Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps

Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps Luca Savelli, MD, a Pierandrea De Iaco, MD, a Donatella Santini, MD, b Federica Rosati, MD, a Tullio Ghi, MD, a Elettra Pignotti, BSc, c and Luciano Bovicelli, MD a Bologna, Italy OBJECTIVE: The purpose of this study was to determine the rate of benign, hyperplastic, and malignant endometrial polyps and whether clinical data can predict histopathologic outcome. STUDY DESIGN: Five hundred nine patients with endometrial polyps who consecutively underwent hysteroscopic removal of endometrial polyps over 48 months were identified from our gynecologic oncology surgical database. Medical reports provided clinical data. Statistical analysis was performed. RESULTS: Histologically, 358 polyps (70.3%) were benign; 131 polyps (25.7%) had simple or complex endometrial hyperplasia, 16 polyps (3.1%) had hyperplasia with atypia, and 4 polyps (0.8%) were cancerous. Polyps were divided into group A and group B, according to the risk of malignancy (group A, benign; group B, atypical hyperplastic and cancerous). Age, menopause status, and hypertension were associated significantly with group B. CONCLUSION: Endometrial polyps rarely become malignant, but hyperplastic changes are more common. Age, menopause status, and hypertension may increase the risk of premalignant and malignant polyps. To achieve complete removal of the polyp and a reliable histologic analysis, operative hysteroscopy should be offered to symptomatic patients or to patients with risk factors. ( 2003;188:927-31.) Key words: Endometrial polyps, hyperplasia, endometrial cancer, risk factors, hysteroscopy From the Departments of Obstetrics and Gynecology a and Pathology b and Rizzoli Research Institute, c University of Bologna. Received for publication June 28, 2002; revised August 14, 2002; accepted December 30, 2002. Reprint requests: Luca Savelli, MD, Department of Obstetrics and Gynecology, University of Bologna Via Massarenti, 13, 40138 Bologna, Italy. E-mail: lucasavelli@rocketmail.com 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/mob.2003.247 Endometrial polyps are localized overgrowths of endometrial tissue that is composed of a variable amount of glands, stroma, and blood vessels that is covered by epithelium. 1 They can be seen by hysteroscopy in women with abnormal uterine bleeding, but even incidentally diagnosed in asymptomatic women during a transvaginal sonography that is performed for other indications. The introduction of saline infusion sonography into clinical practice has led to the diagnosis of an increasing number of polyps. The prevalence in women with abnormal uterine bleeding varies widely in the literature, ranging around 10% to 30% in relation to hormonal status. 2-4 It has been calculated that, as a consistent proportion of endometrial polyps does not produce symptoms, the prevalence in the general female population can be estimated at approximately 24% to 25%. 5-8 The clinician has to face the issue of how to treat endometrial polyps because they are being diagnosed in growing numbers even in asymptomatic women and because their malignant potential is not understood fully yet. Polyps are believed commonly to be a risk factor for endometrial cancer because hyperplastic and neoplastic lesions can be found in their context. Unfortunately, most of the published reports are based on specimens obtained at curettage, which fails to remove many focally growing lesions in the endometrial cavity and often extracts only scarce fragments. 4,9,10 Hysteroscopic polypectomy is the treatment of choice because it ensures the removal of the entire lesion and not the adjacent endometrium. However, hysteroscopy is expensive and may be associated with mild or severe morbidity and even death 11 so that it is not clear whether to offer hysteroscopic polypectomy to any patient, even if the patient is asymptomatic. The objective of this study was to estimate the prevalence of hyperplasia and cancer in a large number of endometrial polyps that were removed entirely by operative hysteroscopy and to evaluate whether clinical parameters may predict the final histopathologic feature of the polyp. Material and methods A surgical database was used to identify all patients who consecutively underwent hysteroscopic removal of endometrial polyps over a 48-month period from January 1998 to December 2001. Women were scheduled for operative hysteroscopy after a diagnosis of endometrial polyp was made either by hysteroscopy or by transvaginal 927

928 Savelli et al April 2003 Table I. Characteristics of the study population: continuous data Characteristic Mean SD Range Age (y) 55.5 12.1 21-88 Weight (kg) 67.9 13.8 42.0-140.0 Body mass index (kg/m 2 ) 25.9 5.3 18.6-51.4 Parity (No.) 1.3 0.9 0-4 Miscarriages (No.) 0.4 1.03 0-6 Table III. Final histopathologic outcome of the polyps that were removed Outcome No. % Benign polyps 358 70.33 Hyperplasia without atypia 131 25.74 Hyperplasia with atypia 16 3.14 Cancerous polyps 4 0.79 Total 509 100 Table II. Characteristics of the study population: grouping data Characteristic No. % of total Menopause 317 62.3 HRT 126 24.8 Oral contraceptives 42 8.3 Tamoxifen 90 17.7 Abnormal uterine bleeding 274 53.8 Diabetes mellitus 16 3.1 Hypertension 94 18.5 sonography alone or combined with saline infusion sonography. Clinical data of the study population were obtained retrospectively from the patients medical reports, and statistical analysis was performed. Women were considered postmenopausal if they reported a period of at least 12 months of amenorrhea after the age of 45 years. Abnormal uterine bleeding was defined as any vaginal bleeding in postmenopausal women not receiving hormonal replacement therapy (HRT) or as unscheduled vaginal bleeding on HRT or in women still actively menstruating. Operative hysteroscopy was performed with general anesthesia by one gynecologic surgeon of the team (L. S., P. D. I.). Hysteroscopy was performed with a 10-mm Storz resectoscope (Karl Storz, Tuttingen, Germany). The uterine cavity was distended with a solution of sorbitol and mannitol up to a pressure of 100 mm Hg, and any focally growing lesion of the uterine cavity was identified and completely removed with the monopolar cutting loop under hysteroscopic control. Endometrial specimens that were resected were placed in a container with 10% formaldehyde and sent to the pathologist of the team (D. S.) for histologic analysis. Pathologic diagnosis distinguished endometrial polyps as atrophic, glandulocystic, with proliferative or secretory changes, hyperplastic (simple hyperplasia, complex hyperplasia, simple or complex hyperplasia with cytologic atypia), and cancerous. The frequency of the different histologic subtypes was analyzed, with special regard to the prevalence of premalignant (hyperplastic endometrial polyps with atypia) and malignant lesions. Polypoid endometrial adenocarcinomas (ie, endometrial carcinomas with a polypoid shape) were distinguished from cancerous polyps (which are thought to be rare) and thus excluded from the analysis. A polypoid adenocarcinoma lacks benign elements in the polypoid mass and is not separated from the surrounding endometrium by benign tissue in the base of the polyp. To consider a polyp to be the origin of a primary malignancy (ie, an endometrial cancer born de novo in the context of a polyp), two criteria must be fulfilled: (1) the base (stalk) of the polyp must be benign, and (2) the surrounding endometrium must be free of malignancy. 1 Then, a number of clinical characteristics and known risk factors for endometrial cancer were evaluated, including age, weight and body mass index, menopausal status, parity, number of previous miscarriages, diabetes mellitus (defined as fasting blood sugar level of >110 mg/dl), hypertension (diastolic blood pressure of >90 mm Hg and/or systolic blood pressure of >140 mm Hg), presence of abnormal uterine bleeding, use of tamoxifen, or HRT. To perform the statistical analysis, polyps were classified in two groups, based on histologic condition: group A, benign (atrophic, glandulocystic, polyps with proliferative or secretory changes; polyps with simple or complex hyperplasia without atypia); group B, premalignant or malignant (simple/ complex hyperplasia with atypia, cancerous polyps). The rationale for this subdivision lies in the opposite rate of progression to endometrial adenocarcinoma: none or approximately 1% for group A, variable from 25 to 100% for group B. 12-14 Statistical analysis. All continuous data are expressed in terms of mean and SD. In univariate analysis, one-way analysis of variance was performed to test hypotheses about the means of the different groups. When the Levene test for homogeneity of variances was significant (P <.05), the Mann-Whitney test (two independent groups) or the Kruskal-Wallis test ( 3 independent groups) were used to check the analysis of variance results. The Pearson χ 2 test, which was calculated by the exact method, was performed to investigate the relationships between the grouping variables. Logistic regression (with Wald statistics) was performed as multivariate analysis to test whether the set of variables, significant with the univariate analysis, produced a good model for the prediction of the premalignant or malignant polyps and also to identify

Volume 188, Number 4 Savelli et al 929 Table IV. Distribution and statistical significance of clinical risk factors for premalignant and malignant endometrial polyps among study participants Factor Group A* Group B P value Mean age (y) 55.1 64.4 0.001 Weight (kg) 67.7 72.3 NS BMI (kg/m 2 ) 25.8 27.8 NS Parity 1.3 1.2 NS Miscarriages (No.) 0.4 0.3 NS Diabetes mellitus (%) 14 (2.9) 2 (10.0) NS Hypertension (%) 84 (17.3) 10 (50.0) 0.001 Menopause (%) 299 (61.1) 18 (90.0) 0.009 HRT (%) 120 (24.5) 6 (30.0) NS Tamoxifen (%) 86 (17.6) 4 (20.0) NS Oral contraceptives (%) 40 (8.2) 2 (10.0) NS Abnormal uterine bleeding (%) 263 (53.8) 11 (55.0) NS NS, Not significant. *Group A: benign and hyperplastic polyps without cytologic atypia (n = 489). Group B: atypical hyperplastic and cancerous polyps (n = 20). Table V. Results of the multivariate analysis 95% CI Variable Odds ratio Lower Upper P value (Wald test) Age 1.04 0.98 1.11.14 Hypertension 1.70 1.04 2.75.03 Menopause status 1.33 0.53 3.35.53 the relative effect in increasing this risk. For all tests, a probability value of <.05 was considered significant. Statistical analysis was carried out by means of the Statistical Package for the Social Sciences (SPSS) software (version 9.0; SPSS Inc, Chicago, Ill). Results Overall, 509 women (mean age, 55.5 ± 12.1 years; range, 21-88 years) underwent operative hysteroscopy for the removal of an endometrial polyp. In all the cases, the procedure was successful with the complete removal of the entire lesion. Characteristics of the study population are shown in Tables I and II. Three hundred seventeen patients (62.3%) were postmenopausal, 192 patients (37.7%) were premenopausal, 126 patients (24.8%) were receiving some form of HRT (mean duration, 3.2 ± 2.6 years, range, 1-15 years), 42 women (8.3%) were receiving oral contraceptives, and 90 women (17.7%) were receiving tamoxifen therapy. The median dose of tamoxifen was 20 mg/patient/day; the median duration of therapy reported was 36 months. Two hundred seventy-four patients (53.8%) reported abnormal uterine bleeding, 235 patients (46.2%) were asymptomatic, 16 women (3.1%) had diabetes mellitus, and 94 women (18.5%) had hypertension. Mean parity was 1.3 ± 0.9 (range, 0-4); the mean number of miscarriages that were reported was 0.4 ± 1.03 (range, 0-6); the mean body mass index (BMI) was 25.9 ± 5.3 kg/m 2 (range, 18.6-51.4). Histopathologic analysis revealed 358 benign polyps (70.3%; atrophic, glandulocystic, with proliferative or secretory changes), 147 hyperplastic polyps (28.8%; 131 cases of simple or complex endometrial hyperplasia without cytologic atypia, 16 cases of simple or complex hyperplasia with atypia). Four polyps (0.8%) were diagnosed as harboring neoplastic cells in their context. Overall, histologic evidence showed hyperplasia or cancer in 151 of 509 patients (29.6%) in our series. Table III summarizes the histopathologic outcome of the polyps that were removed. To perform the statistical analysis, we analyzed the distribution of hypothetic risk factors in the two previously mentioned groups of polyps (group A [n = 489] and group B [n = 20]). Patient age, menopausal status, and hypertension were statistically significant characteristics that were associated with group B polyps (P =.001,.009, and.001, respectively). None of the other parameters that were considered (parity, number of miscarriages, weight, BMI, complaint of abnormal uterine bleeding, diabetes mellitus, assumption of oral contraceptives, tamoxifen, or HRT) showed a statistically significant effect in the prediction of the final pathologic outcome (Table IV). Then we performed a multivariate analysis of the data to identify the relative effect of the variables that were identified as a risk factor for premalignant and malignant histologic condition in the univariate analysis. Logistic regression produced a model yielding a receiver operating characteristic (ROC) curve, with an

930 Savelli et al April 2003 area of 0.748 (95% CI, 0.648-0.848). Table V shows the odds ratio and significance of the variables that were investigated. Because of the small group of premalignant and malignant polyps (n = 20), the model that was obtained from the multivariate analysis cannot be used to predict the risk of malignancy but gives a hint to the relative importance of the variables that were statistically significant at univariate analysis. Hypertension was the most significant variable of the model. Comment Although the prevalence of endometrial polyps in the general female population has been quoted to be as high as 25%, 5-8 their malignant potential still represents an enigma. As far as we are aware, the risk of malignancy of endometrial polyps has not been addressed in a large group of polyps that have been removed entirely at operative hysteroscopy. Most of the published reports are based on specimens that were obtained by curettage or by other sampling techniques, such as pipelle. 15-17 In a consistent proportion of cases, these blind methods fail to extract the whole polyp and obtain only a mixed specimen of polyp and endometrial mucosa. 4,9,10,18-20 In such studies, fragmentation of the polyp, incompleteness of the specimen, and the presence of adjacent endometrium hamper the diagnosis as to whether an endometrial cancer has originated in an antecedent benign polyp or in the surrounding endometrium. Only hysteroscopy gives the possibility of removing the entire polyp with its stalk, leaving intact the adjacent endometrium, so that the risk of malignancy of endometrial polyps can be estimated confidently. 21,22 Primary malignant degeneration of an endometrial polyp has been quoted variably in the scientific literature, ranging from 0.5% 23 to 4.8%. 24 This wide range is due to different sampling techniques and different classifications of polyps by the investigators. We have demonstrated that, in a large unselected population of women with endometrial polyps, the rate of malignancy is low (4/509 women, 0.8%), although the prevalence of hyperplasia is considerably high (hyperplasia without cytologic atypia, 25.7%; hyperplasia with atypia, 3.1%). Because polyps represent a wide spectrum of alterations that range from normal endometrium to cancer, we opted to divide them into two categories on the basis of the different risks of malignancy (group A, benign polyps; group B, premalignant and malignant polyps). Over a panel of clinical characteristics that were considered, only patient age, menopausal status, and hypertension proved to be statistically associated with group B polyps. In particular, no difference in the prevalence of hyperplasia with atypia and endometrial cancer was observed between patients who were asymptomatic and symptomatic (abnormal uterine bleeding). The risk of carrying a premalignant or malignant polyp was not influenced by parity, number of miscarriages, weight, BMI, diabetes mellitus, an assumption of oral contraceptives, tamoxifen, or HRT. In our patient population of 90 women who were receiving tamoxifen therapy, the median duration of treatment was 24 months, which could explain the reason that the drug was not a statistically significant risk factor for group B polyps. Moreover, tamoxifen is known to induce the formation of cystic atrophy, which could account for a large number of group A polyps. The histologic appearance of the endometrium in women receiving HRT varies depending on the dosage, duration of use, and regimen (combined or sequential). 8 It is well established that, by adding a synthetic progestational agent or natural progesterone, the rate of hyperplasia that would be induced by estrogen is reduced substantially when the dose and duration of treatment are optimized. Our results demonstrate that the histologic features of polyps that were removed from patients receiving HRT vary from normal-appearing proliferative or secretory endometrium to complex hyperplasia, being not statistically significant the influence of HRT on the risk of malignancy of endometrial polyps. It has been reported that endometrial polyps are characterized by aberrations of specific chromosome regions that probably involve genes that are related to the proliferative process. 25-27 The progression from simple to complex and atypical hyperplasia takes many years and possibly depends on the accumulation of specific genetic aberrations, which explains the reason that patient age and menopausal status increase the risk of premalignant and malignant polyps. Hypertension is an established risk factor for female hormonerelated cancers (such as adenocarcinoma of the endometrium) 28 ; it may favor cancer growth by impairing apoptosis and subsequently by affecting the regulation of cell turnover. 29 Our results demonstrate that hypertension is a risk factor also for endometrial polyps with premalignant/malignant histologic features and was the most significant variable at multivariate analysis (Table V). Even in the absence of a clear understanding of biologic mechanisms, the definition of a role of hypertension on the neoplastic risk of endometrial polyps has relevant importance when a choice must be made between a conservative treatment and surgical procedure. We admit that the absence of information on the severity of hypertension (ie, values of blood pressure), drug intake, and duration of the disease is an important limitation of the current study. We believe that these results may be of value when women who have been diagnosed as carrying endometrial polyps are counseled. Physicians should reassure their patients because of the low reported prevalence of premalignant and malignant lesions. To achieve complete removal of the polyp and a reliable histologic analysis, operative hysteroscopy is the treatment of choice and should be offered to symptomatic patients or to patients with risk factors (older

Volume 188, Number 4 Savelli et al 931 menopausal patients and patients with hypertension). The lack of data regarding the potential for cancer growth over the years in benign polyps together with the known risks and the expense of operative hysteroscopy does not permit conclusions to be drawn as to whether it is cost-effective to propose a surgical treatment to every patient who is diagnosed with an endometrial polyp. We thank Dr Susanna Marconi for assistance in collecting the data. REFERENCES 1. Peterson WF, Novak ER. Endometrial polyps. Obstet Gynecol 1956;8:40-9. 2. Berliere M, Charles A, Galant C, Donnez J. Uterine side-effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol 1998;91:40-4. 3. Perez-Medina T, Martinez O, Folgueira G, Bjo J. Which endometrial polyps should be resected? J Am Assoc Gynecol Laparosc 1999;6:71-4. 4. Ebstein E, Ramirez A, Skoog L, Valentin L. Dilatation and curettage fails to detect most focal lesions in the uterine cavity in women with postmenopausal bleeding. Acta Obstet Gynecol Scand 2001;1131-6. 5. Mazur MT, Kurman RJ. Polyps. In: Mazur MT, Kurman RJ, editors. Diagnosis of endometrial biopsies and curettings. New York: Springer-Verlag; 1995. p. 1-260. 6. Dahjanov I, Linder J, editors. Anderson s pathology. 10th ed. St. Louis: Mosby Year Book; 1996. p. 2231-309. 7. Anderson MC, Robboy SJ, Russel P, Morse A. Endometritis, metaplasias and polyps. In: Robboy SJ, Anderson MC, Russel P, editors. Pathology of the female reproductive tract. London: Churchill Livingstone; 2002. p. 285-303. 8. Sherman ME, Mazur MT, Kurman RJ. Benign diseases of the endometrium. In: Kurman RJ, editor. Blaunstein s pathology of the female genital tract. New York: Springer; 2002. p. 421-66. 9. Stovall TG, Solomon SK, Ling FW. Endometrial sampling prior to hysterectomy. Obstet Gynecol 1989;73:405-9. 10. Gebauer G, Hafner A, Siebzehnrubl E, Lang N. Role of hysteroscopy in detection and extraction of endometrial polyps: results from a prospective study. 2001;184:59-63. 11. Motashaw ND, Dave S. Complications of hysteroscopy. Gynecol Endosc 2001;10:203-10. 12. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol 1989;160:126-31. 13. Kurman RJ, Kaminsky PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of untreated hyperplasia in 170 patients. Cancer 1985;56:403-12. 14. Sivridis E, Giatromanolaki A. Prognostic aspects of endometrial hyperplasia and neoplasia. Virchows Arch 2001;439:118-26. 15. Armenia CS. Sequential relationship between endometrial polyps and carcinoma of the endometrium. Obstet Gynecol 1967;30:524-9. 16. Pettersson B, Adami HO, Lindgren A, Hesselius I. Endometrial polyps and hyperplasia as risk factors for endometrial carcinoma. Acta Obstet Gynecol Scand 1985;64:653-9. 17. Van Bogaert LJ. Clinicopathologic findings in endometrial polyps. Obstet Gynecol 1988;71:771-3. 18. Farquhar CM, Lethaby A, Sowter M, Verry BHB, Baranyai J. An evaluation of risk factors for endometrial hyperplasia in premenopausal women with abnormal menstrual bleeding. Am J Obstet Gynecol 1999;181:525-9. 19. Orvieto R, Bar-Hava I, Dicker D, Bar J, Ben-Rafael Z, Neri A. Endometrial polyps during menopause: characterization and significance. Acta Obstet Gynecol Scand 1999;78:883-6. 20. Bakour SH, Khan KS, Gupta JH. The risk of premalignant and malignant pathology in endometrial polyps. Acta Obstet Gynecol Scand 2000;79:317-20. 21. Cravello L, de Montgolfier R, D Ercole C, Boubli L, Blanc B. Hysteroscopic surgery in postmenopausal women. Acta Obstet Gynecol Scand 1996;75:563-6. 22. Tjarks M, Van Voorhis BJ. Treatment of endometrial polyps. Obstet Gynecol 2000;96:886-9. 23. Wolfe SA, Mackles A. Malignant lesions arising from benign endometrial polyps. Obstet Gynecol 1962;20:542-51. 24. Goldstein SR, Monteagudo A, Popiolek D, Mayberry P, Timor- Tritsch I. Evaluation of endometrial polyps. 2002;186:669-74. 25. Speleman F, Dal Cin P, Van Roy N, Van Marck E, Buytaert P, Van Den Berghe H, et al. Is t(6;20)(p21;q13) a characteristic chromosome change in endometrial polyps? Genes Chromosome Cancer 1991;3:318-9. 26. Dal Cin P, De Wolf F, Klerckx P, Van Den Berghe H. The 6p21 chromosome is nonrandomly involved in endometrial polyps. Gynecol Oncol 1992;46:393-6. 27. Vanni R, Dal Cin P, Marras S, Moerman P, Andria M, Valdes E, et al. Endometrial polyp: another benign tumor characterized by 12q13-q15 changes. Cancer Genet Cytogenet 1993;68:32-3. 28. Soler M, Chatenoud L, Negri E, Pirazzini F, Franceschi S, La Vecchia C. Hypertension and hormone-related neoplasms in women. Hypertension 1999;34:320-5. 29. Hamet P. Cancer and hypertension: a potential for crosstalk? J Hypertens 1997;15:1573-7.