International Journal of Gynecology and Obstetrics 124 (2014) 156–159
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Prevalence of abnormal Pap smears in a consecutive and previously unscreened population in Romania Simona Stolnicu a,b,⁎, Simona Musca c, Dorian Micu d, Luminita Micu d, Cosmin Moldovan e, Lucian Puscasiu f a
Department of Pathology, University of Medicine Targu Mures, Targu Mures, Romania Histopat-Invest Laboratory, Targu Mures, Romania Citos Laboratory, Iasi, Romania d Citosan Plus Laboratory, Constanta, Romania e Department of Histology, University of Medicine Targu Mures, Targu Mures, Romania f Obstetrics and Gynecology Clinic No. 1, University of Medicine Targu Mures, Targu Mures, Romania b c
a r t i c l e
i n f o
Article history: Received 16 May 2013 Received in revised form 15 July 2013 Accepted 10 October 2013 Keywords: Abnormal cervical smears Cytology Prevalence
a b s t r a c t Objective: To determine the prevalence of abnormal cervical smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other countries in Europe. Methods: In a retrospective study, data were reviewed from smears obtained from women in Romania who had been referred to the gynecologist between January 2006 and December 2011. The smears were collected through 3 regional opportunistic programs of cervical screening and were classified according to the Bethesda system. Results: During the study period, 50 536 smear tests were carried out. Of these, 100 smears (0.2%) were unsatisfactory and excluded from the study. Among the remaining 50 436 smears, 2965 patients (5.9%) had abnormal epithelial changes. Most of the abnormal smears were represented by atypical squamous cells of undetermined significance (2.6% of all smears). The data confirmed that there is a high prevalence of highgrade intraepithelial squamous-type lesions (0.9% of all smears) in Romania, and of abnormal smears in women younger than 25 years of age (14.0% of all abnormal smears). Conclusion: The data show that there is a high prevalence of epithelial abnormalities among cervical smears in Romania compared with other European countries that run a national screening program. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Invasive cervical cancer and cervical intraepithelial neoplasia represent 2 very important health problems for women worldwide. Cervical cancer is a preventable tumor because the premalignant stages can be detected by exfoliative cytology; nevertheless, cervical cancer is still a major cause of death among women living in low-resource countries. Furthermore, within the European Union Romania has the highest incidence of and mortality due to cervical cancer [1,2]. Assessing cervical cytology by the Papanicolaou method (“Pap smear”) is a well-known and very effective method of screening for cervical premalignant and malignant lesions. Since the introduction of Pap smears, a marked reduction in the incidence of and mortality due to cervical cancer has been observed in countries belonging to the European Union and worldwide [3,4]. For the past 20 years, Romania has lacked a national screening program for the early detection of cervical cancer, and began to implement a program only in September 2012; in addition, except for a limited study [5], there are no official data concerning the prevalence of abnormal Pap smears in the country ⁎ Corresponding author at: Department of Pathology, University of Medicine, Str Gh. Marinescu no. 38 Targu Mures, Romania. Tel.: +40 744 765716; fax: +40 365 814950. E-mail address: [email protected] (S. Stolnicu).
before this screening program was started. Therefore, it is mandatory to assess the overall situation of epithelial cell abnormalities and the prevalence of different premalignant and malignant lesions among Pap smears in Romania in order to better develop and implement a national screening program for cervical cancer. The aim of the present study was to determine the prevalence of abnormal Pap smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other European countries where national screening programs have been established. 2. Materials and methods In a retrospective study, data were reviewed from consecutive Pap smears prepared from women who had been referred to the gynecologist for a cervical smear test between January 1, 2006, and December 31, 2011. The present analysis was deemed to be exempt from institutional review board approval by the Ethics Committee of the University of Medicine and Pharmacy Targu Mures, Romania. Informed consent was obtained from each woman. The smears were obtained through 3 regional opportunistic programs of cervical screening among asymptomatic patients. The Pap smears were collected from all over Romania and analyzed in 3 major
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.07.030
S. Stolnicu et al. / International Journal of Gynecology and Obstetrics 124 (2014) 156–159
private laboratories (Targu Mures, central Romania; Iasi, eastern Romania; and Constanta, southern Romania). All 3 centers involved agreed to participate in the study and to complete a standard report form, which was sent together with the sampled material to the regional laboratory. Only conventional cervical smears were performed. All women were instructed to abstain from douching, using antiseptic cream, internal local examination, and coitus within 24 hours of the cytologic examination. In each case, samples were taken by using a special kit for 2-smear sampling of the exocervix and endocervix via an Ayre spatula. All smears were fixed by the same method (95% ethyl alcohol) and then stained with the Pap staining technique. All smears were examined and reported by trained pathologists, in agreement with the Bethesda 2001 system [6]. In all 3 laboratories, quality control of cervical cytology was achieved by rescreening 10% of all smears. After examining the smears, the following categories were excluded from the study: normal cases (negative for intraepithelial lesion or malignancy); cases presenting benign lesions; cases in which the examination revealed unsatisfactory material; and cases where the woman had been previously diagnosed with cervical, vulvar, or vaginal carcinoma and was subject to radiotherapy and/or chemotherapy or premalignant conditions of these organs. For each smear test included in the study, the following clinical parameters were recorded: patient age, reason for gynecologic examination, personal and family history, results of previous cytologic and histopathologic examinations, and date of last menstrual period. The information obtained from the cytology final reports was recorded in Excel worksheets (Microsoft, Redmond, WA, USA). Prevalence was calculated from the number of positive cases divided by the number of specimens tested. Cytopathologic aspects of Pap smears were reviewed according to age distribution. The percentage distribution of each category of abnormal Pap smear was calculated for both abnormal Pap smears and total Pap smear tests.
3. Results During the 6-year study period, 50 536 consecutive Pap smear tests were carried out. Among these, 100 (0.2%) were unsatisfactory and were excluded from the study. Most of the unsatisfactory cases came from 2 of the 3 laboratories (Targu Mures and Constanta). Unsatisfactory smears comprised both inadequate samples and samples concealed by blood. As a result, 50 436 smear results were included in the study: 15 928 from Targu Mures, 15 796 cases from Constanta and 18 712 cases from Iasi. Table 1 shows the distribution of these cases according to year of investigation and laboratory where the diagnosis was established. Overall, 47 471 (93.9%) of all smears were normal, with atrophy or benign cellular changes owing to inflammation or reparative changes (Table 2). The remaining 2965 cases (5.9%) had abnormal epithelial changes. Of these, 1186 cases were diagnosed in Targu Mures, 977 in Constanta, and 802 in Iasi.
Table 1 Distribution of smears per year of investigation and laboratory in Romania. Year of investigation
Number of smears per laboratory Targu Mures
Constanta
Iasi
Total
2006 2007 2008 2009 2010 2011 Total
1044 2486 3052 3306 3784 2256 15 928
2681 3244 2775 2274 2562 2260 15 796
1125 2367 3480 3943 4098 3699 18712
4850 8097 9307 9523 10444 8215 50436
157
Table 2 Distribution of unsatisfactory, normal/benign and abnormal Pap smears in Romania. Cytologic aspect
Number (%) of all smears
Unsatisfactory smear Normal/benign smear Abnormal smear Total
100 (0.2) 47 471 (93.9) 2965 (5.9) 50 536 (100)
Among the 50 436 satisfactory smears, most of the abnormal smears (1339 cases) belonged to the atypical squamous cells of undetermined significance (ASC-US) category (2.6%), whereas only 489 cases (1%) belonged to the “atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesions” (ASC-H) category. Collectively, lowgrade intraepithelial squamous lesion (LSIL) and high-grade intraepithelial squamous lesion (HSIL) comprised 1.7% of all satisfactory smears: LSIL cases represented 0.8% (389 cases) and HSIL cases represented 0.9% (459 cases). Only 39 cases involved squamous carcinoma (SCC) and 24 cases involved adenocarcinoma in situ (AIS) (in both categories, less than 0.1% of cases). Atypical glandular cells (AGCs) represented only 0.4% of cases (205 cases), and less than 0.1% of cases (21 cases) had the appearance of invasive adenocarcinoma on the Pap smear (Table 3). Most abnormal Pap smears were observed among women aged 30–39 years (38.7%), followed women aged 40–49 years (20.0%) (Table 4). A significant number of cases developed among women younger than 30 years: 17.8% of abnormal smears were found for women between 25 and 29 years, and 14.0% for women younger than 24 years. Only 7.1% of abnormal smears were observed among women aged between 50 and 59 years, 1.8% among women aged between 60 and 64 years, and 0.6% among women aged over 65 years. To compare the present data from Romania to those from other countries in Europe, PubMed was searched to find recent studies on the prevalence of abnormal Pap smears in other European countries (Table 5). In 2009, a study in Turkey reported that the percentage of abnormal cytologic smears was 1.8% among 140 334 women. The various categories of lesions comprised ASC-US (1.07%), LSIL (0.3%), HSIL (0.17%), squamous carcinoma (0.08%), and AGC (0.08%) [7]. In 2009, a study in Italy on 6 276 744 satisfactory Pap smears found that 2.4% were positive for the following cytologic abnormalities: ASC-US (1.9%), LSIL (0.71%), HSIL (0.19%) and carcinoma (0.01%) [8]. In a study performed in Croatia in 2010 on 481 women, the prevalence of abnormal cytology was 7.3%. The different categories of lesions comprised ASC-US (1.87%), ASC-H (0.2%), LSIL (2.9%), HSIL (1.25%), and squamous carcinoma (0.4%) [9]. In 2011, a study in Belgium on 600 000 women found that the prevalence of abnormal
Table 3 Distribution of abnormal Pap smears categories in Romania. Category of abnormality
No. of cases
Percentage of abnormal smears
Percentage of satisfactory smears
ASC-US LSIL HSIL ASC-H SCC AIS IAC AGC Total
1339 389 459 489 39 24 21 205 2965
45.16 13.11 15.48 16.49 1.31 0.80 0.70 6.91 –
2.6 0.8 0.9 1.0 0.07 0.04 0.04 0.4 –
Abbreviations: AGC, atypical glandular cells; AIS, adenocarcinoma in situ; ASC-H, atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesions; ASC-US, atypical squamous cells of undetermined significance; HSIL, high-grade intraepithelial squamous lesions; IAC, invasive adenocarcinoma; LSIL, low-grade intraepithelial squamous lesions; SCC, squamous cell carcinoma.
158
S. Stolnicu et al. / International Journal of Gynecology and Obstetrics 124 (2014) 156–159
Table 4 Age distribution of women with abnormal smears in Romania. Age group, y
Percentage of abnormal cases
Under 24
25–29
30–39
40–49
50–59
60–64
Over 65
14.0
17.8
38.7
20.0
7.1
1.8
0.6
Pap smears was 3.7%, of which 2.2% were ASC-US, 1.1% were LSIL, and 0.4% were HSIL [10]. 4. Discussion Cervical cancer is the third most common type of cancer in the world, and ranks second in frequency after breast cancer among women in Romania, where it is the most common cancer among women aged 15–44 years and the leading cause of death among women aged 25–45 years. Worldwide, the incidence of cervical cancer is variable, but 80% of cases are registered in low-income and lowresource countries [11]. The greatest morbidity and mortality rates in Europe are found in Romania [1,2], where the incidence of cervical cancer is 30 cases per 100 000 inhabitants and the mortality is 13 cases per 100 000 inhabitants—a rate that is 6.3 times higher than that in other European countries and has been continuously increasing in the past few decades [12,13]. The incidence and high mortality rate in Romania (5-year survival does not exceed 40%) represent 2 aspects of public health concern for society (the quality of life of the patient and her family are affected) and for international organizations in the field (high healthcare costs are involved) [14]. The early detection of precursor lesions via Pap smears is known to decrease the incidence of cervical cancer [3,4]. In Romania, however, no national screening program to detect early stage cervical cancer or precursor lesions had been implemented before September 2012. Furthermore, no data revealing the overall prevalence of cervical cancer and precursor lesions determined by Pap smears have been documented in Romania. One study, based on 9730 smear tests conducted at a single center in Bucharest, reported that the prevalence of abnormal cytology was 7.0% [5]. In the absence of national data on the epidemiology of cervical cancer and precursor lesions in Romania, the present study was undertaken to estimate the prevalence of abnormal Pap smears and the different types of abnormal cytology. Among 50 536 tests conducted at 3 major laboratory centers collecting Pap smears from all regional areas of Romania, the prevalence of abnormal smears was 5.9%. The prevalence of cervical cytologic anomalies in other European countries varies between 1.2% in Germany and 11.7% in Ireland, and is much higher in low-resource countries in Africa (up to 43.2%) [15–17]. To compare the prevalence of abnormal Pap smears in Romania to that in other European countries, a search on PubMed was conducted that found 4 studies in Turkey, Italy, Croatia, and Belgium with a prevalence of 1.8% [7], 2.4% [8], 7.3% [9], and 3.7% [10], respectively (Table 5). It is well known that the prevalence of precursor and invasive cervical cytologic anomalies varies depending on the study population (e.g. extent of information, religious factors, and socio-economical level); the prevalence of various HPV subtypes; the criteria used for
Table 5 Prevalence of abnormal Pap smears in different countries in European Union. Reference
Place of study
Year of publication
Number of study patients
Prevalence (%)
[7] [8] [9] [10]
Turkey Italy Croatia Belgium
2009 2009 2010 2011
140 334 6 276 744 481 600 000
1.8 2.4 7.3 3.7
diagnosis; and the experience of the cytologists and cytology technicians evaluating the smears. The present rate of 5.9% indicates that there is a high level of precursor lesions in Romania, which demonstrates the necessity of a continuous national screening program in this country. Among the other European studies, only Croatia reported a prevalence higher than Romania—an observation that might be explained by the fact that Croatia was running only an opportunistic screening program in 2010. The prevalence of ASC-US reported in the present study was 2.6%, which is higher than that in Turkey (1.07%), Belgium (2.2%), Croatia (1.87%), and Italy (1.9%). On the other hand, as in the 4 published studies [7–10], ASC-US had the highest prevalence among all cytologic cervical anomalies. In the present study, LSIL represented 0.8% and HSIL 0.9% of all satisfactory smears; this contrasts with data from other European countries where LSIL is more frequent and HSIL much rarer [16,18–20]. The prevalence of LSIL varies between 1.6% and 7.7% in a high-risk population [21]. In Turkey the prevalence of LSIL was only 0.3%, in Italy 0.71%, in Croatia 2.9%, and Belgium 1.1%. By contrast, HSIL represented 0.17% of cases in Turkey, 0.4% of cases in Belgium, and 0.19% of cases in Italy; compared with Romania, the prevalence of HSIL was only higher in Croatia (1.25%). The high prevalence of HSIL in the present study draws attention to the fact that the prevalence of high-risk HPV subtypes is probably much higher in Romania than in other countries [22–26], although these data are from only small study samples. Another explanation might be the unequal distribution of cases by age group in the present study (Table 4): 38.7% of abnormal samples were in the age group 30–39 years; 20.0% in the age group 40–49 years (the incidence of HSIL peaked at approximately 40 years of age); 17.8% in the age group 25–29 years; and 14.0% in the age group 24 years and younger (the incidence of LSIL peaked a decade earlier than that of HSIL). In addition, owing to the fact that this was an opportunistic screening program without pre-established regular scheduled visits, some women in the study group (especially those aged 40–49 years) might have come for an annual Pap smear, whereas others might have had a much larger screening interval. The high prevalence of HSIL and low prevalence of LSIL might be due to the fact that low-grade lesions that could have been diagnosed and treated have been missed and have subsequently transformed into high-grade lesions. Among the satisfactory smears in the present study, 0.07% were classified as invasive squamous carcinomas and 0.04% as invasive adenocarcinomas. In comparison, the study in Turkey reported that 0.08% of smears were invasive squamous carcinomas and 0.02% were invasive adenocarcinomas. In Croatia and Italy, respectively, 0.4% and 0.01% of smears were squamous carcinomas. It should be noted, however, that the present study was not aimed at determining the incidence of invasive cervical cancer because usually this tumor is visible macroscopically and therefore cervical biopsy is preferred to cervical cytology in order to establish the diagnosis. At the same time, the present study did not take into account the monitoring and confirmation of precursor lesions by biopsy. Collectively, the prevalence of AIS (0.04%) and AGC (0.4%) was 0.44% in the present study, compared with 0.04% in Turkey, 0.1% in Belgium, and 0.6% in Croatia. Regarding the distribution according to age, most of the abnormal smears were observed among patients aged 30–39 years (38.7%), but a large number were observed among patients younger than 29 years (17.8% among women aged 25–29 years; 14.0% among women under the age of 24 years). The large number of cases among women under 30 years of age, particular under 25 years, draws attention to the fact that the national screening program should also include women younger than 25 years, even though the norms that have been officially established indicate the initiation of a screening program in women older than 25 years. By contrast, only 0.63% of cases were among women over the age of 65 years, which is in accordance with the national screening program that only includes women younger than 65 years.
S. Stolnicu et al. / International Journal of Gynecology and Obstetrics 124 (2014) 156–159
The present data confirm that there is a high prevalence of cervical precursor lesions (5.9%) and HSIL-type lesions (0.9%) among women in Romania, and a high prevalence of abnormal smears among young women under 25 years of age (14.0% of abnormal cases). They strengthen the importance of continuously implementing the national screening program that was started in 2012. The present study also allows the centralization of important data, which might facilitate a comparison with other European countries and generate new policies of public health. The study is limited in terms of the number of patients and the involvement of only a few regional medical centers, but it represents a pilot that should be continued by similar studies. Conflict of interest The authors have no conflicts of interest. References [1] Arbyn M, Raifu AO, Autier P, Ferlay J. Burden of cervical cancer in Europe: estimates for 2004. Ann Oncol 2007;18(10):1708–15. [2] Arbyn M, Autier P, Ferlay J. Burden of cervical cancer in the 27 member states of the European Union: estimates for 2004. Ann Oncol 2007;18(8):1423–5. [3] 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(7188):904–8. [4] Minelli L, Stracci F, Prandini S, Moffa IF, La Rosa F. Gynaecological cancers in Umbria (Italy): trends of incidence, mortality and survival, 1978-1998. Eur J Obstet Gynecol Reprod Biol 2004;115(1):59–65. [5] Lăzăroiu AM, Comănescu M, Moldovan V, Secară D, Cîrstoiu M, Sajin M, et al. Past experience of SUUB’s Pathology Department in classic based cervico-vaginal cytology. Rom J Morphol Embryol 2009;50(4):619–23. [6] 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(16):2114–9. [7] Turkish Cervical Cancer And Cervical Cytology Research Group. Prevalence of cervical cytological abnormalities in Turkey. Int J Gynecol Obstet 2009;106(3):206–9. [8] Giorgi Rossi P, Ricciardi A, Cohet C, Palazzo F, Furnari G, Valle S, et al. Epidemiology and costs of cervical cancer screening and cervical dysplasia in Italy. BMC Public Health 2009;9:71. [9] Skopljanac-Macina L, Mahovlić V, Ovanin-Rakić A, Barisić A, Rajhvajn S, Juric D, et al. Cervix cancer screening in Croatia within the European Cervical Cancer Prevention Week. Coll Antropol 2010;34(2):613–7.
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[10] Arbyn M, Van Nieuwenhuyse A, Bogers J, De Jonge E, De Beeck LO, Matheï C, et al. Cytological screening for cervical cancer in the province of Limburg, Belgium. Eur J Cancer Prev 2011;20(1):18–24. [11] Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001;2(9):533–43. [12] Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer incidence, mortality and prevalence worldwide. Lyon: IARC Press; 2000. [13] Ferlay J, et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. Lyon: IARC Cancer Base; 2002. [14] Socolov D, Anton C, Azoicăi D, Zanoschi C, Socolov R. National statistical parameters of cervical cancer in Romania: 1992-1997. Rev Med Chir Soc Med Nat Iasi 2000;104(4):123–9. [15] Okonda S, Wright C, Michelow P. The status of cervical cytology in Swaziland, Southern Africa: a descriptive study. Cytojournal 2009;6:14. [16] Sigurdsson K, Sigvaldason H. Longitudinal trends in cervical cytological lesions and the effect of risk factors. A 30-year overview. Acta Obstet Gynecol Scand 2006;85(3):350–8. [17] Ronco G, van Ballegooijen M, Becker N, Chil A, Fender M, Giubilato P, et al. Process performance of cervical screening programmes in Europe. Eur J Cancer 2009;45(15):2659–70. [18] Davey DD, Woodhouse S, Styer P, Stastny J, Mody D. Atypical epithelial cells and specimen adequacy: current laboratory practices of participants in the college of American pathologists interlaboratory comparison program in cervicovaginal cytology. Arch Pathol Lab Med 2000;124(2):203–11. [19] Davey DD, Neal MH, Wilbur DC, Colgan TJ, Styer PE, Mody DR. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med 2004;128(11):1224–9. [20] Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, Bulten J. Liquid compared with conventional cervical cytology: a systematic review and metaanalysis. Obstet Gynecol 2008;111(1):167–77. [21] Jones BA, Davey DD. Quality management in gynecologic cytology using interlaboratory comparison. Arch Pathol Lab Med 2000;124(5):672–81. [22] Melinte-Popescu A, Costăchescu G. Human papilloma virus infection and cervical dysplasia. Rev Med Chir Soc Med Nat Iasi 2012;116(3):853–7. [23] Feticu L, Bocşan IS, Bondor Cl, Boboş C. Prevalence of human papilloma virus isolated from cervix lesions in a female population from Transilvania. Rev Med Chir Soc Med Nat Iasi 2012;116(2):567–74. [24] Feticu L, Bocşan IS, Bondor CI, Boboş C. Geographical distribution of human papillomavirus and their correlation with cytologic abnormalities in cervical lesions and with the age in a female population from Transylvania. Rev Med Chir Soc Med Nat Iasi 2012;116(1):291–8. [25] Ursu RG, Onofriescu M, Nemescu D, Iancu LS. HPV prevalence and type distribution in women with or without cervical lesions in the Northeast region of Romania. Virol J 2011;8:558. [26] Anton G, Peltecu G, Socolov D, Cornitescu F, Bleotu C, Sgarbura Z, et al. Typespecific human papillomavirus detection in cervical smears in Romania. APMIS 2011;119(1):1–9.
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Prevalence of abnormal Pap smears in a consecutive and previously unscreened population in Romania Simona Stolnicu a,b,⁎, Simona Musca c, Dorian Micu d, Luminita Micu d, Cosmin Moldovan e, Lucian Puscasiu f a
Department of Pathology, University of Medicine Targu Mures, Targu Mures, Romania Histopat-Invest Laboratory, Targu Mures, Romania Citos Laboratory, Iasi, Romania d Citosan Plus Laboratory, Constanta, Romania e Department of Histology, University of Medicine Targu Mures, Targu Mures, Romania f Obstetrics and Gynecology Clinic No. 1, University of Medicine Targu Mures, Targu Mures, Romania b c
a r t i c l e
i n f o
Article history: Received 16 May 2013 Received in revised form 15 July 2013 Accepted 10 October 2013 Keywords: Abnormal cervical smears Cytology Prevalence
a b s t r a c t Objective: To determine the prevalence of abnormal cervical smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other countries in Europe. Methods: In a retrospective study, data were reviewed from smears obtained from women in Romania who had been referred to the gynecologist between January 2006 and December 2011. The smears were collected through 3 regional opportunistic programs of cervical screening and were classified according to the Bethesda system. Results: During the study period, 50 536 smear tests were carried out. Of these, 100 smears (0.2%) were unsatisfactory and excluded from the study. Among the remaining 50 436 smears, 2965 patients (5.9%) had abnormal epithelial changes. Most of the abnormal smears were represented by atypical squamous cells of undetermined significance (2.6% of all smears). The data confirmed that there is a high prevalence of highgrade intraepithelial squamous-type lesions (0.9% of all smears) in Romania, and of abnormal smears in women younger than 25 years of age (14.0% of all abnormal smears). Conclusion: The data show that there is a high prevalence of epithelial abnormalities among cervical smears in Romania compared with other European countries that run a national screening program. © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Invasive cervical cancer and cervical intraepithelial neoplasia represent 2 very important health problems for women worldwide. Cervical cancer is a preventable tumor because the premalignant stages can be detected by exfoliative cytology; nevertheless, cervical cancer is still a major cause of death among women living in low-resource countries. Furthermore, within the European Union Romania has the highest incidence of and mortality due to cervical cancer [1,2]. Assessing cervical cytology by the Papanicolaou method (“Pap smear”) is a well-known and very effective method of screening for cervical premalignant and malignant lesions. Since the introduction of Pap smears, a marked reduction in the incidence of and mortality due to cervical cancer has been observed in countries belonging to the European Union and worldwide [3,4]. For the past 20 years, Romania has lacked a national screening program for the early detection of cervical cancer, and began to implement a program only in September 2012; in addition, except for a limited study [5], there are no official data concerning the prevalence of abnormal Pap smears in the country ⁎ Corresponding author at: Department of Pathology, University of Medicine, Str Gh. Marinescu no. 38 Targu Mures, Romania. Tel.: +40 744 765716; fax: +40 365 814950. E-mail address: [email protected] (S. Stolnicu).
before this screening program was started. Therefore, it is mandatory to assess the overall situation of epithelial cell abnormalities and the prevalence of different premalignant and malignant lesions among Pap smears in Romania in order to better develop and implement a national screening program for cervical cancer. The aim of the present study was to determine the prevalence of abnormal Pap smears in a previously unscreened and asymptomatic population in Romania and to compare the data with those from other European countries where national screening programs have been established. 2. Materials and methods In a retrospective study, data were reviewed from consecutive Pap smears prepared from women who had been referred to the gynecologist for a cervical smear test between January 1, 2006, and December 31, 2011. The present analysis was deemed to be exempt from institutional review board approval by the Ethics Committee of the University of Medicine and Pharmacy Targu Mures, Romania. Informed consent was obtained from each woman. The smears were obtained through 3 regional opportunistic programs of cervical screening among asymptomatic patients. The Pap smears were collected from all over Romania and analyzed in 3 major
0020-7292/$ – see front matter © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijgo.2013.07.030
S. Stolnicu et al. / International Journal of Gynecology and Obstetrics 124 (2014) 156–159
private laboratories (Targu Mures, central Romania; Iasi, eastern Romania; and Constanta, southern Romania). All 3 centers involved agreed to participate in the study and to complete a standard report form, which was sent together with the sampled material to the regional laboratory. Only conventional cervical smears were performed. All women were instructed to abstain from douching, using antiseptic cream, internal local examination, and coitus within 24 hours of the cytologic examination. In each case, samples were taken by using a special kit for 2-smear sampling of the exocervix and endocervix via an Ayre spatula. All smears were fixed by the same method (95% ethyl alcohol) and then stained with the Pap staining technique. All smears were examined and reported by trained pathologists, in agreement with the Bethesda 2001 system [6]. In all 3 laboratories, quality control of cervical cytology was achieved by rescreening 10% of all smears. After examining the smears, the following categories were excluded from the study: normal cases (negative for intraepithelial lesion or malignancy); cases presenting benign lesions; cases in which the examination revealed unsatisfactory material; and cases where the woman had been previously diagnosed with cervical, vulvar, or vaginal carcinoma and was subject to radiotherapy and/or chemotherapy or premalignant conditions of these organs. For each smear test included in the study, the following clinical parameters were recorded: patient age, reason for gynecologic examination, personal and family history, results of previous cytologic and histopathologic examinations, and date of last menstrual period. The information obtained from the cytology final reports was recorded in Excel worksheets (Microsoft, Redmond, WA, USA). Prevalence was calculated from the number of positive cases divided by the number of specimens tested. Cytopathologic aspects of Pap smears were reviewed according to age distribution. The percentage distribution of each category of abnormal Pap smear was calculated for both abnormal Pap smears and total Pap smear tests.
3. Results During the 6-year study period, 50 536 consecutive Pap smear tests were carried out. Among these, 100 (0.2%) were unsatisfactory and were excluded from the study. Most of the unsatisfactory cases came from 2 of the 3 laboratories (Targu Mures and Constanta). Unsatisfactory smears comprised both inadequate samples and samples concealed by blood. As a result, 50 436 smear results were included in the study: 15 928 from Targu Mures, 15 796 cases from Constanta and 18 712 cases from Iasi. Table 1 shows the distribution of these cases according to year of investigation and laboratory where the diagnosis was established. Overall, 47 471 (93.9%) of all smears were normal, with atrophy or benign cellular changes owing to inflammation or reparative changes (Table 2). The remaining 2965 cases (5.9%) had abnormal epithelial changes. Of these, 1186 cases were diagnosed in Targu Mures, 977 in Constanta, and 802 in Iasi.
Table 1 Distribution of smears per year of investigation and laboratory in Romania. Year of investigation
Number of smears per laboratory Targu Mures
Constanta
Iasi
Total
2006 2007 2008 2009 2010 2011 Total
1044 2486 3052 3306 3784 2256 15 928
2681 3244 2775 2274 2562 2260 15 796
1125 2367 3480 3943 4098 3699 18712
4850 8097 9307 9523 10444 8215 50436
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Table 2 Distribution of unsatisfactory, normal/benign and abnormal Pap smears in Romania. Cytologic aspect
Number (%) of all smears
Unsatisfactory smear Normal/benign smear Abnormal smear Total
100 (0.2) 47 471 (93.9) 2965 (5.9) 50 536 (100)
Among the 50 436 satisfactory smears, most of the abnormal smears (1339 cases) belonged to the atypical squamous cells of undetermined significance (ASC-US) category (2.6%), whereas only 489 cases (1%) belonged to the “atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesions” (ASC-H) category. Collectively, lowgrade intraepithelial squamous lesion (LSIL) and high-grade intraepithelial squamous lesion (HSIL) comprised 1.7% of all satisfactory smears: LSIL cases represented 0.8% (389 cases) and HSIL cases represented 0.9% (459 cases). Only 39 cases involved squamous carcinoma (SCC) and 24 cases involved adenocarcinoma in situ (AIS) (in both categories, less than 0.1% of cases). Atypical glandular cells (AGCs) represented only 0.4% of cases (205 cases), and less than 0.1% of cases (21 cases) had the appearance of invasive adenocarcinoma on the Pap smear (Table 3). Most abnormal Pap smears were observed among women aged 30–39 years (38.7%), followed women aged 40–49 years (20.0%) (Table 4). A significant number of cases developed among women younger than 30 years: 17.8% of abnormal smears were found for women between 25 and 29 years, and 14.0% for women younger than 24 years. Only 7.1% of abnormal smears were observed among women aged between 50 and 59 years, 1.8% among women aged between 60 and 64 years, and 0.6% among women aged over 65 years. To compare the present data from Romania to those from other countries in Europe, PubMed was searched to find recent studies on the prevalence of abnormal Pap smears in other European countries (Table 5). In 2009, a study in Turkey reported that the percentage of abnormal cytologic smears was 1.8% among 140 334 women. The various categories of lesions comprised ASC-US (1.07%), LSIL (0.3%), HSIL (0.17%), squamous carcinoma (0.08%), and AGC (0.08%) [7]. In 2009, a study in Italy on 6 276 744 satisfactory Pap smears found that 2.4% were positive for the following cytologic abnormalities: ASC-US (1.9%), LSIL (0.71%), HSIL (0.19%) and carcinoma (0.01%) [8]. In a study performed in Croatia in 2010 on 481 women, the prevalence of abnormal cytology was 7.3%. The different categories of lesions comprised ASC-US (1.87%), ASC-H (0.2%), LSIL (2.9%), HSIL (1.25%), and squamous carcinoma (0.4%) [9]. In 2011, a study in Belgium on 600 000 women found that the prevalence of abnormal
Table 3 Distribution of abnormal Pap smears categories in Romania. Category of abnormality
No. of cases
Percentage of abnormal smears
Percentage of satisfactory smears
ASC-US LSIL HSIL ASC-H SCC AIS IAC AGC Total
1339 389 459 489 39 24 21 205 2965
45.16 13.11 15.48 16.49 1.31 0.80 0.70 6.91 –
2.6 0.8 0.9 1.0 0.07 0.04 0.04 0.4 –
Abbreviations: AGC, atypical glandular cells; AIS, adenocarcinoma in situ; ASC-H, atypical squamous cells, cannot exclude high-grade intraepithelial squamous lesions; ASC-US, atypical squamous cells of undetermined significance; HSIL, high-grade intraepithelial squamous lesions; IAC, invasive adenocarcinoma; LSIL, low-grade intraepithelial squamous lesions; SCC, squamous cell carcinoma.
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Table 4 Age distribution of women with abnormal smears in Romania. Age group, y
Percentage of abnormal cases
Under 24
25–29
30–39
40–49
50–59
60–64
Over 65
14.0
17.8
38.7
20.0
7.1
1.8
0.6
Pap smears was 3.7%, of which 2.2% were ASC-US, 1.1% were LSIL, and 0.4% were HSIL [10]. 4. Discussion Cervical cancer is the third most common type of cancer in the world, and ranks second in frequency after breast cancer among women in Romania, where it is the most common cancer among women aged 15–44 years and the leading cause of death among women aged 25–45 years. Worldwide, the incidence of cervical cancer is variable, but 80% of cases are registered in low-income and lowresource countries [11]. The greatest morbidity and mortality rates in Europe are found in Romania [1,2], where the incidence of cervical cancer is 30 cases per 100 000 inhabitants and the mortality is 13 cases per 100 000 inhabitants—a rate that is 6.3 times higher than that in other European countries and has been continuously increasing in the past few decades [12,13]. The incidence and high mortality rate in Romania (5-year survival does not exceed 40%) represent 2 aspects of public health concern for society (the quality of life of the patient and her family are affected) and for international organizations in the field (high healthcare costs are involved) [14]. The early detection of precursor lesions via Pap smears is known to decrease the incidence of cervical cancer [3,4]. In Romania, however, no national screening program to detect early stage cervical cancer or precursor lesions had been implemented before September 2012. Furthermore, no data revealing the overall prevalence of cervical cancer and precursor lesions determined by Pap smears have been documented in Romania. One study, based on 9730 smear tests conducted at a single center in Bucharest, reported that the prevalence of abnormal cytology was 7.0% [5]. In the absence of national data on the epidemiology of cervical cancer and precursor lesions in Romania, the present study was undertaken to estimate the prevalence of abnormal Pap smears and the different types of abnormal cytology. Among 50 536 tests conducted at 3 major laboratory centers collecting Pap smears from all regional areas of Romania, the prevalence of abnormal smears was 5.9%. The prevalence of cervical cytologic anomalies in other European countries varies between 1.2% in Germany and 11.7% in Ireland, and is much higher in low-resource countries in Africa (up to 43.2%) [15–17]. To compare the prevalence of abnormal Pap smears in Romania to that in other European countries, a search on PubMed was conducted that found 4 studies in Turkey, Italy, Croatia, and Belgium with a prevalence of 1.8% [7], 2.4% [8], 7.3% [9], and 3.7% [10], respectively (Table 5). It is well known that the prevalence of precursor and invasive cervical cytologic anomalies varies depending on the study population (e.g. extent of information, religious factors, and socio-economical level); the prevalence of various HPV subtypes; the criteria used for
Table 5 Prevalence of abnormal Pap smears in different countries in European Union. Reference
Place of study
Year of publication
Number of study patients
Prevalence (%)
[7] [8] [9] [10]
Turkey Italy Croatia Belgium
2009 2009 2010 2011
140 334 6 276 744 481 600 000
1.8 2.4 7.3 3.7
diagnosis; and the experience of the cytologists and cytology technicians evaluating the smears. The present rate of 5.9% indicates that there is a high level of precursor lesions in Romania, which demonstrates the necessity of a continuous national screening program in this country. Among the other European studies, only Croatia reported a prevalence higher than Romania—an observation that might be explained by the fact that Croatia was running only an opportunistic screening program in 2010. The prevalence of ASC-US reported in the present study was 2.6%, which is higher than that in Turkey (1.07%), Belgium (2.2%), Croatia (1.87%), and Italy (1.9%). On the other hand, as in the 4 published studies [7–10], ASC-US had the highest prevalence among all cytologic cervical anomalies. In the present study, LSIL represented 0.8% and HSIL 0.9% of all satisfactory smears; this contrasts with data from other European countries where LSIL is more frequent and HSIL much rarer [16,18–20]. The prevalence of LSIL varies between 1.6% and 7.7% in a high-risk population [21]. In Turkey the prevalence of LSIL was only 0.3%, in Italy 0.71%, in Croatia 2.9%, and Belgium 1.1%. By contrast, HSIL represented 0.17% of cases in Turkey, 0.4% of cases in Belgium, and 0.19% of cases in Italy; compared with Romania, the prevalence of HSIL was only higher in Croatia (1.25%). The high prevalence of HSIL in the present study draws attention to the fact that the prevalence of high-risk HPV subtypes is probably much higher in Romania than in other countries [22–26], although these data are from only small study samples. Another explanation might be the unequal distribution of cases by age group in the present study (Table 4): 38.7% of abnormal samples were in the age group 30–39 years; 20.0% in the age group 40–49 years (the incidence of HSIL peaked at approximately 40 years of age); 17.8% in the age group 25–29 years; and 14.0% in the age group 24 years and younger (the incidence of LSIL peaked a decade earlier than that of HSIL). In addition, owing to the fact that this was an opportunistic screening program without pre-established regular scheduled visits, some women in the study group (especially those aged 40–49 years) might have come for an annual Pap smear, whereas others might have had a much larger screening interval. The high prevalence of HSIL and low prevalence of LSIL might be due to the fact that low-grade lesions that could have been diagnosed and treated have been missed and have subsequently transformed into high-grade lesions. Among the satisfactory smears in the present study, 0.07% were classified as invasive squamous carcinomas and 0.04% as invasive adenocarcinomas. In comparison, the study in Turkey reported that 0.08% of smears were invasive squamous carcinomas and 0.02% were invasive adenocarcinomas. In Croatia and Italy, respectively, 0.4% and 0.01% of smears were squamous carcinomas. It should be noted, however, that the present study was not aimed at determining the incidence of invasive cervical cancer because usually this tumor is visible macroscopically and therefore cervical biopsy is preferred to cervical cytology in order to establish the diagnosis. At the same time, the present study did not take into account the monitoring and confirmation of precursor lesions by biopsy. Collectively, the prevalence of AIS (0.04%) and AGC (0.4%) was 0.44% in the present study, compared with 0.04% in Turkey, 0.1% in Belgium, and 0.6% in Croatia. Regarding the distribution according to age, most of the abnormal smears were observed among patients aged 30–39 years (38.7%), but a large number were observed among patients younger than 29 years (17.8% among women aged 25–29 years; 14.0% among women under the age of 24 years). The large number of cases among women under 30 years of age, particular under 25 years, draws attention to the fact that the national screening program should also include women younger than 25 years, even though the norms that have been officially established indicate the initiation of a screening program in women older than 25 years. By contrast, only 0.63% of cases were among women over the age of 65 years, which is in accordance with the national screening program that only includes women younger than 65 years.
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