- Email: [email protected]
Malignancy in endometrial polyps: a 12-year experience
Research
www. AJOG.org
GENERAL GYNECOLOGY
Malignancy in endometrial polyps: a 12-year experience Gabriela Baiocchi, MD; Natalina Manci, MD; Michela Pazzaglia, MD; Laura Giannone, MD; Liliana Burnelli, MD; Ettore Giannone, MD; Daniela Fratini, MD; Gian Carlo Di Renzo, MD, PhD OBJECTIVE: Endometrial polyps (EPs) are common pathological lesions
in all women. The objective of this study was to evaluate the risk of malignancy of EPs and to investigate whether clinical parameters may predict the histopathologic features of these lesions.
nant, and 3.5% malignant lesions were detected. When clinical variables were considered, patient age, menopause, presence of abnormal uterine bleeding, and hypertension were statistically significant characteristics related to premalignant and malignant features.
STUDY DESIGN: A retrospective study was conducted from January 1995 to December 2006 and all consecutive 1242 cases with clinical EPs were included. The charts of all these women were reviewed and clinical data were related to histopathologic results.
CONCLUSION: Older menopausal bleeding patients with hypertension
RESULTS: Histologically, polyps were distinguished as benign, prema-
Key words: endometrial, endometrial cancer, hysteroscopy, polyps, risk factors
lignant, and malignant. Overall, 95.2% benign polyps, 1.3% premalig-
are at high risk for premalignant and malignant polyps. Therefore, besides abnormal bleeding symptoms, this kind of patient needs to have the polyps removed.
Cite this article as: Baiocchi G, Manci N, Pazzaglia M, et al. Malignancy in endometrial polyps: a 12-year experience. Am J Obstet Gynecol 2009;201:462.e1-4.
E
ndometrial polyps are benign, localized overgrowths of endometrial tissue that are covered by epithelium and contain variable amounts of glands, stroma, and blood vessels. Endometrial polyps are common pathological lesions of the uterine corpus and are usually found in perimenopausal women.1-6 The prevalence of endometrial polyps in the general symptomatic female population is estimated to range from approximately 13% to 50%.4,5,7-9 Moreover, if asymptomatic patients are considered, From the Department of Gynecology and Obstetrics (Drs Baiocchi, Pazzaglia, L. Giannone, Burnelli, E. Giannone, and Di Renzo), Santa Maria della Misericordia University Hospital, Perugia; the Department of Gynecology and Obstetrics (Dr Manci), La Sapienza University, Policlinico Umberto I, Rome; and the Institute of Pathology, Perugia University, Perugia (Dr Fratini), Italy. Received Nov. 12, 2008; revised April 10, 2009; accepted May 28, 2009. Reprints: Gian Carlo Di Renzo, MD, PhD, Department of Obstetrics and Gynecology and Centre for Perinatal and Reproductive Medicine, Santa Maria della Misericordia University Hospital, 06132 San Sisto-Perugia, Italy. [email protected]. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.05.055
462.e1
endometrial polyps can be found in 2055%2,6,10,11 of women who have imaging studies done in the pelvis for a variety of reasons. Overexpression of steroid receptors found in glandular epithelium of polyps suggests a crucial role played by hormonal exposure.12 To support this notion, tamoxifen or hormone replacement therapy (HRT) frequently are associated with the development of endometrial polyps. This finding presumably is due to their agonistic estrogenic effects.13,14 Abnormal uterine bleeding is frequently the presenting symptom of the endometrial polyps. However, polyps are often asymptomatic and are incidentally found during routine transvaginal ultrasound or infertility investigations.1-6,7 Polyps are in general benign growths, although malignancy confined to a polyp has also been identified.15,16 The incidence of carcinoma confined to endometrial polyps (malignant polyps) varies between 0% and 4.8%, depending on the selection of patients and the methods used in making the diagnosis.16-19 The objective of this study was to evaluate the risk of premalignant and malignant changes in endometrial polyps and to investigate whether some clinical parameters could predict the histopathologic features of these lesions.
American Journal of Obstetrics & Gynecology NOVEMBER 2009
M ATERIALS AND M ETHODS From January 1995 to December 2006, all consecutive patients with endometrial polyps clinically diagnosed and/or endometrial postmenopausal thickening (ⱖ5 mm) and/or abnormal uterine bleeding underwent hysteroscopy and retrospectively analyzed. Women being treated with HRT and postmenopausal women being treated with tamoxifen as an adjuvant treatment for breast cancer were also included in the study group. Reproductive-aged patients with abnormal uterine bleeding as menorrhagia, metrorrhagia, and menometrorrhagia that was resistant to medical therapy were also studied. Among these patients, a total of 1242 patients with endometrial polyps was found, and it represents the study population of our study. The charts of these women (median age, 55 years; range, 23–78) were reviewed and clinical data collected were related to histopathologic results. 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 HRT or as irregular vaginal bleeding in women still actively menstruating or being treated with HRT.
General Gynecology
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TABLE 1
Patient characteristics (1242 cases) Clinical variables Age (median, range)
Patients, n
(%)
55 (23-78)
...........................................................................................................
Parity
..................................................................................................
Nullipara
211
17.0
Pluripara
1031
83.0
.................................................................................................. ...........................................................................................................
Menopausal status
..................................................................................................
Premenopause
619
49.0
Menopause
623
51.0
.................................................................................................. ...........................................................................................................
Abnormal uterine bleeding (AUB)
..................................................................................................
Yes
360
29.0
No
882
71.0
55
4.4
128
10.3
69
5.8
.................................................................................................. ...........................................................................................................
HRT
...........................................................................................................
Tamoxifen
...........................................................................................................
Diabetes mellitus
...........................................................................................................
HRT, hormonal replacement therapy. Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
Diagnostic outpatient hysteroscopy was performed using CO2 as a distention medium, and a Storz endoscope (Tuttlingen, Karl Storz, Tuttlingen, Germany) with a 5 mm diagnostic sheath was used. Myomas or polyps were hysteroscopically distinguished and additional information about surrounding endometrium was obtained. Cases of TABLE 2
Histopathologic results of endometrial polyps Histology
Patients, n
Benign polyps
1182
95.2
Hyperplasia with atypia
15
1.3
Cancerous polyps or invasive endometrial cancer
45
%
...........................................................................................................
...........................................................................................................
3.5
...........................................................................................................
Total
1242
100
...........................................................................................................
Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
submucous leiomyoma were excluded by the analysis. Patients found to have endometrial polyps underwent to a next session under general anesthesia during which cervical dilatation was performed. Polyps and fragments of the adjacent endometrial mucosa were sliced and removed with the cutting loop of the 10 mm Storz resectoscope (Karl Storz). Histopathological analysis was made by the pathologist of the team (D.F.). Diagnosis distinguished between polyps that were recognized as benign (atrophic, proliferative, or hyperplastic polyps and simple hyperplasia and complex hyperplasia without atypia), premalignant (complex hyperplasia with atypia), and those harboring carcinoma.20 The histopathologic definitions of endometrial hyperplasia and adenocarcinoma were according to the following definitions. Endometrial simple hyperplasia was defined by the endometrial architecture that is moderately distorted. The lining epithelium of the glands is pseudostratified showing mitotic activity with no atypia of cells. Atypical simple hyperplasia was defined by architecture similar to simple hyperplasia, but the glands are more irregular. The glands are lined by atypical cells. Endometrial carcinoma was defined by crowded malignant tubular glands varying in size and invading the stroma. Clinical characteristics as age, parity, menopausal status, hypertension (defined as diastolic pressure ⬎90 mm Hg and/or systolic pressure ⬎140 mm Hg), abnormal uterine bleeding, diabetes (fasting glucose ⬎110 mg/dL) were also reported in the medical record. Retrospectively clinical data were related to histopathologic results and statistical analysis was performed using Student t test and 2 test.
R ESULTS Patients characteristics of the study population are described in Table 1. The histological results of 1242 patients with endometrial polyps are shown in Table 2. It is worthwhile to note that 60 patients (4.8%) had premalignant and malignant changes of polyps.
Research
Correlation between clinical parameters and histopathologic findings are presented in Table 3. When age of the patients was related to the histopathologic results (Table 3), it was found that hyperplasia with atypia and invasive endometrial carcinoma were statistically more frequent in older women. In fact, 38 of 60 patients (66.7%) with premalignant and malignant lesions were older than 60 years. Only 11 of 417 women (2.6%) younger than 50 years had cancerous polyps. Among the other clinical data considered, menopausal status and the presence of hypertension and abnormal uterine bleeding were found to be more frequently present in patients with premalignant and malignant changes of endometrial polyps. In fact, 49 of 60 patients (81.6%) with malignant polyps were observed in menopausal patients; conversely only 11 of 60 patients (18.4%) were found in premenopausal women (P ⬍ .05). Similarly, 32 of 45 patients with cancer (71.1%) had hypertension (P ⬍ .05), compared with only 13 patients (29%) with malignant polyps and normal blood pressure. Patients with symptomatic bleeding with endometrial polyps are higher risk of cancer than those women without bleeding. Among the 60 patients with malignant changes, 39 had abnormal uterine bleeding. None of the other clinical variables considered (diabetes mellitus and use of tamoxifen or HRT) were statistically related to the histopathologic results.
C OMMENT Endometrial polyps are usually localized excrescences of the endometrial lining. They represent the most common causes of menometrorrhagia resistant to medical therapy in premenopausal women or can cause abnormal bleeding in postmenopausal patients. However, more often polyps are asymptomatic and are incidentally found during routine gynecologic examination. Our study, including a very large population of women (1242 cases), found that a high rate (4.8%) of malignant or premalignant conditions confined to the polyps can be
NOVEMBER 2009 American Journal of Obstetrics & Gynecology
462.e2
Research
General Gynecology
www.AJOG.org
TABLE 3
Relationship between clinical parameters and histologic results
Variable
Benign polyps and hyperplasia without atypia (1182 cases)
Hyperplasia with atypia (15 cases)
Cancerous polyps (45 cases)
n
n
n
%
%
%
P value
Age, y
.......................................................................................................................................................................................................................................................................................................................................................................
⬍40
169
14.3
0
—
0
—
40-50
248
21.9
4
26.6
7
15.5
50-60
451
38.2
3
20.0
8
17.8
⬎60
314
25.6
8
53.4
30
66.7
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................
⬍ .05
................................................................................................................................................................................................................................................................................................................................................................................
Menopausal status
.......................................................................................................................................................................................................................................................................................................................................................................
Premenopause
646
54.7
5
33.4
6
13.4
Menopause
536
45.3
10
66.6
39
86.6
.......................................................................................................................................................................................................................................................................................................................................................................
⬍ .05
................................................................................................................................................................................................................................................................................................................................................................................
Symptoms
.......................................................................................................................................................................................................................................................................................................................................................................
AUB
358
30.2
13
86.6
26
57.7
Not AUB
824
69.8
2
13.4
19
43.3
....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
Associated conditions
.......................................................................................................................................................................................................................................................................................................................................................................
Diabetes mellitus
69
5.8
0
—
0
—
228
19.2
0
—
32
71.1 0.1
.......................................................................................................................................................................................................................................................................................................................................................................
Hypertension
⬍ .05
.......................................................................................................................................................................................................................................................................................................................................................................
HRT
53
4.48
0
—
1
128
10.83
0
—
0
.......................................................................................................................................................................................................................................................................................................................................................................
Tamoxifen
—
................................................................................................................................................................................................................................................................................................................................................................................
AUB, abnormal uterine bleeding; HRT, hormonal replacement therapy. Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
observed in patients with polyps hysteroscopically diagnosed. In fact, histopathologic results identified hyperplasia with atypia and cancer in 1.3% and 3.5% of cases studied, respectively. These findings seem to be similar to those reported in previous studies in which malignancy rate was described to vary between 0% and 4.8%. Orvieto et al10 examined 146 endometrial polyps and they found 10% of cases with hyperplasia (2.5% with atypia); however, no 1 case of carcinoma was detected. Malignancy was found in 4.8% of the patients in the series by Goldstein et al.6 Recently Savelli et al19 found that 16 of 509 patients with polyps (3.1%) had hyperplasia with atypia, and 4 polyps (0.8%) were cancerous. Given the large series considered in our study (1242 patients), it could be hypothesized that the high prevalence of premalignant and malignancy (4.8%) found in our population is more realistic than that reported in other smaller series. Therefore, the presence of prema462.e3
lignant and malignant changes in almost 5% of the patients with polyps has to be taken into account. Considering this remarkable incidence, it would be helpful to have new noninvasive diagnostic tools and/or detect clinical characteristics as reliable risk factors related to malignant polyps. This last target was the second endpoint of the present study. The present study, according to the work of Hikmet et al,21 surprisingly does not show any statistically significant difference between asymptomatic and symptomatic women. Older age, menopausal status, presence of abnormal uterine bleeding, and hypertension were identified as significant factors associated with premalignancy or malignancy in endometrial polyps in univariate analysis (Table 3).11,21 Similar observations were also reported by other authors.19,22-24 In particular Antunes et al23 and Hileeto et al24 reported that women older than 60 years have a prevalence of malignant polyps about 5 times greater than younger
American Journal of Obstetrics & Gynecology NOVEMBER 2009
women. According to the series by Giordano et al22 and the paper by Savelli et al,19 hypertension is confirmed as risk factor related to malignant changes of endometrial polyps. None of the other clinical variables considered could be significantly associated with cancerous polyps. In particular, all studies but one23 published in the literature so far reported that presence of bleeding does not appear to be a predictive factor of cancerous polyps. A possible explanation of this fact could be related to earlier diagnosis of polyps by using transvaginal ultrasound that detects small polyps, as endometrial thickness, before they start bleeding. It is well known that tamoxifen treatment and HRT are risk factors for endometrial cancer. In the current study, different from other studies,25,26 these hormonal treatments were not significant predictors of cancer. Probably this discrepancy can be due to the small number of women being treated with HRT and tamoxifen, included in the present study.
www.AJOG.org In conclusion, older menopausal patients with hypertension are at high risk to have premalignant and malignant changes of endometrial polyps. Therefore, regardless of symptoms, this kind of patient needs to have the polyps removed. f REFERENCES 1. Schlaen I, Bergeron C, Ferenczy A, Wong P, Naves A. Endometrial polyps: a study of 204 cases. Surg Pathol 1988;1:375-82. 2. DeWaay DJ, Syrop CH, Nygaard IE, Davis WA, Van Voorhis BJ. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002;100:3-7. 3. De Vries L, Dijkhuizen F, Mol B, Brolmann H, Moret E, Heintz A. Comparison of transvaginal sonography, saline infusion sonography, and hysteroscopy in premenopausal women with abnormal uterine bleeding. J Clin Ultrasound 2000;28:217-23. 4. Widrich T, Bradley L, Mitchinson A, Collins R. Comparison of saline infused sonography with office hysteroscopy for the evaluation of the endometrium. Am J Obstet Gynecol 1996; 174:1327-34. 5. Sherman ME, Mazur MT, Kurman RJ. Benign diseases of the endometrium. In: Kurman RJ, ed. Blaunstein’s pathology of the female genital tract, 3rd ed. New York, NY: Springer; 2002. 6. Goldstein SR, Monteagudo A, Popiolek D, Mayberry P, Timor-Tritsch I. Evaluation of endometrial polyps. Am J Obstet Gynecol 2002;186: 669-74. 7. Caspi B, Appelman Z, Goldchmit R, Ashkenazi M, Haruvy Y, Hagay Z. The bright edge of the endometrial polyp. Ultrasound Obstet Gynecol 2000;15:327-30. 8. Clevenger-Hoeft M, Syrop CH, Stovall DW, Van Voorhis BJ. Sonohysterography in pre-
General Gynecology menopausal women with and without abnormal bleeding. Obstet Gynecol 1999;94:516-20 9. Cohen I, Azaria R, Aviram R, et al. Postmenopausal endometrial pathologies with tamoxifen treatment: comparison between hysteroscopic and hysterectomy findings. Gynecol Obstet Invest 1999;48:187-92. 10. Orovieto 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. 11. Ben-Arie A, Goldchmit C, Laviv Y, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol 2004;115:206-10. 12. Sant’Ana de Almeida EC, Nogueira AA, Candido dos Reis FJ, Zambelli Ramalho LN, Zucoloto S. Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women. Maturitas 2004; 49:229-33. 13. Cheng WF, Lin HH, Torng PL, Huang SC. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol Oncol 1997;66: 233-7. 14. McGurgan P, Taylor LJ, Duffy SR, O’Donovan PJ. An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to HRT. Maturitas 2006;53;454-61. 15. Salm R. The incidence and significance of early carcinomas in endometrial polyps. Pathology 1972;108:47-53. 16. Anastasiadis PG, Koutlaki NG, Skaphida PG, Galazios GC, Tsikouras PN, Liberis VA. Endometrial polyps: prevalence, detection, and malignant potential in women with abnormal uterine bleeding. Eur J Gynaecol Oncol 2000;21:180-3. 17. Wolfe SA, Mackles A. Malignant lesions arising from benign endometrial polyps. Obstet Gynecol 1962,20:542-50.
Research
18. Bakour SH, Khan KS, Gupta JK. The risk of premalignant and malignant pathology in endometrial polyps Acta Obstet Gynecol Scand 2000;79:317-20. 19. Savelli L, De Iaco P, Santini D, et al. Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps. Am J Obstet Gynecol 2003;188:927-31. 20. Kurman RJ, ed. Blaustein’s pathology of the female genital tract, 5th ed. New York: Springer-Verlag; 2002. 21. Hassa H, Tekin B, Senses T, Kaya M, Karatas A. Are the site, diameter, and number of endometrial polyps related with the symptomatology? Am J Obstet Gynecol 2006; 194:718-21. 22. Giordano G, Gnetti L, Merisio C, Melpignano M. Postmenopausal status, hypertension and obesity as risk factors for malignant transformation in endometrial polyps. Maturitas 2007;20:190-7. 23. Antunes A Jr, Costa-Paiva L, Arthuso M, Costa JV, Pinto-Neto AM. Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy. Maturitas 2007; 57:415-21. 24. Hileeto D, Fadare O, Martel M, Zheng W. Age dependent association of endometrial polyps with increased risk of cancer involvement. World J Surg Oncol 2005;3:8. 25. Oguz S, Sargin A, Kelekci S, Aytan H, Tapisiz OL, Mollamahmutoglu L. The role of hormone replacement therapy in endometrial polyp formation. Maturitas 2005;50:231-6. 26. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT Group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet 2000;356:881-7.
NOVEMBER 2009 American Journal of Obstetrics & Gynecology
462.e4
www. AJOG.org
GENERAL GYNECOLOGY
Malignancy in endometrial polyps: a 12-year experience Gabriela Baiocchi, MD; Natalina Manci, MD; Michela Pazzaglia, MD; Laura Giannone, MD; Liliana Burnelli, MD; Ettore Giannone, MD; Daniela Fratini, MD; Gian Carlo Di Renzo, MD, PhD OBJECTIVE: Endometrial polyps (EPs) are common pathological lesions
in all women. The objective of this study was to evaluate the risk of malignancy of EPs and to investigate whether clinical parameters may predict the histopathologic features of these lesions.
nant, and 3.5% malignant lesions were detected. When clinical variables were considered, patient age, menopause, presence of abnormal uterine bleeding, and hypertension were statistically significant characteristics related to premalignant and malignant features.
STUDY DESIGN: A retrospective study was conducted from January 1995 to December 2006 and all consecutive 1242 cases with clinical EPs were included. The charts of all these women were reviewed and clinical data were related to histopathologic results.
CONCLUSION: Older menopausal bleeding patients with hypertension
RESULTS: Histologically, polyps were distinguished as benign, prema-
Key words: endometrial, endometrial cancer, hysteroscopy, polyps, risk factors
lignant, and malignant. Overall, 95.2% benign polyps, 1.3% premalig-
are at high risk for premalignant and malignant polyps. Therefore, besides abnormal bleeding symptoms, this kind of patient needs to have the polyps removed.
Cite this article as: Baiocchi G, Manci N, Pazzaglia M, et al. Malignancy in endometrial polyps: a 12-year experience. Am J Obstet Gynecol 2009;201:462.e1-4.
E
ndometrial polyps are benign, localized overgrowths of endometrial tissue that are covered by epithelium and contain variable amounts of glands, stroma, and blood vessels. Endometrial polyps are common pathological lesions of the uterine corpus and are usually found in perimenopausal women.1-6 The prevalence of endometrial polyps in the general symptomatic female population is estimated to range from approximately 13% to 50%.4,5,7-9 Moreover, if asymptomatic patients are considered, From the Department of Gynecology and Obstetrics (Drs Baiocchi, Pazzaglia, L. Giannone, Burnelli, E. Giannone, and Di Renzo), Santa Maria della Misericordia University Hospital, Perugia; the Department of Gynecology and Obstetrics (Dr Manci), La Sapienza University, Policlinico Umberto I, Rome; and the Institute of Pathology, Perugia University, Perugia (Dr Fratini), Italy. Received Nov. 12, 2008; revised April 10, 2009; accepted May 28, 2009. Reprints: Gian Carlo Di Renzo, MD, PhD, Department of Obstetrics and Gynecology and Centre for Perinatal and Reproductive Medicine, Santa Maria della Misericordia University Hospital, 06132 San Sisto-Perugia, Italy. [email protected]. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.05.055
462.e1
endometrial polyps can be found in 2055%2,6,10,11 of women who have imaging studies done in the pelvis for a variety of reasons. Overexpression of steroid receptors found in glandular epithelium of polyps suggests a crucial role played by hormonal exposure.12 To support this notion, tamoxifen or hormone replacement therapy (HRT) frequently are associated with the development of endometrial polyps. This finding presumably is due to their agonistic estrogenic effects.13,14 Abnormal uterine bleeding is frequently the presenting symptom of the endometrial polyps. However, polyps are often asymptomatic and are incidentally found during routine transvaginal ultrasound or infertility investigations.1-6,7 Polyps are in general benign growths, although malignancy confined to a polyp has also been identified.15,16 The incidence of carcinoma confined to endometrial polyps (malignant polyps) varies between 0% and 4.8%, depending on the selection of patients and the methods used in making the diagnosis.16-19 The objective of this study was to evaluate the risk of premalignant and malignant changes in endometrial polyps and to investigate whether some clinical parameters could predict the histopathologic features of these lesions.
American Journal of Obstetrics & Gynecology NOVEMBER 2009
M ATERIALS AND M ETHODS From January 1995 to December 2006, all consecutive patients with endometrial polyps clinically diagnosed and/or endometrial postmenopausal thickening (ⱖ5 mm) and/or abnormal uterine bleeding underwent hysteroscopy and retrospectively analyzed. Women being treated with HRT and postmenopausal women being treated with tamoxifen as an adjuvant treatment for breast cancer were also included in the study group. Reproductive-aged patients with abnormal uterine bleeding as menorrhagia, metrorrhagia, and menometrorrhagia that was resistant to medical therapy were also studied. Among these patients, a total of 1242 patients with endometrial polyps was found, and it represents the study population of our study. The charts of these women (median age, 55 years; range, 23–78) were reviewed and clinical data collected were related to histopathologic results. 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 HRT or as irregular vaginal bleeding in women still actively menstruating or being treated with HRT.
General Gynecology
www.AJOG.org
TABLE 1
Patient characteristics (1242 cases) Clinical variables Age (median, range)
Patients, n
(%)
55 (23-78)
...........................................................................................................
Parity
..................................................................................................
Nullipara
211
17.0
Pluripara
1031
83.0
.................................................................................................. ...........................................................................................................
Menopausal status
..................................................................................................
Premenopause
619
49.0
Menopause
623
51.0
.................................................................................................. ...........................................................................................................
Abnormal uterine bleeding (AUB)
..................................................................................................
Yes
360
29.0
No
882
71.0
55
4.4
128
10.3
69
5.8
.................................................................................................. ...........................................................................................................
HRT
...........................................................................................................
Tamoxifen
...........................................................................................................
Diabetes mellitus
...........................................................................................................
HRT, hormonal replacement therapy. Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
Diagnostic outpatient hysteroscopy was performed using CO2 as a distention medium, and a Storz endoscope (Tuttlingen, Karl Storz, Tuttlingen, Germany) with a 5 mm diagnostic sheath was used. Myomas or polyps were hysteroscopically distinguished and additional information about surrounding endometrium was obtained. Cases of TABLE 2
Histopathologic results of endometrial polyps Histology
Patients, n
Benign polyps
1182
95.2
Hyperplasia with atypia
15
1.3
Cancerous polyps or invasive endometrial cancer
45
%
...........................................................................................................
...........................................................................................................
3.5
...........................................................................................................
Total
1242
100
...........................................................................................................
Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
submucous leiomyoma were excluded by the analysis. Patients found to have endometrial polyps underwent to a next session under general anesthesia during which cervical dilatation was performed. Polyps and fragments of the adjacent endometrial mucosa were sliced and removed with the cutting loop of the 10 mm Storz resectoscope (Karl Storz). Histopathological analysis was made by the pathologist of the team (D.F.). Diagnosis distinguished between polyps that were recognized as benign (atrophic, proliferative, or hyperplastic polyps and simple hyperplasia and complex hyperplasia without atypia), premalignant (complex hyperplasia with atypia), and those harboring carcinoma.20 The histopathologic definitions of endometrial hyperplasia and adenocarcinoma were according to the following definitions. Endometrial simple hyperplasia was defined by the endometrial architecture that is moderately distorted. The lining epithelium of the glands is pseudostratified showing mitotic activity with no atypia of cells. Atypical simple hyperplasia was defined by architecture similar to simple hyperplasia, but the glands are more irregular. The glands are lined by atypical cells. Endometrial carcinoma was defined by crowded malignant tubular glands varying in size and invading the stroma. Clinical characteristics as age, parity, menopausal status, hypertension (defined as diastolic pressure ⬎90 mm Hg and/or systolic pressure ⬎140 mm Hg), abnormal uterine bleeding, diabetes (fasting glucose ⬎110 mg/dL) were also reported in the medical record. Retrospectively clinical data were related to histopathologic results and statistical analysis was performed using Student t test and 2 test.
R ESULTS Patients characteristics of the study population are described in Table 1. The histological results of 1242 patients with endometrial polyps are shown in Table 2. It is worthwhile to note that 60 patients (4.8%) had premalignant and malignant changes of polyps.
Research
Correlation between clinical parameters and histopathologic findings are presented in Table 3. When age of the patients was related to the histopathologic results (Table 3), it was found that hyperplasia with atypia and invasive endometrial carcinoma were statistically more frequent in older women. In fact, 38 of 60 patients (66.7%) with premalignant and malignant lesions were older than 60 years. Only 11 of 417 women (2.6%) younger than 50 years had cancerous polyps. Among the other clinical data considered, menopausal status and the presence of hypertension and abnormal uterine bleeding were found to be more frequently present in patients with premalignant and malignant changes of endometrial polyps. In fact, 49 of 60 patients (81.6%) with malignant polyps were observed in menopausal patients; conversely only 11 of 60 patients (18.4%) were found in premenopausal women (P ⬍ .05). Similarly, 32 of 45 patients with cancer (71.1%) had hypertension (P ⬍ .05), compared with only 13 patients (29%) with malignant polyps and normal blood pressure. Patients with symptomatic bleeding with endometrial polyps are higher risk of cancer than those women without bleeding. Among the 60 patients with malignant changes, 39 had abnormal uterine bleeding. None of the other clinical variables considered (diabetes mellitus and use of tamoxifen or HRT) were statistically related to the histopathologic results.
C OMMENT Endometrial polyps are usually localized excrescences of the endometrial lining. They represent the most common causes of menometrorrhagia resistant to medical therapy in premenopausal women or can cause abnormal bleeding in postmenopausal patients. However, more often polyps are asymptomatic and are incidentally found during routine gynecologic examination. Our study, including a very large population of women (1242 cases), found that a high rate (4.8%) of malignant or premalignant conditions confined to the polyps can be
NOVEMBER 2009 American Journal of Obstetrics & Gynecology
462.e2
Research
General Gynecology
www.AJOG.org
TABLE 3
Relationship between clinical parameters and histologic results
Variable
Benign polyps and hyperplasia without atypia (1182 cases)
Hyperplasia with atypia (15 cases)
Cancerous polyps (45 cases)
n
n
n
%
%
%
P value
Age, y
.......................................................................................................................................................................................................................................................................................................................................................................
⬍40
169
14.3
0
—
0
—
40-50
248
21.9
4
26.6
7
15.5
50-60
451
38.2
3
20.0
8
17.8
⬎60
314
25.6
8
53.4
30
66.7
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................
⬍ .05
................................................................................................................................................................................................................................................................................................................................................................................
Menopausal status
.......................................................................................................................................................................................................................................................................................................................................................................
Premenopause
646
54.7
5
33.4
6
13.4
Menopause
536
45.3
10
66.6
39
86.6
.......................................................................................................................................................................................................................................................................................................................................................................
⬍ .05
................................................................................................................................................................................................................................................................................................................................................................................
Symptoms
.......................................................................................................................................................................................................................................................................................................................................................................
AUB
358
30.2
13
86.6
26
57.7
Not AUB
824
69.8
2
13.4
19
43.3
....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
Associated conditions
.......................................................................................................................................................................................................................................................................................................................................................................
Diabetes mellitus
69
5.8
0
—
0
—
228
19.2
0
—
32
71.1 0.1
.......................................................................................................................................................................................................................................................................................................................................................................
Hypertension
⬍ .05
.......................................................................................................................................................................................................................................................................................................................................................................
HRT
53
4.48
0
—
1
128
10.83
0
—
0
.......................................................................................................................................................................................................................................................................................................................................................................
Tamoxifen
—
................................................................................................................................................................................................................................................................................................................................................................................
AUB, abnormal uterine bleeding; HRT, hormonal replacement therapy. Baiocchi. Malignant endometrial polyps. Am J Obstet Gynecol 2009.
observed in patients with polyps hysteroscopically diagnosed. In fact, histopathologic results identified hyperplasia with atypia and cancer in 1.3% and 3.5% of cases studied, respectively. These findings seem to be similar to those reported in previous studies in which malignancy rate was described to vary between 0% and 4.8%. Orvieto et al10 examined 146 endometrial polyps and they found 10% of cases with hyperplasia (2.5% with atypia); however, no 1 case of carcinoma was detected. Malignancy was found in 4.8% of the patients in the series by Goldstein et al.6 Recently Savelli et al19 found that 16 of 509 patients with polyps (3.1%) had hyperplasia with atypia, and 4 polyps (0.8%) were cancerous. Given the large series considered in our study (1242 patients), it could be hypothesized that the high prevalence of premalignant and malignancy (4.8%) found in our population is more realistic than that reported in other smaller series. Therefore, the presence of prema462.e3
lignant and malignant changes in almost 5% of the patients with polyps has to be taken into account. Considering this remarkable incidence, it would be helpful to have new noninvasive diagnostic tools and/or detect clinical characteristics as reliable risk factors related to malignant polyps. This last target was the second endpoint of the present study. The present study, according to the work of Hikmet et al,21 surprisingly does not show any statistically significant difference between asymptomatic and symptomatic women. Older age, menopausal status, presence of abnormal uterine bleeding, and hypertension were identified as significant factors associated with premalignancy or malignancy in endometrial polyps in univariate analysis (Table 3).11,21 Similar observations were also reported by other authors.19,22-24 In particular Antunes et al23 and Hileeto et al24 reported that women older than 60 years have a prevalence of malignant polyps about 5 times greater than younger
American Journal of Obstetrics & Gynecology NOVEMBER 2009
women. According to the series by Giordano et al22 and the paper by Savelli et al,19 hypertension is confirmed as risk factor related to malignant changes of endometrial polyps. None of the other clinical variables considered could be significantly associated with cancerous polyps. In particular, all studies but one23 published in the literature so far reported that presence of bleeding does not appear to be a predictive factor of cancerous polyps. A possible explanation of this fact could be related to earlier diagnosis of polyps by using transvaginal ultrasound that detects small polyps, as endometrial thickness, before they start bleeding. It is well known that tamoxifen treatment and HRT are risk factors for endometrial cancer. In the current study, different from other studies,25,26 these hormonal treatments were not significant predictors of cancer. Probably this discrepancy can be due to the small number of women being treated with HRT and tamoxifen, included in the present study.
www.AJOG.org In conclusion, older menopausal patients with hypertension are at high risk to have premalignant and malignant changes of endometrial polyps. Therefore, regardless of symptoms, this kind of patient needs to have the polyps removed. f REFERENCES 1. Schlaen I, Bergeron C, Ferenczy A, Wong P, Naves A. Endometrial polyps: a study of 204 cases. Surg Pathol 1988;1:375-82. 2. DeWaay DJ, Syrop CH, Nygaard IE, Davis WA, Van Voorhis BJ. Natural history of uterine polyps and leiomyomata. Obstet Gynecol 2002;100:3-7. 3. De Vries L, Dijkhuizen F, Mol B, Brolmann H, Moret E, Heintz A. Comparison of transvaginal sonography, saline infusion sonography, and hysteroscopy in premenopausal women with abnormal uterine bleeding. J Clin Ultrasound 2000;28:217-23. 4. Widrich T, Bradley L, Mitchinson A, Collins R. Comparison of saline infused sonography with office hysteroscopy for the evaluation of the endometrium. Am J Obstet Gynecol 1996; 174:1327-34. 5. Sherman ME, Mazur MT, Kurman RJ. Benign diseases of the endometrium. In: Kurman RJ, ed. Blaunstein’s pathology of the female genital tract, 3rd ed. New York, NY: Springer; 2002. 6. Goldstein SR, Monteagudo A, Popiolek D, Mayberry P, Timor-Tritsch I. Evaluation of endometrial polyps. Am J Obstet Gynecol 2002;186: 669-74. 7. Caspi B, Appelman Z, Goldchmit R, Ashkenazi M, Haruvy Y, Hagay Z. The bright edge of the endometrial polyp. Ultrasound Obstet Gynecol 2000;15:327-30. 8. Clevenger-Hoeft M, Syrop CH, Stovall DW, Van Voorhis BJ. Sonohysterography in pre-
General Gynecology menopausal women with and without abnormal bleeding. Obstet Gynecol 1999;94:516-20 9. Cohen I, Azaria R, Aviram R, et al. Postmenopausal endometrial pathologies with tamoxifen treatment: comparison between hysteroscopic and hysterectomy findings. Gynecol Obstet Invest 1999;48:187-92. 10. Orovieto 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. 11. Ben-Arie A, Goldchmit C, Laviv Y, et al. The malignant potential of endometrial polyps. Eur J Obstet Gynecol 2004;115:206-10. 12. Sant’Ana de Almeida EC, Nogueira AA, Candido dos Reis FJ, Zambelli Ramalho LN, Zucoloto S. Immunohistochemical expression of estrogen and progesterone receptors in endometrial polyps and adjacent endometrium in postmenopausal women. Maturitas 2004; 49:229-33. 13. Cheng WF, Lin HH, Torng PL, Huang SC. Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients. Gynecol Oncol 1997;66: 233-7. 14. McGurgan P, Taylor LJ, Duffy SR, O’Donovan PJ. An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to HRT. Maturitas 2006;53;454-61. 15. Salm R. The incidence and significance of early carcinomas in endometrial polyps. Pathology 1972;108:47-53. 16. Anastasiadis PG, Koutlaki NG, Skaphida PG, Galazios GC, Tsikouras PN, Liberis VA. Endometrial polyps: prevalence, detection, and malignant potential in women with abnormal uterine bleeding. Eur J Gynaecol Oncol 2000;21:180-3. 17. Wolfe SA, Mackles A. Malignant lesions arising from benign endometrial polyps. Obstet Gynecol 1962,20:542-50.
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18. Bakour SH, Khan KS, Gupta JK. The risk of premalignant and malignant pathology in endometrial polyps Acta Obstet Gynecol Scand 2000;79:317-20. 19. Savelli L, De Iaco P, Santini D, et al. Histopathologic features and risk factors for benignity, hyperplasia, and cancer in endometrial polyps. Am J Obstet Gynecol 2003;188:927-31. 20. Kurman RJ, ed. Blaustein’s pathology of the female genital tract, 5th ed. New York: Springer-Verlag; 2002. 21. Hassa H, Tekin B, Senses T, Kaya M, Karatas A. Are the site, diameter, and number of endometrial polyps related with the symptomatology? Am J Obstet Gynecol 2006; 194:718-21. 22. Giordano G, Gnetti L, Merisio C, Melpignano M. Postmenopausal status, hypertension and obesity as risk factors for malignant transformation in endometrial polyps. Maturitas 2007;20:190-7. 23. Antunes A Jr, Costa-Paiva L, Arthuso M, Costa JV, Pinto-Neto AM. Endometrial polyps in pre- and postmenopausal women: factors associated with malignancy. Maturitas 2007; 57:415-21. 24. Hileeto D, Fadare O, Martel M, Zheng W. Age dependent association of endometrial polyps with increased risk of cancer involvement. World J Surg Oncol 2005;3:8. 25. Oguz S, Sargin A, Kelekci S, Aytan H, Tapisiz OL, Mollamahmutoglu L. The role of hormone replacement therapy in endometrial polyp formation. Maturitas 2005;50:231-6. 26. Bergman L, Beelen ML, Gallee MP, Hollema H, Benraadt J, van Leeuwen FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres’ ALERT Group. Assessment of liver and endometrial cancer risk following tamoxifen. Lancet 2000;356:881-7.
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