears with and without endocervical cells. Diagn Cytopathol 1990;6:18e21. [7] Robertson JH, Woodend B. Negative cytology preceding cervical cancer: causes and prevention. J Clin Pathol 1993;46:700e2. [8] Ribeiro AA, Santos Sdo C, de Souza e Silva SRR, Nascimento MA, FonsechiCarvasan GA, Carneiro MA, et al. Endocervical component in conventional cervical smears: influence on detection of squamous cytologic abnormalities. Diagn Cytopathol 2007;35:209e12. [9] Mitchell H, Medley G. Longitudinal study of women with negative cervical smears according to endocervical status. Lancet 1991;337:265e7. [10] Mitchell H. Longitudinal analysis of histologic high-grade disease after negative cervical cytology according to endocervical status. Cancer 2001;93:237e40. [11] Elumir-Tanner LM, Doraty M, Southern Alberta Primary Care Research Network (SAPCReN). Management of Papanicolaou test results that lack endocervical cells. CMAJ 2011;183:563e8. [12] Davey DD, Austin RM, Birdsong G, Buck HW, Cox JT, Darragh TM, et al. ASCCP patient management guidelines: Pap test specimen adequacy and quality indicators. Am J Clin Path 2002;118:714e8. [13] Lu CH, Chang CC, Ho ES, Chen SJ, Lin SJ, Fu TF, et al. Should adequacy criteria in cervico-vaginal cytology be modified after radiotherapy, chemotherapy, or hysterectomy? Cancer Cytopathol 2010;118:474e81. [14] Lu CH, Chang CC, Chang MC, Chen SJ, Jan YJ, Fu TF, et al. Clinical parameters associated with unsatisfactory specimens of conventional cervical smears. Diagn Cytopathol 2011;39:87e91. [15] Davey DD, Cox JT, Austin RM, Birdsong G, Colgan TJ, Howell LP, et al. Cervical cytology specimen adequacy: patient management guidelines and optimizing specimen collection. J Low Genit Tract Dis 2008;12:71e81.
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