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Specific hysteroscopic findings can efficiently distinguish the differences between malignant and benign endometrial polyps
Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 85e90
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Specific hysteroscopic findings can efficiently distinguish the differences between malignant and benign endometrial polyps Yeh Giin Ngo a, Hung-Chun Fu b, Li-Ching Chu a, Chih-Wen Tseng a, Chao-Yu Chen a, Chung-Yuan Lee a, c, Yu-Che Ou a, b, * a b c
Department of Obstetrics and Gynecology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Nursing, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 16 September 2019
Objective: To evaluate differences in hysteroscopic findings between benign endometrial polyps and endometrial cancer. Materials and methods: From January 2012 to December 2016, we extracted 179 cases with endometrial polyps from 3066 women who underwent hysteroscopy followed by dilatation and curettage or transcervical resection, with 154 and 25 cases of benign and malignant endometrial polyps, respectively. Clinical characteristics, histopathological and hysteroscopic findings of the women were evaluated retrospectively. Results: The hysteroscopic findings of malignant polyps were hyper-vascular (72%, 18/25), ulcerative (64%, 16/25) and polyps with irregular surfaces (24%, 6/25). In contrast, pedunculate small growths with smooth surfaces were usually seen in the benign endometrial polyps (38.3%, 59/154). Hyper-vascular (OR: 142.6, 95% CI: 25.98e783.4) and polyps with irregular surfaces (OR: 12.02, 95% CI: 1.765e81.83) in hysteroscopic findings were significant strong predictors of endometrial polyps with endometrial cancer. Hysteroscopic findings of ulcerative changes were most strongly associated with a diagnosis of malignant polyps, with sensitivity, specificity, negative (NPV) and positive (PPV) predictive values of 64.0%, 100%, 94.5%, and 100%, respectively. Conclusion: Women with hysteroscopic findings of endometrial polyps with hyper-vascular, ulcerative, and polyps with irregular surfaces had a high likelihood of endometrial cancer. A target biopsy of the polyps with these specific appearances should be performed to exclude malignant lesions. © 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Differential diagnoses Endometrial cancer Hysteroscopy Polyps
Introduction Endometrial polyps are hyperplastic overgrowths of endometrial glands and stroma projecting above the epithelium [1]. Endometrial polyps are one of the most common etiologies of abnormal uterine bleeding (AUB) in both premenopausal and postmenopausal women [2,3]. Endometrial polyps can be diagnosed with both noninvasive and invasive techniques [4]. Transvaginal ultrasound (TVUS) has been reported to have a sensitivity of 51% and specificity of 95% for diagnosing endometrial polyps [5,6]. Saline infusion sonography is also used to detect endometrial polyps, with a reported sensitivity * Corresponding author. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. E-mail address: [email protected] (Y.-C. Ou).
of 87% and specificity of 93%. However, it is difficult to differentiate benign and malignant endometrial polyps under ultrasonography [6]. Hysteroscopy is widely used because of its ability to detect endometrial polyps with a specificity of 93% and sensitivity of 90% [3,4]. The direct visualization provided by hysteroscopy allows for biopsy of the most suspicious lesions. The gold standard method to detect malignant polyps is a biopsy with histologic examination. It is important to perform an accurate biopsy of the lesions, as blind sampling or biopsy with dilatation and curettage (D&C) is inaccurate since it has low sensitivity but high specificity [4,7]. In addition, Su et al. reported that transcervical resection (TCR) can provide more precise grading information than D&C [8]. Older age [9,10], postmenopausal bleeding [2,11,12], and larger polyp size [13] have been significantly associated with malignant changes. In addition, Su et al. reported that a glomerular pattern
https://doi.org/10.1016/j.tjog.2019.11.013 1028-4559/© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. 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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was associated with a high risk of moderate or high-grade endometrioid adenocarcinoma [14]. However, little is known about differences in hysteroscopic findings between benign and malignant endometrial polyps. We hypothesized that hysteroscopy could be used to identify lesions that need further evaluation. Hence, in this study, we focused on the hysteroscopic findings of endometrial lesions projecting out from the endometrium with a final pathologic diagnosis of carcinoma and benign polyps. The aim of this study was to investigate the morphology of benign and malignant endometrial polyps under hysteroscopy using statistical analysis so that practitioners can promptly identify endometrial malignancies.
Materials and methods Patients From January 2012 to December 2016, we retrospectively reviewed 3066 women who underwent hysteroscopy due to abnormal vaginal bleeding, intrauterine cavity lesions suspected on ultrasonography, recurrent spontaneous abortion, or to evaluate infertility at Chiayi Chang Gung Memorial Hospital. We enrolled 214 cases with endometrial polyps which were found during hysteroscopy and subject to D&C or TCR, and their tissues were obtained for a pathological diagnosis.
Fig. 1. Study selection process.
Y.G. Ngo et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 85e90
87
We reviewed the chart records and imaging findings of hysteroscopy described by Dr. YG Ngo and Dr. YC Ou to reduce potential bias. After a panel discussion, we excluded 35 cases with unsatisfactory hysteroscopic findings such as poor visibility, active profuse uterine bleeding, and submucosal myoma. We eventually included 179 cases with endometrial polyps or polyps with endometrial cancer (Fig. 1). Clinical characteristics including age, parity, body mass index (BMI), signs and symptoms, clinical presentation, menopausal status, medical diseases, and breast cancer treated with tamoxifen were recorded. All tissues obtained were sent for pathologic evaluations. This study was approved by the Ethics Committee of Chang Gung Medical Foundation Institutional Review Board (approval reference number: 201700136B0; date of approval: 20 February 2017).
intertwined branching (marked with arrowheads in Fig. 2A) on the surface of the endometrial polyps (Fig. 2A).
Hysteroscopic appearance
Reddish color, congestion, pedunculate and smooth surface
In this study, three major features of malignant polyps were identified, including hyper-vascular, ulcerative, and polyps with irregular surfaces. In addition, polyps with a reddish color and congestion signs were also described. Medical records and images were available for all patients.
Congested, reddish, pedunculate small growths with a smooth surface without atypia rinsing in infused water were also noted (Fig. 2D, E, F).
Hyper-vascular
We analyzed the characteristics of the hysteroscopic findings and final pathology reports. Final pathologies were based on tissues obtained during surgery, either from hysteroscopy and D&C or TCR. Women with endometrial polyps were divided into two groups:
Hyper-vascular was defined as tortuous vascularization with irregular or deformed structures, blind ends, and abnormal
Ulcerative The pattern of ulcerative was defined as a focal yellowish coating (marked with asterisk in Fig. 2B) on the surface of the polyps (Fig. 2B). Polyps with irregular surfaces Soft colonies of polyps projecting from the endometrium were noted during hysteroscopy (Fig. 2C) and were defined as polyps with irregular surfaces.
Data analysis
Fig. 2. (A) Hyper-vascular (marked with arrowheads) on the surface of endometrial polyps. (B) Focal ulcerative changes (marked with asterisk *) on the surface of polyps. (C) Polyps with irregular surfaces. (D,E,F) Benign endometrial polyps.
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those with a final pathology of endometrial cancer in Group 1, and those with benign endometrial polyps in Group 2. Statistical analysis We used Fisher's exact test and the Student's t-test to retrospectively analyze correlations between clinical data, hysteroscopic findings, and final histopathologic results. Multivariate analysis using regression analysis was used to evaluate the predictors of endometrial polyps with endometrial cancer and included the covariates in univariate analysis with p-values <0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A p-value <0.05 was considered to be statistically significant. Sensitivity and specificity of receiver operating characteristic (ROC) curves were calculated using Youden's Index. Negative (NPV) and positive predictive values (PPV) of each specific hysteroscopic finding in diagnosing benign and malignant polyps were calculated. All statistical calculations were performed using SPSS software for Windows version 20 (SPSS Inc., Chicago, IL, USA). Results The mean ages of the 179 cases with endometrial polyps or polyps with endometrial cancer were 44.1 years (SD: ±9.6) and 55.3 years (SD: ±14.7), respectively. The characteristics and hysteroscopy findings of the women are shown in Table 1. Of the 179 cases, the polyps in 60 (33.5%) women had a congested appearance, and 98.3% (59/60) of these cases were benign endometrial polyps. All of the patients with malignant disease had endometrial cancer, and 88% (22/25) of these cases had the
endometrioid type. The majority of these patients (72%, 18/25) had endometrial polyps with hyper-vascular (deformed structures or vascular atypia on the surface of the polyps), 64% (16/25) had ulcerative on the polyps, 56.3% (9/16) had focal changes on the base of the polyps, and others had yellowish ulcerative changes on top of the polyps or on the whole polyp surface. In addition, 6/25 (24%) patients had polyps with irregular surfaces on the endometrial surface (Table 1). In order to evaluate the factors associated with the risk of endometrial polyps with endometrial cancer, we performed multivariate analysis on the following variables: age, gravida, parity, BMI, menopausal status, and hysteroscopy findings (Table 2 and Table 3). The results of the multivariate analysis revealed that older age (OR: 1.115, 95% CI ¼ 1.013e1.228), higher BMI (OR:1.168, 95% CI: 1.019e1.337), and endometrium thickness (OR: 6.506, CI: 2.109e20.06) were significant predictors of endometrial polyps with endometrial cancer. Hyper-vascular (OR: 142.6, 95% CI: 25.98e783.4), polyps with irregular surfaces (OR: OR: 12.02, 95% CI: 1.765e81.83) in hysteroscopy findings were significant strong predictors of endometrial polyps with endometrial cancer. In contrast, congestive changes were found mostly in benign endometrial polyps (OR: 0.46, 95% CI: 0.004e0.544). The specific hysteroscopic findings of malignant endometrial polyps had different degrees of diagnostic accuracy, with the PPV ranging from 50.0% for polyps with irregular surfaces to 100% for ulcerative changes. The sensitivities, specificities, NPVs and PPVs are listed in Table 4. For the diagnosis of malignant endometrial polyps, we performed ROC curve analysis to assess the diagnostic value of specific hysteroscopic findings. The areas under the curve (AUC) of hyper-
Table 1 The characteristics of the women. Baseline Characteristic
Overalla
Benign endometrial polypsa
Endometrial polyps with cancera
Age (years) Gravida Parity BMI (kg/m2) Menopausal status (%) PMB Tamoxifen usec (%) Hysteroscopy findings Hyper-vascular (%) Ulcerative (%) Polyps with irregular surfaces (%) Congestive changes (%)
22 16 12 60
(n ¼ 179)
(n ¼ 154)
(n ¼ 25)
45.7 ± 11.1 2.2 ± 1.3 2.1 ± 1.3 23.7 ± 4.8 55 (30.7) 22 (12.4) 11 (6.2)
44.1 ± 9.6 2.1 ± 1.2 2.0 ± 1.3 23.1 ± 4.3 39 (25.3) 11 (7.2) 10 (6.5)
55.3 ± 14.7 2.5 ± 1.6 2.3 ± 1.6 26.79 ± 6.2 16 (64.0) 11 (44.0) 1 (4.0)
<0.05* 0.23 0.44 0.011* <0.001* <0.001* 0.625
4 (2.6) 0 (0.0) 6 (3.9) 59 (38.3)
18 (72.0) 16 (64.0) 6 (24.0) 1 (4.0)
<0.001* <0.001* 0.002* 0.001*
(12.3) (8.9) (6.7) (33.5)
p-valueb
BMI: body mass index, PMB: postmenopausal bleeding. *p-value < 0.05. a Values are expressed as mean ± standard deviation, or number (%) of patients. b Analyzed using SPSS Ver. 22, Independent-Sample T Test. c Breast cancer treated with tamoxifen. Table 2 Univariate and multivariate regression analyses of clinical data with the risk of endometrial cancer. Variable
Age (years) Gravida yes vs no Parity yes vs no BMI (kg/m2) Menopause yes vs no PMB yes vs no Breast cancer yes vs no EM thickness
Univariate analysis
Multivariate analysis
OR
95% CI
p value
OR
95% C.I.
p-value
1.092 1.503 0.983 1.17 5.242 10.14 1.678 3.101
1.048e1.137 0.418e5.409 0.340e2.840 1.059e1.293 2.145e12.81 3.732e27.57 0.205e13.71 1.578e5.742
<0.001* 0.533 0.983 0.002* <0.001* <0.001* 0.629 0.001*
1.115 1.240 0.096 1.168 1.218 7.500 0.054 6.506
1.013e1.228 0.365e4.216 0.005e1.727 1.019e1.337 0.158e9.386 0.958e58.67 0.002e1.557 2.109e20.06
0.026* 0.161 0.112 0.024* 0.849 0.054 0.088 0.001*
Abbreviations: OR: odds ratio, CI: confidence interval, BMI: body mass index, PMB: postmenopausal bleeding, EM: endometrium. *p-value < 0.05.
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Table 3 Univariate and multivariate regression analyses of different hysteroscopy findings with the risk of endometrial cancer. Variable
Univariate analysis
Hyper-vascular yes vs no polyps with irregular surfaces yes vs no Congestive changes yes vs no
Multivariate analysis
OR
95% CI
p value
OR
95% CI
p-value
96.42 7.789 0.067
25.70e361.7 2.281e26.60 0.009e0.509
<0.001* 0.001* 0.009*
142.6 12.02 0.46
25.98e783.4 1.765e81.83 0.004e0.544
<0.001* 0.011* 0.015*
Abbreviations: OR: odds ratio, CI: confidence interval. *p-value < 0.05.
vascular (Fig. 3A), ulcerative (Fig. 3B) and polyps with irregular surfaces (Fig. 3C) were 0.847 (95% CI: 0.740e0.954), 0.82 (95% CI: 0.703e0.937) and 0.601 (95% CI: 0.468e0.733), respectively. If we combined the findings to differentiate malignant polyps, the AUC
was 0.968 (95% CI: 0.922e1.0) (Fig. 3D). The sensitivity and specificity were 96% and 93.5%, respectively. Combined, the specific findings were significant in discriminating patients with malignant polyps from those with benign polyps.
Table 4 Accuracy of specific hysteroscopic findings.
Sensitivity (%) Specificity (%) Negative predictive value (%) Positive predictive value (%)
Benign
Malignant
Congestive changes
Hyper- vascular
Ulcerative changes
Polyps with irregular surfaces
38.3 96.0 20.2 98.3
72.0 97.4 95.5 81.8
64.0 100 94.5 100
24 96.1 88.6 50.0
Fig. 3. ROC curve of hysteroscopic appearance of malignant polyps. (A) Hyper-vascular. (B) Focal ulcerative changes on the surface of polyps. (C) Polyps with irregular surfaces. (D) Combinations of all these findings.
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Discussion In this retrospective study, hysteroscopic findings of endometrial polyps with hyper-vascular (deformed structures or vascular atypia on the surface of the polyps), ulcerative or polyps with irregular surfaces were significant predictors of malignant endometrial polyps with a high AUC (0.968 [95% CI: 0.922e1.0]), sensitivity of 96% and specificity of 93.5%. Specific hysteroscopic findings could significantly differentiate malignant polyps from benign polyps (Fig. 2). Older age [9,10], postmenopausal bleeding [2,11,12], and larger polyp size have been reported to be significantly associated with malignant changes. Being older than 60 years and having postmenopausal bleeding have also been associated with increased risks of pre-neoplastic and neoplastic lesions [15,16]. Our findings are similar, in that older age (OR: 1.115, 95% CI: 1.013e1.228), higher BMI (OR: 1.168, 95% CI: 1.019e1.337), and endometrium thickness (OR: 6.506, CI: 2.109e20.06) were significant predictors of malignant endometrial polyps. Dias et al. reported that postmenopausal bleeding, endometrial hypervascularization and vascular atypia in diagnostic hysteroscopy were strongly associated with endometrial cancer [16]. In addition, they reported that signs of diffuse hypervascularization with vascular atypia were observed in 36.4% of their patients with endometrial cancer, although without statistical significance. Su et al. analyzed only endometrial glomerular patterns, and concluded that women with hysteroscopic glomerular patterns had a high rate of moderate or high-grade adenocarcinoma [14]. In 2018, Dueholm et al. reported that risk of endometrial cancer (REC) scoring system for TVUS had a sensitivity of 92.5% and specificity of 93% for predicting endometrial cancer with REC scores of 3 [17]. The current study is the first to statistically analyze more than one specific appearance of benign and malignant endometrial polyps in hysteroscopy. Our findings may provide a more efficient diagnostic strategy during daily practice [18,19]. There are several limitations to this study, including the number of cases, the retrospective review of medical records of hysteroscopic findings and descriptions of medical records with individual differences. In addition, the number of cases was unbalanced between the benign and malignant polyp groups. Moreover, the potential of selection bias and individual differences in the descriptions of hysteroscopic findings are the main limitation of this retrospective study. Medical records and images were available for all patients, and all images were reviewed with the pathology and patient characteristics blinded to reduce potential bias. Under the number of cases, our data showed that specific hysteroscopic findings were significantly associated with malignant lesions. Prospective research and more studies are necessary to confirm our findings. Conclusions Women with hysteroscopic findings of endometrial polyps with hyper-vascular, ulcerative, and polyps with irregular surfaces had a high likelihood of endometrial cancer, with PPVs ranging from 50.0% for an appearance of polyps with irregular surfaces to 100% for polyps with ulcerative. These findings may facilitate decision-
making during surgery and help to perform accurate biopsies. Target biopsies of polyps with these special appearances should be performed to exclude malignant lesions. Declaration of Competing Interest The authors have no conflicts of interest relevant to this article. Acknowledgment We thank ATS Medical Editing Services for language editing. We appreciated the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistical work. References [1] Garuti G, et al. Prognostic significance of hysteroscopic imaging in endometrioid endometrial adenocarcinoma. Gynecol Oncol 2001;81(3):408e13. [2] Stephanie Cruz Lee M, Andrew M, Kaunitz MD, Luis Sanchez-Ramos MD, Ronald M, Rhatigan MD. The oncogenic potential of endometrial polyps. Obstet Gynecol 2010;116(5). [3] Gkrozou F, et al. Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies. Arch Gynecol Obstet 2015;291(6):1347e54. [4] Salim S, et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol 2011;18(5):569e81. [5] Alev Ozer SO. Mine Kanat-Pektas, Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Turkish women with abnormal uterine bleeding. J Obstet Gynaecol Res 2016;42(5):573e8. [6] Maheux-Lacroix S, et al. Imaging for polyps and leiomyomas in women with abnormal uterine bleeding: a systematic review. Obstet Gynecol 2016;128(6): 1425e36. [7] van Hanegem N, et al. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2016;197:147e55. [8] Su H, et al. Accuracy of hysteroscopic biopsy, compared to dilation and curettage, as a predictor of final pathology in patients with endometrial cancer. Taiwan J Obstet Gynecol 2015;54(6):757e60. [9] Baiocchi G, et al. Malignancy in endometrial polyps: a 12-year experience. Am J Obstet Gynecol 2009;201(5):462 e1e4. [10] Sandra Bel CB. Julien godet, victor viviani, cherif akladios, aline host, emilie faller, thomas boisrame, michel hummel, jean-jacques baldauf, lise lecointre, olivier garbin, Risk of malignancy on suspicion of polyps in menopausal women. Eur J Obstet Gynecol Reprod Biol 2017;216:138e42. [11] Wethington SL, et al. Risk and predictors of malignancy in women with endometrial polyps. Ann Surg Oncol 2011;18(13):3819e23. [12] Sasaki LMP, et al. Factors associated with malignancy in hysteroscopically resected endometrial polyps: a systematic review and meta-analysis. J Minim Invasive Gynecol 2018;25(5):777e85. [13] Ben-Arie A, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004;115(2):206e10. [14] Su H, et al. A novel hysteroscopic pattern of microvascular architecture in uterine endometrioid adenocarcinoma: initial clinical experience. Gynecol Minim Invasive Ther 2016;5(4):152e5. [15] Daniele A, Ferrero A, Maggiorotto F, Perrini G, Volpi E, Sismondi P. Suspecting malignancy in endometrial polyps: value of hysteroscopy. Tumori 2013;99(2): 204e9. [16] Dias DS, et al. Usefulness of clinical, ultrasonographic, hysteroscopic, and immunohistochemical parameters in differentiating endometrial polyps from endometrial cancer. J Minim Invasive Gynecol 2014;21(2):296e302. [17] Dueholm M, et al. Ultrasound scoring of endometrial pattern for fast-track identification or exclusion of endometrial cancer in women with postmenopausal bleeding. J Minim Invasive Gynecol 2018. [18] Elyashiv O, et al. Hysterscopic resection of premalignant and malignant endometrial polyps: is it a safe alternative to hysterectomy? J Minim Invasive Gynecol 2017;24(7):1200e3. [19] Pivano A, et al. Risk of coexisting endometrial carcinoma in case of atypical endometrial hyperplasia diagnosed on total hysteroscopic resection. Eur J Obstet Gynecol Reprod Biol 2016;203:210e3.
Contents lists available at ScienceDirect
Taiwanese Journal of Obstetrics & Gynecology journal homepage: www.tjog-online.com
Original Article
Specific hysteroscopic findings can efficiently distinguish the differences between malignant and benign endometrial polyps Yeh Giin Ngo a, Hung-Chun Fu b, Li-Ching Chu a, Chih-Wen Tseng a, Chao-Yu Chen a, Chung-Yuan Lee a, c, Yu-Che Ou a, b, * a b c
Department of Obstetrics and Gynecology, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Department of Nursing, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 16 September 2019
Objective: To evaluate differences in hysteroscopic findings between benign endometrial polyps and endometrial cancer. Materials and methods: From January 2012 to December 2016, we extracted 179 cases with endometrial polyps from 3066 women who underwent hysteroscopy followed by dilatation and curettage or transcervical resection, with 154 and 25 cases of benign and malignant endometrial polyps, respectively. Clinical characteristics, histopathological and hysteroscopic findings of the women were evaluated retrospectively. Results: The hysteroscopic findings of malignant polyps were hyper-vascular (72%, 18/25), ulcerative (64%, 16/25) and polyps with irregular surfaces (24%, 6/25). In contrast, pedunculate small growths with smooth surfaces were usually seen in the benign endometrial polyps (38.3%, 59/154). Hyper-vascular (OR: 142.6, 95% CI: 25.98e783.4) and polyps with irregular surfaces (OR: 12.02, 95% CI: 1.765e81.83) in hysteroscopic findings were significant strong predictors of endometrial polyps with endometrial cancer. Hysteroscopic findings of ulcerative changes were most strongly associated with a diagnosis of malignant polyps, with sensitivity, specificity, negative (NPV) and positive (PPV) predictive values of 64.0%, 100%, 94.5%, and 100%, respectively. Conclusion: Women with hysteroscopic findings of endometrial polyps with hyper-vascular, ulcerative, and polyps with irregular surfaces had a high likelihood of endometrial cancer. A target biopsy of the polyps with these specific appearances should be performed to exclude malignant lesions. © 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Differential diagnoses Endometrial cancer Hysteroscopy Polyps
Introduction Endometrial polyps are hyperplastic overgrowths of endometrial glands and stroma projecting above the epithelium [1]. Endometrial polyps are one of the most common etiologies of abnormal uterine bleeding (AUB) in both premenopausal and postmenopausal women [2,3]. Endometrial polyps can be diagnosed with both noninvasive and invasive techniques [4]. Transvaginal ultrasound (TVUS) has been reported to have a sensitivity of 51% and specificity of 95% for diagnosing endometrial polyps [5,6]. Saline infusion sonography is also used to detect endometrial polyps, with a reported sensitivity * Corresponding author. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. E-mail address: [email protected] (Y.-C. Ou).
of 87% and specificity of 93%. However, it is difficult to differentiate benign and malignant endometrial polyps under ultrasonography [6]. Hysteroscopy is widely used because of its ability to detect endometrial polyps with a specificity of 93% and sensitivity of 90% [3,4]. The direct visualization provided by hysteroscopy allows for biopsy of the most suspicious lesions. The gold standard method to detect malignant polyps is a biopsy with histologic examination. It is important to perform an accurate biopsy of the lesions, as blind sampling or biopsy with dilatation and curettage (D&C) is inaccurate since it has low sensitivity but high specificity [4,7]. In addition, Su et al. reported that transcervical resection (TCR) can provide more precise grading information than D&C [8]. Older age [9,10], postmenopausal bleeding [2,11,12], and larger polyp size [13] have been significantly associated with malignant changes. In addition, Su et al. reported that a glomerular pattern
https://doi.org/10.1016/j.tjog.2019.11.013 1028-4559/© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. 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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was associated with a high risk of moderate or high-grade endometrioid adenocarcinoma [14]. However, little is known about differences in hysteroscopic findings between benign and malignant endometrial polyps. We hypothesized that hysteroscopy could be used to identify lesions that need further evaluation. Hence, in this study, we focused on the hysteroscopic findings of endometrial lesions projecting out from the endometrium with a final pathologic diagnosis of carcinoma and benign polyps. The aim of this study was to investigate the morphology of benign and malignant endometrial polyps under hysteroscopy using statistical analysis so that practitioners can promptly identify endometrial malignancies.
Materials and methods Patients From January 2012 to December 2016, we retrospectively reviewed 3066 women who underwent hysteroscopy due to abnormal vaginal bleeding, intrauterine cavity lesions suspected on ultrasonography, recurrent spontaneous abortion, or to evaluate infertility at Chiayi Chang Gung Memorial Hospital. We enrolled 214 cases with endometrial polyps which were found during hysteroscopy and subject to D&C or TCR, and their tissues were obtained for a pathological diagnosis.
Fig. 1. Study selection process.
Y.G. Ngo et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 85e90
87
We reviewed the chart records and imaging findings of hysteroscopy described by Dr. YG Ngo and Dr. YC Ou to reduce potential bias. After a panel discussion, we excluded 35 cases with unsatisfactory hysteroscopic findings such as poor visibility, active profuse uterine bleeding, and submucosal myoma. We eventually included 179 cases with endometrial polyps or polyps with endometrial cancer (Fig. 1). Clinical characteristics including age, parity, body mass index (BMI), signs and symptoms, clinical presentation, menopausal status, medical diseases, and breast cancer treated with tamoxifen were recorded. All tissues obtained were sent for pathologic evaluations. This study was approved by the Ethics Committee of Chang Gung Medical Foundation Institutional Review Board (approval reference number: 201700136B0; date of approval: 20 February 2017).
intertwined branching (marked with arrowheads in Fig. 2A) on the surface of the endometrial polyps (Fig. 2A).
Hysteroscopic appearance
Reddish color, congestion, pedunculate and smooth surface
In this study, three major features of malignant polyps were identified, including hyper-vascular, ulcerative, and polyps with irregular surfaces. In addition, polyps with a reddish color and congestion signs were also described. Medical records and images were available for all patients.
Congested, reddish, pedunculate small growths with a smooth surface without atypia rinsing in infused water were also noted (Fig. 2D, E, F).
Hyper-vascular
We analyzed the characteristics of the hysteroscopic findings and final pathology reports. Final pathologies were based on tissues obtained during surgery, either from hysteroscopy and D&C or TCR. Women with endometrial polyps were divided into two groups:
Hyper-vascular was defined as tortuous vascularization with irregular or deformed structures, blind ends, and abnormal
Ulcerative The pattern of ulcerative was defined as a focal yellowish coating (marked with asterisk in Fig. 2B) on the surface of the polyps (Fig. 2B). Polyps with irregular surfaces Soft colonies of polyps projecting from the endometrium were noted during hysteroscopy (Fig. 2C) and were defined as polyps with irregular surfaces.
Data analysis
Fig. 2. (A) Hyper-vascular (marked with arrowheads) on the surface of endometrial polyps. (B) Focal ulcerative changes (marked with asterisk *) on the surface of polyps. (C) Polyps with irregular surfaces. (D,E,F) Benign endometrial polyps.
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those with a final pathology of endometrial cancer in Group 1, and those with benign endometrial polyps in Group 2. Statistical analysis We used Fisher's exact test and the Student's t-test to retrospectively analyze correlations between clinical data, hysteroscopic findings, and final histopathologic results. Multivariate analysis using regression analysis was used to evaluate the predictors of endometrial polyps with endometrial cancer and included the covariates in univariate analysis with p-values <0.05. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A p-value <0.05 was considered to be statistically significant. Sensitivity and specificity of receiver operating characteristic (ROC) curves were calculated using Youden's Index. Negative (NPV) and positive predictive values (PPV) of each specific hysteroscopic finding in diagnosing benign and malignant polyps were calculated. All statistical calculations were performed using SPSS software for Windows version 20 (SPSS Inc., Chicago, IL, USA). Results The mean ages of the 179 cases with endometrial polyps or polyps with endometrial cancer were 44.1 years (SD: ±9.6) and 55.3 years (SD: ±14.7), respectively. The characteristics and hysteroscopy findings of the women are shown in Table 1. Of the 179 cases, the polyps in 60 (33.5%) women had a congested appearance, and 98.3% (59/60) of these cases were benign endometrial polyps. All of the patients with malignant disease had endometrial cancer, and 88% (22/25) of these cases had the
endometrioid type. The majority of these patients (72%, 18/25) had endometrial polyps with hyper-vascular (deformed structures or vascular atypia on the surface of the polyps), 64% (16/25) had ulcerative on the polyps, 56.3% (9/16) had focal changes on the base of the polyps, and others had yellowish ulcerative changes on top of the polyps or on the whole polyp surface. In addition, 6/25 (24%) patients had polyps with irregular surfaces on the endometrial surface (Table 1). In order to evaluate the factors associated with the risk of endometrial polyps with endometrial cancer, we performed multivariate analysis on the following variables: age, gravida, parity, BMI, menopausal status, and hysteroscopy findings (Table 2 and Table 3). The results of the multivariate analysis revealed that older age (OR: 1.115, 95% CI ¼ 1.013e1.228), higher BMI (OR:1.168, 95% CI: 1.019e1.337), and endometrium thickness (OR: 6.506, CI: 2.109e20.06) were significant predictors of endometrial polyps with endometrial cancer. Hyper-vascular (OR: 142.6, 95% CI: 25.98e783.4), polyps with irregular surfaces (OR: OR: 12.02, 95% CI: 1.765e81.83) in hysteroscopy findings were significant strong predictors of endometrial polyps with endometrial cancer. In contrast, congestive changes were found mostly in benign endometrial polyps (OR: 0.46, 95% CI: 0.004e0.544). The specific hysteroscopic findings of malignant endometrial polyps had different degrees of diagnostic accuracy, with the PPV ranging from 50.0% for polyps with irregular surfaces to 100% for ulcerative changes. The sensitivities, specificities, NPVs and PPVs are listed in Table 4. For the diagnosis of malignant endometrial polyps, we performed ROC curve analysis to assess the diagnostic value of specific hysteroscopic findings. The areas under the curve (AUC) of hyper-
Table 1 The characteristics of the women. Baseline Characteristic
Overalla
Benign endometrial polypsa
Endometrial polyps with cancera
Age (years) Gravida Parity BMI (kg/m2) Menopausal status (%) PMB Tamoxifen usec (%) Hysteroscopy findings Hyper-vascular (%) Ulcerative (%) Polyps with irregular surfaces (%) Congestive changes (%)
22 16 12 60
(n ¼ 179)
(n ¼ 154)
(n ¼ 25)
45.7 ± 11.1 2.2 ± 1.3 2.1 ± 1.3 23.7 ± 4.8 55 (30.7) 22 (12.4) 11 (6.2)
44.1 ± 9.6 2.1 ± 1.2 2.0 ± 1.3 23.1 ± 4.3 39 (25.3) 11 (7.2) 10 (6.5)
55.3 ± 14.7 2.5 ± 1.6 2.3 ± 1.6 26.79 ± 6.2 16 (64.0) 11 (44.0) 1 (4.0)
<0.05* 0.23 0.44 0.011* <0.001* <0.001* 0.625
4 (2.6) 0 (0.0) 6 (3.9) 59 (38.3)
18 (72.0) 16 (64.0) 6 (24.0) 1 (4.0)
<0.001* <0.001* 0.002* 0.001*
(12.3) (8.9) (6.7) (33.5)
p-valueb
BMI: body mass index, PMB: postmenopausal bleeding. *p-value < 0.05. a Values are expressed as mean ± standard deviation, or number (%) of patients. b Analyzed using SPSS Ver. 22, Independent-Sample T Test. c Breast cancer treated with tamoxifen. Table 2 Univariate and multivariate regression analyses of clinical data with the risk of endometrial cancer. Variable
Age (years) Gravida yes vs no Parity yes vs no BMI (kg/m2) Menopause yes vs no PMB yes vs no Breast cancer yes vs no EM thickness
Univariate analysis
Multivariate analysis
OR
95% CI
p value
OR
95% C.I.
p-value
1.092 1.503 0.983 1.17 5.242 10.14 1.678 3.101
1.048e1.137 0.418e5.409 0.340e2.840 1.059e1.293 2.145e12.81 3.732e27.57 0.205e13.71 1.578e5.742
<0.001* 0.533 0.983 0.002* <0.001* <0.001* 0.629 0.001*
1.115 1.240 0.096 1.168 1.218 7.500 0.054 6.506
1.013e1.228 0.365e4.216 0.005e1.727 1.019e1.337 0.158e9.386 0.958e58.67 0.002e1.557 2.109e20.06
0.026* 0.161 0.112 0.024* 0.849 0.054 0.088 0.001*
Abbreviations: OR: odds ratio, CI: confidence interval, BMI: body mass index, PMB: postmenopausal bleeding, EM: endometrium. *p-value < 0.05.
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Table 3 Univariate and multivariate regression analyses of different hysteroscopy findings with the risk of endometrial cancer. Variable
Univariate analysis
Hyper-vascular yes vs no polyps with irregular surfaces yes vs no Congestive changes yes vs no
Multivariate analysis
OR
95% CI
p value
OR
95% CI
p-value
96.42 7.789 0.067
25.70e361.7 2.281e26.60 0.009e0.509
<0.001* 0.001* 0.009*
142.6 12.02 0.46
25.98e783.4 1.765e81.83 0.004e0.544
<0.001* 0.011* 0.015*
Abbreviations: OR: odds ratio, CI: confidence interval. *p-value < 0.05.
vascular (Fig. 3A), ulcerative (Fig. 3B) and polyps with irregular surfaces (Fig. 3C) were 0.847 (95% CI: 0.740e0.954), 0.82 (95% CI: 0.703e0.937) and 0.601 (95% CI: 0.468e0.733), respectively. If we combined the findings to differentiate malignant polyps, the AUC
was 0.968 (95% CI: 0.922e1.0) (Fig. 3D). The sensitivity and specificity were 96% and 93.5%, respectively. Combined, the specific findings were significant in discriminating patients with malignant polyps from those with benign polyps.
Table 4 Accuracy of specific hysteroscopic findings.
Sensitivity (%) Specificity (%) Negative predictive value (%) Positive predictive value (%)
Benign
Malignant
Congestive changes
Hyper- vascular
Ulcerative changes
Polyps with irregular surfaces
38.3 96.0 20.2 98.3
72.0 97.4 95.5 81.8
64.0 100 94.5 100
24 96.1 88.6 50.0
Fig. 3. ROC curve of hysteroscopic appearance of malignant polyps. (A) Hyper-vascular. (B) Focal ulcerative changes on the surface of polyps. (C) Polyps with irregular surfaces. (D) Combinations of all these findings.
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Discussion In this retrospective study, hysteroscopic findings of endometrial polyps with hyper-vascular (deformed structures or vascular atypia on the surface of the polyps), ulcerative or polyps with irregular surfaces were significant predictors of malignant endometrial polyps with a high AUC (0.968 [95% CI: 0.922e1.0]), sensitivity of 96% and specificity of 93.5%. Specific hysteroscopic findings could significantly differentiate malignant polyps from benign polyps (Fig. 2). Older age [9,10], postmenopausal bleeding [2,11,12], and larger polyp size have been reported to be significantly associated with malignant changes. Being older than 60 years and having postmenopausal bleeding have also been associated with increased risks of pre-neoplastic and neoplastic lesions [15,16]. Our findings are similar, in that older age (OR: 1.115, 95% CI: 1.013e1.228), higher BMI (OR: 1.168, 95% CI: 1.019e1.337), and endometrium thickness (OR: 6.506, CI: 2.109e20.06) were significant predictors of malignant endometrial polyps. Dias et al. reported that postmenopausal bleeding, endometrial hypervascularization and vascular atypia in diagnostic hysteroscopy were strongly associated with endometrial cancer [16]. In addition, they reported that signs of diffuse hypervascularization with vascular atypia were observed in 36.4% of their patients with endometrial cancer, although without statistical significance. Su et al. analyzed only endometrial glomerular patterns, and concluded that women with hysteroscopic glomerular patterns had a high rate of moderate or high-grade adenocarcinoma [14]. In 2018, Dueholm et al. reported that risk of endometrial cancer (REC) scoring system for TVUS had a sensitivity of 92.5% and specificity of 93% for predicting endometrial cancer with REC scores of 3 [17]. The current study is the first to statistically analyze more than one specific appearance of benign and malignant endometrial polyps in hysteroscopy. Our findings may provide a more efficient diagnostic strategy during daily practice [18,19]. There are several limitations to this study, including the number of cases, the retrospective review of medical records of hysteroscopic findings and descriptions of medical records with individual differences. In addition, the number of cases was unbalanced between the benign and malignant polyp groups. Moreover, the potential of selection bias and individual differences in the descriptions of hysteroscopic findings are the main limitation of this retrospective study. Medical records and images were available for all patients, and all images were reviewed with the pathology and patient characteristics blinded to reduce potential bias. Under the number of cases, our data showed that specific hysteroscopic findings were significantly associated with malignant lesions. Prospective research and more studies are necessary to confirm our findings. Conclusions Women with hysteroscopic findings of endometrial polyps with hyper-vascular, ulcerative, and polyps with irregular surfaces had a high likelihood of endometrial cancer, with PPVs ranging from 50.0% for an appearance of polyps with irregular surfaces to 100% for polyps with ulcerative. These findings may facilitate decision-
making during surgery and help to perform accurate biopsies. Target biopsies of polyps with these special appearances should be performed to exclude malignant lesions. Declaration of Competing Interest The authors have no conflicts of interest relevant to this article. Acknowledgment We thank ATS Medical Editing Services for language editing. We appreciated the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistical work. References [1] Garuti G, et al. Prognostic significance of hysteroscopic imaging in endometrioid endometrial adenocarcinoma. Gynecol Oncol 2001;81(3):408e13. [2] Stephanie Cruz Lee M, Andrew M, Kaunitz MD, Luis Sanchez-Ramos MD, Ronald M, Rhatigan MD. The oncogenic potential of endometrial polyps. Obstet Gynecol 2010;116(5). [3] Gkrozou F, et al. Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies. Arch Gynecol Obstet 2015;291(6):1347e54. [4] Salim S, et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol 2011;18(5):569e81. [5] Alev Ozer SO. Mine Kanat-Pektas, Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Turkish women with abnormal uterine bleeding. J Obstet Gynaecol Res 2016;42(5):573e8. [6] Maheux-Lacroix S, et al. Imaging for polyps and leiomyomas in women with abnormal uterine bleeding: a systematic review. Obstet Gynecol 2016;128(6): 1425e36. [7] van Hanegem N, et al. The accuracy of endometrial sampling in women with postmenopausal bleeding: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2016;197:147e55. [8] Su H, et al. Accuracy of hysteroscopic biopsy, compared to dilation and curettage, as a predictor of final pathology in patients with endometrial cancer. Taiwan J Obstet Gynecol 2015;54(6):757e60. [9] Baiocchi G, et al. Malignancy in endometrial polyps: a 12-year experience. Am J Obstet Gynecol 2009;201(5):462 e1e4. [10] Sandra Bel CB. Julien godet, victor viviani, cherif akladios, aline host, emilie faller, thomas boisrame, michel hummel, jean-jacques baldauf, lise lecointre, olivier garbin, Risk of malignancy on suspicion of polyps in menopausal women. Eur J Obstet Gynecol Reprod Biol 2017;216:138e42. [11] Wethington SL, et al. Risk and predictors of malignancy in women with endometrial polyps. Ann Surg Oncol 2011;18(13):3819e23. [12] Sasaki LMP, et al. Factors associated with malignancy in hysteroscopically resected endometrial polyps: a systematic review and meta-analysis. J Minim Invasive Gynecol 2018;25(5):777e85. [13] Ben-Arie A, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol Reprod Biol 2004;115(2):206e10. [14] Su H, et al. A novel hysteroscopic pattern of microvascular architecture in uterine endometrioid adenocarcinoma: initial clinical experience. Gynecol Minim Invasive Ther 2016;5(4):152e5. [15] Daniele A, Ferrero A, Maggiorotto F, Perrini G, Volpi E, Sismondi P. Suspecting malignancy in endometrial polyps: value of hysteroscopy. Tumori 2013;99(2): 204e9. [16] Dias DS, et al. Usefulness of clinical, ultrasonographic, hysteroscopic, and immunohistochemical parameters in differentiating endometrial polyps from endometrial cancer. J Minim Invasive Gynecol 2014;21(2):296e302. [17] Dueholm M, et al. Ultrasound scoring of endometrial pattern for fast-track identification or exclusion of endometrial cancer in women with postmenopausal bleeding. J Minim Invasive Gynecol 2018. [18] Elyashiv O, et al. Hysterscopic resection of premalignant and malignant endometrial polyps: is it a safe alternative to hysterectomy? J Minim Invasive Gynecol 2017;24(7):1200e3. [19] Pivano A, et al. Risk of coexisting endometrial carcinoma in case of atypical endometrial hyperplasia diagnosed on total hysteroscopic resection. Eur J Obstet Gynecol Reprod Biol 2016;203:210e3.