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Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer
Gynecologic Oncology 130 (2013) 470–473
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer Mi Kyoung Kim a, Seok Ju Seong a,⁎, Taejong Song a, Mi-La Kim a, Bo Sung Yoon a, Hye Sun Jun a, Gun Ho Lee b, Yoon Hee Lee c a b c
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Korea Department of Obstetrics and Gynecology, CHA Gumi Medical Center, CHA University, Seoul, Korea Department of Pathology, CHA Gangnam Medical Center, CHA University, Seoul, Korea
H I G H L I G H T S • This is the first study about comparison of D&C and endometrial aspiration biopsy accuracy in case of using LNG-IUS. • Endometrial aspiration biopsy with LNG-IUS in place is less accurate than D&C after removal of LNG-IUS.
a r t i c l e
i n f o
Article history: Received 9 April 2013 Accepted 25 June 2013 Available online 30 June 2013 Keywords: Endometrial cancer Progesterone Endometrial biopsy Dilatation & curettage LNG-IUS
a b s t r a c t Objective. To compare the diagnostic accuracy of dilatation & curettage (D&C) vs. endometrial aspiration biopsy in follow-up evaluation of patients treated with high-dose oral progestin plus levonorgestrel intrauterine system (LNG-IUS) for early-stage endometrial cancer (EC). Method. A prospective observational study was conducted with 11 patients with FIGO grade 1 or 2, clinical stage IA endometrioid adenocarcinoma. Patients were aged up to 40 years wishing to preserve fertility treated with high-dose oral progestin plus LNG-IUS. Treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy with LNG-IUS in place and D&C after removal of LNG-IUS. We identified 28 cases; the histologic results were compared. Kappa statistics were used to assess the agreement of two methods. Results. Diagnostic concordance between examinations was assessed for 9 out of 28 cases examined (32.1%). These consisted of three cases with both examination results of normal, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia, 2 cases with material insufficient for diagnosis. Endometrioid adenocarcinoma on D&C was diagnosed in 9 out of 28 cases, but from endometrial aspiration biopsy, only 3 of these 9 cases were diagnosed with endometrioid adenocarcinoma, giving the diagnostic concordance at 33% (kappa value = 0.27). From endometrial aspiration biopsy, 17 out of 28 cases (60.7%) had material insufficiency for diagnosis. Conclusion. In patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC, endometrial aspiration biopsy with LNG-IUS in place may be not reliable as a follow-up evaluation method. © 2013 Published by Elsevier Inc.
Introduction Endometrial cancer (EC) is the world's second most common gynecologic malignancy and the incidence is rising steadily [1]. While a majority of cases are diagnosed in post-menopausal women, up to 14% of
⁎ Corresponding author at: Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 650-9, Yoksam-dong, Gangnam-gu, Seoul 135-913, Korea. Fax: +82 2 558 1112. E-mail address: [email protected] (S.J. Seong). 0090-8258/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ygyno.2013.06.035
cases will be in pre-menopausal women, including 4% diagnosed in women younger than 40 years of age. With the recent increase in the number of young patients with EC, the fertility-sparing conservative treatment is attracting growing attention. A number of studies have reported the effectiveness of hormonal therapy using systemic progestin in women clinically diagnosed with early endometrial adenocarcinoma at stage IA, grade 1, who want to maintain reproductive potential [2–10]. In addition, several recent studies reported the use of a levonorgestrel intrauterine system (LNG-IUS) to reduce systemic adverse effects and increase the local effectiveness to the endometrium [11–19]. However, there are few reports evaluating the response of the endometrium
M.K. Kim et al. / Gynecologic Oncology 130 (2013) 470–473
in follow-up, especially when using LNG-IUS. According to the reported literature, in cases of conservative treatment using LNG-IUS, endometrial response was evaluated by endometrial aspiration biopsy with LNGIUS in uterus or a dilatation & curettage (D&C) after removal of LNGIUS [11–20]. Nevertheless, there has been no report comparing the accuracy of these methods. Therefore we conducted a prospective observational study to evaluate the diagnostic accuracy of endometrial aspiration biopsy with the LNG-IUS in place in the uterus compared with a D&C after removal of LNG-IUS in the evaluation of endometrial response in patients treated with high-dose oral progestin plus LNG-IUS for early endometrial adenocarcinoma at stage IA, grade 1 or 2.
471
Table 2 Comparison of pathologic result from D&C and endometrial aspiration biopsy. D&C
N (%)
Endometrial aspiration biopsy
Normal
10 (35.7)
Cancer
9 (32.1)
Complex endometrial hyperplasia
7 (25)
Normal Material insufficiency Cancer Normal Material insufficiency Complex endometrial hyperplasia Normal Material insufficiency Material insufficiency Total
Material insufficiency Total
2 (7.1) 28 (100)
N 3 7 3 3 3 1 1 5 2 28
D&C: dilatation and curettage.
Patients and methods A prospective observational study conducted with 11 Patients with FIGO grade 1 or 2, clinical stage I endometrioid adenocarcinoma treated at CHA Gangnam Medical Center, Seoul, Korea from January 2010 to February 2012. Eligible subjects were young women less than 40 years of age, with histologically confirmed grade 1 or 2 endometrioid adenocarcinoma that is presumably confined to the endometrium. Endometrial tissue sampling for diagnosis was carried out by D&C and the clinical stage was determined based on the evaluation with pelvic examination, pelvic ultrasound, and magnetic resonance imaging to exclude myometrial invasion or any extrauterine lesion. Patients were treated with high-dose oral progestin (medroxyprogesterone acetate 500 mg/day) plus LNG-IUS for conservative treatment to preserve fertility potential. Follow-up and treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy using a pipelle with LNG-IUS in place and D&C after removal of LNG-IUS. In the operating room, endometrial aspiration biopsy was done with LNG-IUS in uterus and then, LNG-IUS was removed. Right after that, D&C was done. Every endometrial aspiration and D&C was done in this way. The histologic results of two methods were compared. All pathologic specimens were reassessed independently by pathologist specialized in gynecology. Kappa statistics were used to assess the agreement of two methods. Our Institutional Review Board approved this study protocol. All patients were counselled on the nature of procedure and all provided informed consent. Result During the study period, we performed 28 endometrial biopsies in 11 patients. Each patient got an average of 2.5 ± 0.9 biopsies (range, 1–4). Table 1 summarizes the clinical characteristics of the patients. The mean age of the subjects was 32.6 ± 3.9 years (range, 29–40 years); there were 10 patients with FIGO grade 1 and 1 patient with FIGO grade 2 tumors. Their mean body mass index (BMI) was 22.1 ± 1.1 kg/m2 (range, 16.8–36.3 kg/m2). Among the 11 patients, 3 women had high BMI N 30 kg/m2 (36.3, 32.0, 34.8) and 8 patients had normal or low BMI (range, 17.0–23.3 kg/m2). A total of 11 patients had complete response in average 11.1 ± 9.6 months (range, 3–35 months). One
Table 1 Patient clinical characteristics (n = 11). Clinical characteristic
SD or n (range)
Age (years) BMI(kg/m2) Parity FIGO grade Grade 1 Grade 2
32.6 ± 3.9 (29–40) 22.1 ± 1.1 (16.8 – 36.3) 0 10 1
Data expressed by means ± standard deviation (SD) or number (n).
patient underwent hysterectomy due to a recurrence of cancer 6 months after the combined treatment of MPA and LNG-IUS was stopped. The pathology was shown grade 2 endometrioid adenocarcinoma. The comparison of pathologic result from D&C and endometrial aspiration biopsy are summarized in Table 2. In endometrial biopsy, normal endometrium was defined as the sample that had adequate endometrial tissue for interpretation and normal endometrial glands without any cancerous or hyperplasic lesion. The histologic results by D&C were 10 (35.7%) with normal endometrium, nine (32.1%) with endometrioid adenocarcinoma, seven (25%) with complex endometrial hyperplasia and two (7.1%) with insufficient tissue for pathologic evaluation. By endometrial aspiration biopsy, among the 10 cases of normal endometrium, three cases were diagnosed as normal endometrium, and among the seven cases of complex endometrial hyperplasia, only one case was diagnosed as complex endometrial hyperplasia. There were nine cases of endometrioid adenocarcinoma in the D&C result, but three cases were diagnosed by endometrial aspiration biopsy while the remainder included three normal endometrium and three insufficient tissues for diagnosis. Among women with normal results by endometrial aspiration biopsy, three women (42.8%) had EC, and one woman (14.2%) had complex endometrial hyperplasia by D&C. When the diagnostic concordance between D&C and endometrial biopsy was assessed, nine of 28 cases (32.1%) had diagnostic concordance, consisting of the three cases potentially with normal endometrium, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia and 2 cases with insufficient tissue for diagnosis. Endometrioid adenocarcinoma on D&C had been diagnosed in nine cases out of 28, but only three of these nine cases were diagnosed with endometrioid adenocarcinoma from endometrial aspiration biopsy, so the diagnostic concordance was 33.3% in cancer. The kappa value was 0.27, meaning nearly no concordance between the results of two examinations. In addition, in the case of histological examination in use of endometrial aspiration biopsy, 17 of 28 cases (60.7%) had material insufficiency for diagnosis. Among these 17 cases, 7 cases had normal endometrium, 3 cases had cancer, 5 cases had complex endometrial hyperplasia and 2 cases had material insufficiency by follow-up D&C (Table 2). There was no significant difference in the correlation between aspiration biopsy and D&C according to each patient, and also within the number of sampling; the first or second or third sampling. There were no cases of complication related to treatment including expulsion of LNG-IUS. Discussion For young women with early stage EC desiring to preserve their fertility, conservative treatment such as the administration of high-dose oral progesterone has been recommended [2–10]. In addition, several recent studies reported the use of a LNG-IUS [11–19]. However, the result is unsatisfactory, especially compared with the high cure rate
472
M.K. Kim et al. / Gynecologic Oncology 130 (2013) 470–473
Table 3 Diagnostic and evaluation method of treatment with LNG-IUS. Author
n
Treatment method
Diagnostic method
Follow-up evaluation
Etc.
Giannopoulos et al. 2004 12 Dhar et al. 2005 13 Fambrini et al.2009 14 Cade et al. 2010 15
1 4 1 3 9 14 5 11 1
Oral progestins + LNG-IUS LNG-IUS LNG-IUS LNG-IUS Oral progestins + LNG-IUS GnRH agonist + LNG-IUS Oral progestins + LNG-IUS GnRH agonist + LNG-IUS LNG-IUS
Aspiration biopsy Hysteroscopic biopsy D&C D&C D&C D&C D&C Aspiration biopsy and hysteroscopic biopsy D&C
Aspiration biopsy Aspiration biopsy or hysteroscopy Hysteroscopy with Aspiration biopsy D&C D& C Hysteroscopy and Aspiration biopsy or D&C D&C Aspiration biopsy and/or hysteroscopy Alternating between Aspiration biopsy with IUD in place and hysteroscopy with D&C
Grade 2
Minig et al. 2010 16 Kim et al.2011 17 Pashov et al. 2012 18 Brown et al. 2012 19
D&C: dilatation and curettage. LNG-IUS: levonogestrel containing intrauterine system. GnRH: gonadotropin releasing hormone. Etc.: et cetera. IUD: intrauterine device.
(N93%) of surgically treated early-stage EC already noted. Therefore, to achieve a therapeutic progesterone level with less adverse systemic effects of high-dose progestin, we tried a pilot study of MPA 500 mg/day plus LNG-IUS for early-stage EC in young women and found that complete remission occurred in 4 of 5 patients, while one patient showed partial remission [17]. When performing these conservative managements of endometrial carcinoma, accurate assessment of response of the endometrium to hormonal therapy is most important. Therefore, endometrial evaluation should be performed periodically during the treatment, and usually treatment response is assessed every 3–6 months by endometrial biopsy [6,7]. Table 3 summarized the diagnostic and follow-up evaluation methods used for conservative treatment with LNG-IUS in women with EC. However, there was no data about the most accurate method among various methods such as endometrial aspiration biopsy with LNG-IUS in place, D&C after removal of LNG-IUS and hysteroscopic biopsy. Because a reliable assessment for therapeutic effectiveness is essential to determine the sustainability of conservative hormonal treatment of EC, we compared a diagnostic accuracy of D&C under the condition that LNG-IUS was removed with endometrial aspiration biopsy versus the LNG-IUS kept in the uterus. The clinical significance of this study is the first study to do endometrial assessment when using the LNG-IUS. There have been several studies about the accuracy of D&C and endometrial aspiration biopsy for diagnosis of EC when LNG-IUS is not in the uterus. Until recently, the gold standard for diagnosis of EC is considered D&C but endometrial aspiration biopsy seems to be as accurate in the detection of endometrial carcinoma as D&C [21]. However, Leitao et al. reported that the accuracy of these two methods in determining FIGO grade appears to differ. According to the study, D&C provides a more accurate reflection of true FIGO grade than does endometrial aspiration biopsy; the final post-hysterectomy FIGO grade was higher in 16/187 (8.7%) cases diagnosed by D&C compared to 52/298(17.4%) diagnosed by endometrial aspiration biopsy. Therefore they said that in patients being considered for uterine preservation, D&C should be performed prior to initiating progestational therapies [22]. Our results showed that the diagnostic accuracy of endometrial aspiration biopsy with LNG-IUS in place was very poor. Furthermore, a high prevalence of insufficient tissue for pathologic evaluation was noted with endometrial aspiration biopsy. It is likely that the volume of endometrial tissues being collected for endometrial aspiration biopsy was less due to oral progestin and LNG-IUS-induced endometrial atrophy and due to LNG-IUS mechanical interference with the aspiration biopsy. Clark et al. reported the positive predictive value of endometrial aspiration biopsy as 81.7% in their systematic quantitative review that analyzed published research of endometrial aspiration biopsy done for diagnosing EC in women with abnormal uterine bleeding. However, they announced that in postmenopausal women, the percentage of
histologically inadequate samples (no specimen obtained or insufficient for adequate assessment) was up to 20% [23]. In addition, according to a prospective cohort study of 913 women presenting with postmenopausal bleeding by van Doorn et al., among 403 patients who underwent office endometrial sampling, 66 patients had tissue not sufficient for pathologic characterization and further investigation revealed an endometrial malignancy in 3 of these 66 women [24]. When using oral progestin and LNG-IUS, the number of cases where there is insufficient tissue for pathologic evaluation could be increased due to endometrial atrophy like postmenopausal status. Therefore in these cases, we must pay more attention because non-diagnostic endometrial tissue does not rule out EC. However, endometrial aspiration biopsy may be useful in sometime, because there was no false positive case. So endometrial aspiration biopsy cannot be substitute of D&C, but it may detect unnecessary D&C. In conclusion, endometrial aspiration biopsy with LNG-IUS in place is less accurate than D&C after removal of LNG-IUS and may be not reliable for follow-up evaluation method in patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC. This study has limitations in that only a small number of patients participated in the study, so a large scale prospective study is required to confirm our finding. Conflict of interest The authors report no conflict of interest.
References [1] Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011. CA Cancer J Clin 2011;61:212–36. [2] Kesterson Joshua P, Fanning James. Fertility-sparing treatment of endometrial cancer: options, outcomes and pitfalls. J Gynecol Oncol 2012;23:120–4. [3] Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progesterone alone as primary treatment of endometrial carcinoma in pre-menopausal women: report of seven cases and review of the literature. Cancer 1997;79:320–7. [4] Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and welldifferentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol 1997;90:434–40. [5] Kaku T, Yoshikavw H, Tsuda H, Sakamoto A, Fukunaga M, Kuwabara Y, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett 2001;167:39–48. [6] Imai M, Jobo T, Sato R, Kawaguchi M, Kuramoto H. Medroxyprogesterone acetate therapy for patients with adenocarcinoma of the endometrium who wish to preserve the uterusVusefulness and limitations. Eur J Gynaecol Oncol 2001;22:217–20. [7] Wang CB, Wang CJ, Huang HJ, Hsueh S, Chou HH, Soong YK, et al. Fertilitypreserving treatment in young patients with endometrial adenocarcinoma. Cancer 2002;94:2192–8. [8] Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, et al. Outcome of fertility sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol 2003;102:215–8. [9] Joshua P. Kesterson, James Fanning, Fertility-sparing treatment of endometrial cancer: options, outcomes and pitfalls. J Gynecol Oncol 2012;2:120–4.
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[17] Kim MK, Yoon BS, Park H, Seong SJ, Chung HH, Kim JW, et al. Conservative treatment with medroxyprogesterone acetate plus levonorgestrel intrauterine system for early-stage endometrial cancer in young women: pilot study. Int J Gynecol Cancer 2011;21(4):673–7. [18] Pashov AI, Tskhay VB, Ionouchene SV. The combined GnRH-agonist and intrauterine levonorgestrel-releasing system treatment of complicated atypical hyperplasia and endometrial cancer: a pilot study. Gynecol Endocrinol 2012;28(7):559–61. [19] Brown AJ, Westin SN, Broaddus RR, Schmeler K. Progestin intrauterine device in an adolescent with grade 2 endometrial cancer. Obstet Gynecol 2012;119:423–6. [20] Benshushan A. Endometrial adenocarcinoma in young patients; Evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol 2004;117:132–7. [21] Dijkhuizen FPHLJ, Mol BWJ, Brolmann HAM, Heintz APM. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000;89:1765–7172. [22] Leitao MM Jr, Kehoe S, Barakat RR, Alektiar K, Gattoc LP, Rabbitt C, et al. Comparison of D&C and office endometrial biopsy accuracy in patients with FIGO grade 1 endometrial adenocarcinoma. Gynecol Oncol 2009;113:105–8. [23] Clark TJ, Mann CH, Shah N, Khan KS, Song F, Gupta JK. Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial cancer: a systematic quantitative review. BJOG 2002;109:313–21. [24] van Doorn HC, Opmeer BC, Burger CW, Duk MJ, Kooi GS, Mol BW. Inadequate office endometrial sample requires further evaluation in women with postmenopausal bleeding and abnormal ultrasound results. Int J Gynaecol Obstet 2007;99:100–4.
Contents lists available at SciVerse ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Comparison of dilatation & curettage and endometrial aspiration biopsy accuracy in patients treated with high-dose oral progestin plus levonorgestrel intrauterine system for early-stage endometrial cancer Mi Kyoung Kim a, Seok Ju Seong a,⁎, Taejong Song a, Mi-La Kim a, Bo Sung Yoon a, Hye Sun Jun a, Gun Ho Lee b, Yoon Hee Lee c a b c
Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, Seoul, Korea Department of Obstetrics and Gynecology, CHA Gumi Medical Center, CHA University, Seoul, Korea Department of Pathology, CHA Gangnam Medical Center, CHA University, Seoul, Korea
H I G H L I G H T S • This is the first study about comparison of D&C and endometrial aspiration biopsy accuracy in case of using LNG-IUS. • Endometrial aspiration biopsy with LNG-IUS in place is less accurate than D&C after removal of LNG-IUS.
a r t i c l e
i n f o
Article history: Received 9 April 2013 Accepted 25 June 2013 Available online 30 June 2013 Keywords: Endometrial cancer Progesterone Endometrial biopsy Dilatation & curettage LNG-IUS
a b s t r a c t Objective. To compare the diagnostic accuracy of dilatation & curettage (D&C) vs. endometrial aspiration biopsy in follow-up evaluation of patients treated with high-dose oral progestin plus levonorgestrel intrauterine system (LNG-IUS) for early-stage endometrial cancer (EC). Method. A prospective observational study was conducted with 11 patients with FIGO grade 1 or 2, clinical stage IA endometrioid adenocarcinoma. Patients were aged up to 40 years wishing to preserve fertility treated with high-dose oral progestin plus LNG-IUS. Treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy with LNG-IUS in place and D&C after removal of LNG-IUS. We identified 28 cases; the histologic results were compared. Kappa statistics were used to assess the agreement of two methods. Results. Diagnostic concordance between examinations was assessed for 9 out of 28 cases examined (32.1%). These consisted of three cases with both examination results of normal, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia, 2 cases with material insufficient for diagnosis. Endometrioid adenocarcinoma on D&C was diagnosed in 9 out of 28 cases, but from endometrial aspiration biopsy, only 3 of these 9 cases were diagnosed with endometrioid adenocarcinoma, giving the diagnostic concordance at 33% (kappa value = 0.27). From endometrial aspiration biopsy, 17 out of 28 cases (60.7%) had material insufficiency for diagnosis. Conclusion. In patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC, endometrial aspiration biopsy with LNG-IUS in place may be not reliable as a follow-up evaluation method. © 2013 Published by Elsevier Inc.
Introduction Endometrial cancer (EC) is the world's second most common gynecologic malignancy and the incidence is rising steadily [1]. While a majority of cases are diagnosed in post-menopausal women, up to 14% of
⁎ Corresponding author at: Department of Obstetrics and Gynecology, CHA Gangnam Medical Center, CHA University, 650-9, Yoksam-dong, Gangnam-gu, Seoul 135-913, Korea. Fax: +82 2 558 1112. E-mail address: [email protected] (S.J. Seong). 0090-8258/$ – see front matter © 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ygyno.2013.06.035
cases will be in pre-menopausal women, including 4% diagnosed in women younger than 40 years of age. With the recent increase in the number of young patients with EC, the fertility-sparing conservative treatment is attracting growing attention. A number of studies have reported the effectiveness of hormonal therapy using systemic progestin in women clinically diagnosed with early endometrial adenocarcinoma at stage IA, grade 1, who want to maintain reproductive potential [2–10]. In addition, several recent studies reported the use of a levonorgestrel intrauterine system (LNG-IUS) to reduce systemic adverse effects and increase the local effectiveness to the endometrium [11–19]. However, there are few reports evaluating the response of the endometrium
M.K. Kim et al. / Gynecologic Oncology 130 (2013) 470–473
in follow-up, especially when using LNG-IUS. According to the reported literature, in cases of conservative treatment using LNG-IUS, endometrial response was evaluated by endometrial aspiration biopsy with LNGIUS in uterus or a dilatation & curettage (D&C) after removal of LNGIUS [11–20]. Nevertheless, there has been no report comparing the accuracy of these methods. Therefore we conducted a prospective observational study to evaluate the diagnostic accuracy of endometrial aspiration biopsy with the LNG-IUS in place in the uterus compared with a D&C after removal of LNG-IUS in the evaluation of endometrial response in patients treated with high-dose oral progestin plus LNG-IUS for early endometrial adenocarcinoma at stage IA, grade 1 or 2.
471
Table 2 Comparison of pathologic result from D&C and endometrial aspiration biopsy. D&C
N (%)
Endometrial aspiration biopsy
Normal
10 (35.7)
Cancer
9 (32.1)
Complex endometrial hyperplasia
7 (25)
Normal Material insufficiency Cancer Normal Material insufficiency Complex endometrial hyperplasia Normal Material insufficiency Material insufficiency Total
Material insufficiency Total
2 (7.1) 28 (100)
N 3 7 3 3 3 1 1 5 2 28
D&C: dilatation and curettage.
Patients and methods A prospective observational study conducted with 11 Patients with FIGO grade 1 or 2, clinical stage I endometrioid adenocarcinoma treated at CHA Gangnam Medical Center, Seoul, Korea from January 2010 to February 2012. Eligible subjects were young women less than 40 years of age, with histologically confirmed grade 1 or 2 endometrioid adenocarcinoma that is presumably confined to the endometrium. Endometrial tissue sampling for diagnosis was carried out by D&C and the clinical stage was determined based on the evaluation with pelvic examination, pelvic ultrasound, and magnetic resonance imaging to exclude myometrial invasion or any extrauterine lesion. Patients were treated with high-dose oral progestin (medroxyprogesterone acetate 500 mg/day) plus LNG-IUS for conservative treatment to preserve fertility potential. Follow-up and treatment response assessment was done at three month intervals. Endometrial tissues were obtained via endometrial aspiration biopsy using a pipelle with LNG-IUS in place and D&C after removal of LNG-IUS. In the operating room, endometrial aspiration biopsy was done with LNG-IUS in uterus and then, LNG-IUS was removed. Right after that, D&C was done. Every endometrial aspiration and D&C was done in this way. The histologic results of two methods were compared. All pathologic specimens were reassessed independently by pathologist specialized in gynecology. Kappa statistics were used to assess the agreement of two methods. Our Institutional Review Board approved this study protocol. All patients were counselled on the nature of procedure and all provided informed consent. Result During the study period, we performed 28 endometrial biopsies in 11 patients. Each patient got an average of 2.5 ± 0.9 biopsies (range, 1–4). Table 1 summarizes the clinical characteristics of the patients. The mean age of the subjects was 32.6 ± 3.9 years (range, 29–40 years); there were 10 patients with FIGO grade 1 and 1 patient with FIGO grade 2 tumors. Their mean body mass index (BMI) was 22.1 ± 1.1 kg/m2 (range, 16.8–36.3 kg/m2). Among the 11 patients, 3 women had high BMI N 30 kg/m2 (36.3, 32.0, 34.8) and 8 patients had normal or low BMI (range, 17.0–23.3 kg/m2). A total of 11 patients had complete response in average 11.1 ± 9.6 months (range, 3–35 months). One
Table 1 Patient clinical characteristics (n = 11). Clinical characteristic
SD or n (range)
Age (years) BMI(kg/m2) Parity FIGO grade Grade 1 Grade 2
32.6 ± 3.9 (29–40) 22.1 ± 1.1 (16.8 – 36.3) 0 10 1
Data expressed by means ± standard deviation (SD) or number (n).
patient underwent hysterectomy due to a recurrence of cancer 6 months after the combined treatment of MPA and LNG-IUS was stopped. The pathology was shown grade 2 endometrioid adenocarcinoma. The comparison of pathologic result from D&C and endometrial aspiration biopsy are summarized in Table 2. In endometrial biopsy, normal endometrium was defined as the sample that had adequate endometrial tissue for interpretation and normal endometrial glands without any cancerous or hyperplasic lesion. The histologic results by D&C were 10 (35.7%) with normal endometrium, nine (32.1%) with endometrioid adenocarcinoma, seven (25%) with complex endometrial hyperplasia and two (7.1%) with insufficient tissue for pathologic evaluation. By endometrial aspiration biopsy, among the 10 cases of normal endometrium, three cases were diagnosed as normal endometrium, and among the seven cases of complex endometrial hyperplasia, only one case was diagnosed as complex endometrial hyperplasia. There were nine cases of endometrioid adenocarcinoma in the D&C result, but three cases were diagnosed by endometrial aspiration biopsy while the remainder included three normal endometrium and three insufficient tissues for diagnosis. Among women with normal results by endometrial aspiration biopsy, three women (42.8%) had EC, and one woman (14.2%) had complex endometrial hyperplasia by D&C. When the diagnostic concordance between D&C and endometrial biopsy was assessed, nine of 28 cases (32.1%) had diagnostic concordance, consisting of the three cases potentially with normal endometrium, 3 cases with endometrioid adenocarcinoma, 1 case with complex endometrial hyperplasia and 2 cases with insufficient tissue for diagnosis. Endometrioid adenocarcinoma on D&C had been diagnosed in nine cases out of 28, but only three of these nine cases were diagnosed with endometrioid adenocarcinoma from endometrial aspiration biopsy, so the diagnostic concordance was 33.3% in cancer. The kappa value was 0.27, meaning nearly no concordance between the results of two examinations. In addition, in the case of histological examination in use of endometrial aspiration biopsy, 17 of 28 cases (60.7%) had material insufficiency for diagnosis. Among these 17 cases, 7 cases had normal endometrium, 3 cases had cancer, 5 cases had complex endometrial hyperplasia and 2 cases had material insufficiency by follow-up D&C (Table 2). There was no significant difference in the correlation between aspiration biopsy and D&C according to each patient, and also within the number of sampling; the first or second or third sampling. There were no cases of complication related to treatment including expulsion of LNG-IUS. Discussion For young women with early stage EC desiring to preserve their fertility, conservative treatment such as the administration of high-dose oral progesterone has been recommended [2–10]. In addition, several recent studies reported the use of a LNG-IUS [11–19]. However, the result is unsatisfactory, especially compared with the high cure rate
472
M.K. Kim et al. / Gynecologic Oncology 130 (2013) 470–473
Table 3 Diagnostic and evaluation method of treatment with LNG-IUS. Author
n
Treatment method
Diagnostic method
Follow-up evaluation
Etc.
Giannopoulos et al. 2004 12 Dhar et al. 2005 13 Fambrini et al.2009 14 Cade et al. 2010 15
1 4 1 3 9 14 5 11 1
Oral progestins + LNG-IUS LNG-IUS LNG-IUS LNG-IUS Oral progestins + LNG-IUS GnRH agonist + LNG-IUS Oral progestins + LNG-IUS GnRH agonist + LNG-IUS LNG-IUS
Aspiration biopsy Hysteroscopic biopsy D&C D&C D&C D&C D&C Aspiration biopsy and hysteroscopic biopsy D&C
Aspiration biopsy Aspiration biopsy or hysteroscopy Hysteroscopy with Aspiration biopsy D&C D& C Hysteroscopy and Aspiration biopsy or D&C D&C Aspiration biopsy and/or hysteroscopy Alternating between Aspiration biopsy with IUD in place and hysteroscopy with D&C
Grade 2
Minig et al. 2010 16 Kim et al.2011 17 Pashov et al. 2012 18 Brown et al. 2012 19
D&C: dilatation and curettage. LNG-IUS: levonogestrel containing intrauterine system. GnRH: gonadotropin releasing hormone. Etc.: et cetera. IUD: intrauterine device.
(N93%) of surgically treated early-stage EC already noted. Therefore, to achieve a therapeutic progesterone level with less adverse systemic effects of high-dose progestin, we tried a pilot study of MPA 500 mg/day plus LNG-IUS for early-stage EC in young women and found that complete remission occurred in 4 of 5 patients, while one patient showed partial remission [17]. When performing these conservative managements of endometrial carcinoma, accurate assessment of response of the endometrium to hormonal therapy is most important. Therefore, endometrial evaluation should be performed periodically during the treatment, and usually treatment response is assessed every 3–6 months by endometrial biopsy [6,7]. Table 3 summarized the diagnostic and follow-up evaluation methods used for conservative treatment with LNG-IUS in women with EC. However, there was no data about the most accurate method among various methods such as endometrial aspiration biopsy with LNG-IUS in place, D&C after removal of LNG-IUS and hysteroscopic biopsy. Because a reliable assessment for therapeutic effectiveness is essential to determine the sustainability of conservative hormonal treatment of EC, we compared a diagnostic accuracy of D&C under the condition that LNG-IUS was removed with endometrial aspiration biopsy versus the LNG-IUS kept in the uterus. The clinical significance of this study is the first study to do endometrial assessment when using the LNG-IUS. There have been several studies about the accuracy of D&C and endometrial aspiration biopsy for diagnosis of EC when LNG-IUS is not in the uterus. Until recently, the gold standard for diagnosis of EC is considered D&C but endometrial aspiration biopsy seems to be as accurate in the detection of endometrial carcinoma as D&C [21]. However, Leitao et al. reported that the accuracy of these two methods in determining FIGO grade appears to differ. According to the study, D&C provides a more accurate reflection of true FIGO grade than does endometrial aspiration biopsy; the final post-hysterectomy FIGO grade was higher in 16/187 (8.7%) cases diagnosed by D&C compared to 52/298(17.4%) diagnosed by endometrial aspiration biopsy. Therefore they said that in patients being considered for uterine preservation, D&C should be performed prior to initiating progestational therapies [22]. Our results showed that the diagnostic accuracy of endometrial aspiration biopsy with LNG-IUS in place was very poor. Furthermore, a high prevalence of insufficient tissue for pathologic evaluation was noted with endometrial aspiration biopsy. It is likely that the volume of endometrial tissues being collected for endometrial aspiration biopsy was less due to oral progestin and LNG-IUS-induced endometrial atrophy and due to LNG-IUS mechanical interference with the aspiration biopsy. Clark et al. reported the positive predictive value of endometrial aspiration biopsy as 81.7% in their systematic quantitative review that analyzed published research of endometrial aspiration biopsy done for diagnosing EC in women with abnormal uterine bleeding. However, they announced that in postmenopausal women, the percentage of
histologically inadequate samples (no specimen obtained or insufficient for adequate assessment) was up to 20% [23]. In addition, according to a prospective cohort study of 913 women presenting with postmenopausal bleeding by van Doorn et al., among 403 patients who underwent office endometrial sampling, 66 patients had tissue not sufficient for pathologic characterization and further investigation revealed an endometrial malignancy in 3 of these 66 women [24]. When using oral progestin and LNG-IUS, the number of cases where there is insufficient tissue for pathologic evaluation could be increased due to endometrial atrophy like postmenopausal status. Therefore in these cases, we must pay more attention because non-diagnostic endometrial tissue does not rule out EC. However, endometrial aspiration biopsy may be useful in sometime, because there was no false positive case. So endometrial aspiration biopsy cannot be substitute of D&C, but it may detect unnecessary D&C. In conclusion, endometrial aspiration biopsy with LNG-IUS in place is less accurate than D&C after removal of LNG-IUS and may be not reliable for follow-up evaluation method in patients treated with high-dose oral progestin plus LNG-IUS for early-stage EC. This study has limitations in that only a small number of patients participated in the study, so a large scale prospective study is required to confirm our finding. Conflict of interest The authors report no conflict of interest.
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