Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis | Endometrial Cancer | JAMA Internal Medicine | JAMA Network
[Skip to Navigation]
Figure 1.  Prevalence of Postmenopausal Bleeding (PMB) in Women With Endometrial Cancer
Prevalence of Postmenopausal Bleeding (PMB) in Women With Endometrial Cancer

The pooled prevalence of PMB is indicated by the dotted line. ES indicates effect size; LR, likelihood ratio; and diamond, pooled risk.

Figure 2.  Risk of Endometrial Cancer in Women With Postmenopausal Bleeding
Risk of Endometrial Cancer in Women With Postmenopausal Bleeding

The pooled risk of endometrial cancer in all 92 studies is indicated by the dotted line. ES indicates effect size.

Figure 3.  Risk of Endometrial Cancer in Women With Postmenopausal Bleeding
Risk of Endometrial Cancer in Women With Postmenopausal Bleeding

Figure 3 is a continuation of Figure 2. The pooled risk of endometrial cancer in all 92 studies is indicated by the dotted line. ES indicates effect size; LR, likelihood ratio; and diamond, pooled risk.

Figure 4.  Risk of Endometrial Cancer in Women With Postmenopausal Bleeding in Studies That Excluded Women Using HT
Risk of Endometrial Cancer in Women With Postmenopausal Bleeding in Studies That Excluded Women Using HT

The pooled risk of endometrial cancer in all 92 studies is indicated by the dotted line. ES indicates effect size; HT, hormone therapy; LR, likelihood ratio; and diamond, pooled risk.

Table.  Clinical Performance of Transvaginal Ultrasonography and an Experimental Assay for Endometrial Cancer Detection Across Risk Estimates in a Hypothetical Population of 10 000 Women With PMBa
Clinical Performance of Transvaginal Ultrasonography and an Experimental Assay for Endometrial Cancer Detection Across Risk Estimates in a Hypothetical Population of 10 000 Women With PMBa
1.
Ferlay  J, Soerjomataram  I, Dikshit  R,  et al.  Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.  Int J Cancer. 2015;136(5):E359-E386. doi:10.1002/ijc.29210PubMedGoogle ScholarCrossref
2.
Setiawan  VW, Yang  HP, Pike  MC,  et al; Australian National Endometrial Cancer Study Group.  Type I and II endometrial cancers: have they different risk factors?  J Clin Oncol. 2013;31(20):2607-2618. doi:10.1200/JCO.2012.48.2596PubMedGoogle ScholarCrossref
3.
Jamison  PM, Noone  AM, Ries  LA, Lee  NC, Edwards  BK.  Trends in endometrial cancer incidence by race and histology with a correction for the prevalence of hysterectomy, SEER 1992 to 2008.  Cancer Epidemiol Biomarkers Prev. 2013;22(2):233-241. doi:10.1158/1055-9965.EPI-12-0996PubMedGoogle ScholarCrossref
4.
Torre  LA, Islami  F, Siegel  RL, Ward  EM, Jemal  A.  Global cancer in women: burden and trends.  Cancer Epidemiol Biomarkers Prev. 2017;26(4):444-457. doi:10.1158/1055-9965.EPI-16-0858PubMedGoogle ScholarCrossref
5.
Wartko  P, Sherman  ME, Yang  HP, Felix  AS, Brinton  LA, Trabert  B.  Recent changes in endometrial cancer trends among menopausal-age US women.  Cancer Epidemiol. 2013;37(4):374-377. doi:10.1016/j.canep.2013.03.008PubMedGoogle ScholarCrossref
6.
Siegel  RL, Miller  KD, Jemal  A.  Cancer Statistics, 2017.  CA Cancer J Clin. 2017;67(1):7-30. doi:10.3322/caac.21387PubMedGoogle ScholarCrossref
7.
Lortet-Tieulent  J, Ferlay  J, Bray  F, Jemal  A.  International patterns and trends in endometrial cancer incidence, 1978-2013.  J Natl Cancer Inst. 2018;110(4):354-361. doi:10.1093/jnci/djx214PubMedGoogle Scholar
8.
Lindemann  K, Eskild  A, Vatten  LJ, Bray  F.  Endometrial cancer incidence trends in Norway during 1953-2007 and predictions for 2008-2027.  Int J Cancer. 2010;127(11):2661-2668. doi:10.1002/ijc.25267PubMedGoogle ScholarCrossref
9.
Gaber  C, Meza  R, Ruterbusch  JJ, Cote  ML.  Endometrial cancer trends by race and histology in the USA: projecting the number of new cases from 2015 to 2040.  J Racial Ethn Health Disparities. Published online October 17, 2016.PubMedGoogle Scholar
10.
Sheikh  MA, Althouse  AD, Freese  KE,  et al.  USA endometrial cancer projections to 2030: should we be concerned?  Future Oncol. 2014;10(16):2561-2568. doi:10.2217/fon.14.192PubMedGoogle ScholarCrossref
11.
Smittenaar  CR, Petersen  KA, Stewart  K, Moitt  N.  Cancer incidence and mortality projections in the UK until 2035.  Br J Cancer. 2016;115(9):1147-1155. doi:10.1038/bjc.2016.304PubMedGoogle ScholarCrossref
12.
Weiderpass  E, Antoine  J, Bray  FI, Oh  JK, Arbyn  M.  Trends in corpus uteri cancer mortality in member states of the European Union.  Eur J Cancer. 2014;50(9):1675-1684. doi:10.1016/j.ejca.2014.02.020PubMedGoogle ScholarCrossref
13.
Creasman  WT, Odicino  F, Maisonneuve  P,  et al.  Carcinoma of the corpus uteri: FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer.  Int J Gynaecol Obstet. 2006;95(suppl 1):S105-S143. doi:10.1016/S0020-7292(06)60031-3PubMedGoogle ScholarCrossref
14.
UK CR. Uterine cancer statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/uterine-cancer. Updated July 3, 2017. Accessed January 18, 2018.
15.
Kitson  SJ, Evans  DG, Crosbie  EJ.  Identifying high-risk women for endometrial cancer prevention strategies: proposal of an endometrial cancer risk prediction model.  Cancer Prev Res (Phila). 2017;10(1):1-13. doi:10.1158/1940-6207.CAPR-16-0224PubMedGoogle ScholarCrossref
16.
Castle  PE, Katki  HA.  Screening: a risk-based framework to decide who benefits from screening.  Nat Rev Clin Oncol. 2016;13(9):531-532. doi:10.1038/nrclinonc.2016.101PubMedGoogle ScholarCrossref
17.
Girschik  J, Miller  LJ, Addiscott  T,  et al.  Precision in setting cancer prevention priorities: synthesis of data, literature, and expert opinion.  Front Public Health. 2017;5:125. doi:10.3389/fpubh.2017.00125PubMedGoogle ScholarCrossref
18.
van Hanegem  N, Breijer  MC, Khan  KS,  et al.  Diagnostic evaluation of the endometrium in postmenopausal bleeding: an evidence-based approach.  Maturitas. 2011;68(2):155-164. doi:10.1016/j.maturitas.2010.11.010PubMedGoogle ScholarCrossref
19.
ACOG Committee opinion No. 734:  The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding.  Obstet Gynecol. 2018;131:e124-e129. doi:10.1097/AOG.0000000000002631PubMedGoogle ScholarCrossref
20.
Breijer  MC, Timmermans  A, van Doorn  HC, Mol  BW, Opmeer  BC.  Diagnostic strategies for postmenopausal bleeding.  Obstet Gynecol Int. 2010;2010:850812. doi:10.1155/2010/850812PubMedGoogle ScholarCrossref
21.
Burbos  N, Musonda  P, Duncan  TJ, Crocker  SG, Nieto  JJ, Morris  EP.  Postmenopausal vaginal bleeding in women using hormone replacement therapy.  Menopause Int. 2012;18(1):5-9. doi:10.1258/mi.2011.011111PubMedGoogle ScholarCrossref
22.
van Doorn  HC, Opmeer  BC, Jitze Duk  M, Kruitwagen  RF, Dijkhuizen  FP, Mol  BW.  The relation between age, time since menopause, and endometrial cancer in women with postmenopausal bleeding.  Int J Gynecol Cancer. 2007;17(5):1118-1123. doi:10.1111/j.1525-1438.2007.00925.xPubMedGoogle ScholarCrossref
23.
Schindler  AE, Schmidt  G.  Post-menopausal bleeding: a study of more than 1000 cases.  Maturitas. 1980;2(4):269-274. doi:10.1016/0378-5122(80)90028-6PubMedGoogle ScholarCrossref
24.
Randelzhofer  B, Prömpeler  HJ, Sauerbrei  W, Madjar  H, Emons  G.  Value of sonomorphological criteria of the endometrium in women with postmenopausal bleeding: a multivariate analysis.  Ultrasound Obstet Gynecol. 2002;19(1):62-68. doi:10.1046/j.0960-7692.2001.00618.xPubMedGoogle ScholarCrossref
25.
Mantalenakis  SJ, Papapostolou  MG.  Genital bleeding in women aged 50 and over.  Int Surg. 1977;62(2):103-105.PubMedGoogle Scholar
26.
Critchley  HO, Warner  P, Lee  AJ, Brechin  S, Guise  J, Graham  B.  Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.  Health Technol Assess. 2004;8(34):iii-iv, 1-139. doi:10.3310/hta8340PubMedGoogle ScholarCrossref
27.
Burbos  N, Musonda  P, Crocker  SG, Morris  EP, Nieto  JJ, Duncan  TJ.  Management of postmenopausal women with vaginal bleeding when the endometrium can not be visualized.  Acta Obstet Gynecol Scand. 2012;91(6):686-691. doi:10.1111/j.1600-0412.2012.01407.xPubMedGoogle ScholarCrossref
28.
van Hanegem  N, Breijer  MC, Opmeer  BC, Mol  BW, Timmermans  A.  Prediction models in women with postmenopausal bleeding: a systematic review.  Womens Health (Lond). 2012;8(3):251-262. doi:10.2217/WHE.12.10PubMedGoogle ScholarCrossref
29.
Wentzensen  N, Wacholder  S.  From differences in means between cases and controls to risk stratification: a business plan for biomarker development.  Cancer Discov. 2013;3(2):148-157. doi:10.1158/2159-8290.CD-12-0196PubMedGoogle ScholarCrossref
30.
Talhouk  A, McConechy  MK, Leung  S,  et al.  Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.  Cancer. 2017;123(5):802-813. doi:10.1002/cncr.30496PubMedGoogle ScholarCrossref
31.
Wentzensen  N, Bakkum-Gamez  JN, Killian  JK,  et al.  Discovery and validation of methylation markers for endometrial cancer.  Int J Cancer. 2014;135(8):1860-1868. doi:10.1002/ijc.28843PubMedGoogle ScholarCrossref
32.
Bakkum-Gamez  JN, Wentzensen  N, Maurer  MJ,  et al.  Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.  Gynecol Oncol. 2015;137(1):14-22. doi:10.1016/j.ygyno.2015.01.552PubMedGoogle ScholarCrossref
33.
Stelloo  E, Bosse  T, Nout  RA,  et al.  Refining prognosis and identifying targetable pathways for high-risk endometrial cancer: a TransPORTEC initiative.  Mod Pathol. 2015;28(6):836-844. doi:10.1038/modpathol.2015.43PubMedGoogle ScholarCrossref
34.
Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006PubMedGoogle ScholarCrossref
35.
Wells  G, Shea  B, O’Connell  D,  et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf. 2014. Accessed July 2017.
36.
Whiting  PF, Rutjes  AW, Westwood  ME,  et al; QUADAS-2 Group.  QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.  Ann Intern Med. 2011;155(8):529-536. doi:10.7326/0003-4819-155-8-201110180-00009PubMedGoogle ScholarCrossref
37.
Higgins  JP, Thompson  SG, Spiegelhalter  DJ.  A re-evaluation of random-effects meta-analysis.  J R Stat Soc Ser A Stat Soc. 2009;172(1):137-159. doi:10.1111/j.1467-985X.2008.00552.xPubMedGoogle ScholarCrossref
38.
Nyaga  VN, Arbyn  M, Aerts  M.  Metaprop: a Stata command to perform meta-analysis of binomial data.  Arch Public Health. 2014;72(1):39. doi:10.1186/2049-3258-72-39PubMedGoogle ScholarCrossref
39.
Mackillop  WJ, Pringle  JF.  Stage III endometrial carcinoma: a review of 90 cases.  Cancer. 1985;56(10):2519-2523. doi:10.1002/1097-0142(19851115)56:10<2519::AID-CNCR2820561033>3.0.CO;2-MPubMedGoogle ScholarCrossref
40.
Pliskow  S, Penalver  M, Averette  HE.  Stage III and stage IV endometrial carcinoma: a review of 41 cases.  Gynecol Oncol. 1990;38(2):210-215. doi:10.1016/0090-8258(90)90043-KPubMedGoogle ScholarCrossref
41.
Williams  SC, Lopez  C, Yoong  A, McHugo  JM.  Developing a robust and efficient pathway for the referral and investigation of women with post-menopausal bleeding using a cut-off of < or =4 mm for normal thickness.  Br J Radiol. 2007;80(957):719-723. doi:10.1259/bjr/87219886PubMedGoogle ScholarCrossref
42.
de Kroon  CD, Hiemstra  E, Trimbos  JB, Jansen  FW.  Power Doppler area in the diagnosis of endometrial cancer.  Int J Gynecol Cancer. 2010;20(7):1160-1165. doi:10.1111/IGC.0b013e3181f0df98PubMedGoogle ScholarCrossref
43.
Alcazar  JL, Galvan  R.  Three-dimensional power Doppler ultrasound scanning for the prediction of endometrial cancer in women with postmenopausal bleeding and thickened endometrium.  Am J Obstet Gynecol. 2009;200(1):44.e1-44.e6. doi:10.1016/j.ajog.2008.08.027PubMedGoogle ScholarCrossref
44.
Opolskiene  G, Sladkevicius  P, Jokubkiene  L, Valentin  L.  Three-dimensional ultrasound imaging for discrimination between benign and malignant endometrium in women with postmenopausal bleeding and sonographic endometrial thickness of at least 4.5 mm.  Ultrasound Obstet Gynecol. 2010;35(1):94-102. doi:10.1002/uog.7445PubMedGoogle ScholarCrossref
45.
Elfayomy  AK, El Tarhouny  SA.  Ovarian volume assessment in relation to histologic findings and sex hormone levels in women with postmenopausal bleeding and thickened endometrium.  Ann Saudi Med. 2012;32(6):588-592. doi:10.5144/0256-4947.2012.588PubMedGoogle ScholarCrossref
46.
Rossi  A, Forzano  L, Romanello  I, Fachechi  G, Marchesoni  D.  Assessment of endometrial volume and vascularization using transvaginal 3D power Doppler angiography in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 2012;119(1):14-17. doi:10.1016/j.ijgo.2012.05.023PubMedGoogle ScholarCrossref
47.
Makled  AK, Elmekkawi  SF, El-Refaie  TA, El-Sherbiny  MA.  Three-dimensional power Doppler and endometrial volume as predictors of malignancy in patients with postmenopausal bleeding.  J Obstet Gynaecol Res. 2013;39(5):1045-1051. doi:10.1111/j.1447-0756.2012.02066.xPubMedGoogle ScholarCrossref
48.
Salman  MC, Bozdag  G, Dogan  S, Yuce  K.  Role of postmenopausal bleeding pattern and women’s age in the prediction of endometrial cancer.  Aust N Z J Obstet Gynaecol. 2013;53(5):484-488.PubMedGoogle Scholar
49.
Dueholm  M, Møller  C, Rydbjerg  S, Hansen  ES, Ørtoft  G.  An ultrasound algorithm for identification of endometrial cancer.  Ultrasound Obstet Gynecol. 2014;43(5):557-568. doi:10.1002/uog.13205PubMedGoogle ScholarCrossref
50.
Giannella  L, Mfuta  K, Setti  T, Cerami  LB, Bergamini  E, Boselli  F.  A risk-scoring model for the prediction of endometrial cancer among symptomatic postmenopausal women with endometrial thickness > 4 mm.  Biomed Res Int. 2014;2014:130569. doi:10.1155/2014/130569PubMedGoogle ScholarCrossref
51.
Fernández-Parra  J, Rodríguez Oliver  A, López Criado  S, Parrilla Fernández  F, Montoya Ventoso  F.  Hysteroscopic evaluation of endometrial polyps.  Int J Gynaecol Obstet. 2006;95(2):144-148. doi:10.1016/j.ijgo.2006.07.007PubMedGoogle ScholarCrossref
52.
Domingues  AP, Lopes  H, Dias  I, De Oliveira  CF.  Endometrial polyps in postmenopausal women.  Acta Obstet Gynecol Scand. 2009;88(5):618-620. doi:10.1080/00016340902818188PubMedGoogle ScholarCrossref
53.
Golan  A, Cohen-Sahar  B, Keidar  R, Condrea  A, Ginath  S, Sagiv  R.  Endometrial polyps: symptomatology, menopausal status and malignancy.  Gynecol Obstet Invest. 2010;70(2):107-112. doi:10.1159/000298767PubMedGoogle ScholarCrossref
54.
Mossa  B, Torcia  F, Avenoso  F, Tucci  S, Marziani  R.  Occurrence of malignancy in endometrial polyps during postmenopause.  Eur J Gynaecol Oncol. 2010;31(2):165-168.PubMedGoogle Scholar
55.
Ronghe  R, Gaudoin  M.  Women with recurrent postmenopausal bleeding should be re-investigated but are not more likely to have endometrial cancer.  Menopause Int. 2010;16(1):9-11. doi:10.1258/mi.2010.010008PubMedGoogle ScholarCrossref
56.
Wethington  SL, Herzog  TJ, Burke  WM,  et al.  Risk and predictors of malignancy in women with endometrial polyps.  Ann Surg Oncol. 2011;18(13):3819-3823. doi:10.1245/s10434-011-1815-zPubMedGoogle ScholarCrossref
57.
Cavkaytar  S, Kokanali  MK, Ceran  U, Topcu  HO, Sirvan  L, Doganay  M.  Roles of sonography and hysteroscopy in the detection of premalignant and malignant polyps in women presenting with postmenopausal bleeding and thickened endometrium.  Asian Pac J Cancer Prev. 2014;15(13):5355-5358. doi:10.7314/APJCP.2014.15.13.5355PubMedGoogle ScholarCrossref
58.
Ciatto  S, Cecchini  S, Gervasi  G, Landini  A, Zappa  M, Crocetti  E.  Association of endometrial thickness assessed at trans-vaginal ultrasonography to endometrial cancer in postmenopausal women asymptomatic or with abnormal uterine bleeding.  Radiol Med. 2002;104(5-6):437-442.PubMedGoogle Scholar
59.
Kodama  J, Seki  N, Ojima  Y, Nakamura  K, Hongo  A, Hiramatsu  Y.  Correlation of presenting symptoms and patient characteristics with endometrial cancer prognosis in Japanese women.  Int J Gynaecol Obstet. 2005;91(2):151-156. doi:10.1016/j.ijgo.2005.08.002PubMedGoogle ScholarCrossref
60.
Franceschi  S, La Vecchia  C, Gallus  G,  et al.  Delayed diagnosis of endometrial cancer in Italy.  Cancer. 1983;51(6):1176-1178. doi:10.1002/1097-0142(19830315)51:6<1176::AID-CNCR2820510634>3.0.CO;2-OPubMedGoogle ScholarCrossref
61.
Horwitz  RI, Feinstein  AR.  Alternative analytic methods for case-control studies of estrogens and endometrial cancer.  N Engl J Med. 1978;299(20):1089-1094. doi:10.1056/NEJM197811162992001PubMedGoogle ScholarCrossref
62.
Khunnarong  J, Tangjitgamol  S, Srijaipracharoen  S.  Other gynecologic pathology in endometrial cancer patients.  Asian Pac J Cancer Prev. 2016;17(2):713-717. doi:10.7314/APJCP.2016.17.2.713PubMedGoogle ScholarCrossref
63.
Le  T, Menard  C, Samant  R,  et al.  Longitudinal assessments of quality of life in endometrial cancer patients: effect of surgical approach and adjuvant radiotherapy.  Int J Radiat Oncol Biol Phys. 2009;75(3):795-802. doi:10.1016/j.ijrobp.2008.11.018PubMedGoogle ScholarCrossref
64.
Sharon  Z, Shani  M, Modan  B.  Clinicoepidemiologic study of uterine cancer: comparative aspects of the endometrial and cervical sites.  Obstet Gynecol. 1977;50(5):536-540.PubMedGoogle Scholar
65.
Hulka  BS, Grimson  RC, Greenberg  BG,  et al.  “Alternative” controls in a case-control study of endometrial cancer and exogenous estrogen.  Am J Epidemiol. 1980;112(3):376-387. doi:10.1093/oxfordjournals.aje.a113003PubMedGoogle ScholarCrossref
66.
Liu  JR, Conaway  M, Rodriguez  GC, Soper  JT, Clarke-Pearson  DL, Berchuck  A.  Relationship between race and interval to treatment in endometrial cancer.  Obstet Gynecol. 1995;86(4, pt 1):486-490. doi:10.1016/0029-7844(95)00238-MPubMedGoogle ScholarCrossref
67.
Piura  B, Bar-Dayan  A, Cohen  Y, Yanai-Inbar  I, Glezerman  M.  Endometrial carcinoma in the south of Israel: study of 231 cases.  J Surg Oncol. 1997;66(3):189-195. doi:10.1002/(SICI)1096-9098(199711)66:3<189::AID-JSO7>3.0.CO;2-8PubMedGoogle ScholarCrossref
68.
Schneider  D, Halperin  R, Langer  R, Bukovsky  I, Hermann  A.  Well-differentiated versus less-differentiated endometrial carcinoma.  Eur J Gynaecol Oncol. 1998;19(3):242-245.PubMedGoogle Scholar
69.
Tsuda  H, Kawabata  M, Yamamoto  K, Inoue  T, Umesaki  N.  Prospective study to compare endometrial cytology and transvaginal ultrasonography for identification of endometrial malignancies.  Gynecol Oncol. 1997;65(3):383-386. doi:10.1006/gyno.1997.4699PubMedGoogle ScholarCrossref
70.
Barak  F, Kalichman  L, Gdalevich  M,  et al.  The influence of early diagnosis of endometrioid endometrial cancer on disease stage and survival.  Arch Gynecol Obstet. 2013;288(6):1361-1364. doi:10.1007/s00404-013-2898-5PubMedGoogle ScholarCrossref
71.
Chandavarkar  U, Kuperman  JM, Muderspach  LI, Opper  N, Felix  JC, Roman  L.  Endometrial echo complex thickness in postmenopausal endometrial cancer.  Gynecol Oncol. 2013;131(1):109-112. doi:10.1016/j.ygyno.2013.07.109PubMedGoogle ScholarCrossref
72.
Seebacher  V, Schmid  M, Polterauer  S,  et al.  The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study.  BMC Cancer. 2009;9:460. doi:10.1186/1471-2407-9-460PubMedGoogle ScholarCrossref
73.
Wang  J, Wieslander  C, Hansen  G, Cass  I, Vasilev  S, Holschneider  CH.  Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers.  Gynecol Oncol. 2006;101(1):120-125. doi:10.1016/j.ygyno.2005.09.042PubMedGoogle ScholarCrossref
74.
Dvalishvili  I, Charkviani  L, Turashvili  G, Burkadze  G.  Clinical characteristics of prognostic factors in uterine endometrioid adenocarcinoma of various grade.  Georgian Med News. 2006;(132):24-27.PubMedGoogle Scholar
75.
Kimura  T, Kamiura  S, Yamamoto  T, Seino-Noda  H, Ohira  H, Saji  F.  Abnormal uterine bleeding and prognosis of endometrial cancer.  Int J Gynaecol Obstet. 2004;85(2):145-150. doi:10.1016/j.ijgo.2003.12.001PubMedGoogle ScholarCrossref
76.
Krissi  H, Chetrit  A, Menczer  J.  Presenting symptoms of patients with endometrial carcinoma: effect on prognosis.  Eur J Gynaecol Oncol. 1996;17(1):25-28.PubMedGoogle Scholar
77.
Pakish  JB, Lu  KH, Sun  CC,  et al.  Endometrial cancer associated symptoms: a case-control study.  J Womens Health (Larchmt). 2016;25(11):1187-1192. doi:10.1089/jwh.2015.5657PubMedGoogle ScholarCrossref
78.
Swingler  GR, Cave  DG, Mitchard  P.  Diagnostic accuracy of the MiMark endometrial cell sampler in 101 patients with postmenopausal bleeding.  Br J Obstet Gynaecol. 1979;86(10):816-818. doi:10.1111/j.1471-0528.1979.tb10699.xPubMedGoogle ScholarCrossref
79.
Goldberg  GL, Tsalacopoulos  G, Davey  DA.  A comparison of endometrial sampling with the Accurette and Vabra aspirator and uterine curettage.  S Afr Med J. 1982;61(4):114-116.PubMedGoogle Scholar
80.
Nasri  MN, Coast  GJ.  Correlation of ultrasound findings and endometrial histopathology in postmenopausal women.  Br J Obstet Gynaecol. 1989;96(11):1333-1338. doi:10.1111/j.1471-0528.1989.tb03233.xPubMedGoogle ScholarCrossref
81.
Alberico  S, Conoscenti  G, Vegliò  P, Bogatti  P, Di Bonito  L, Mandruzzato  G.  A clinical and epidemiological study of 245 postmenopausal metrorrhagia patients.  Clin Exp Obstet Gynecol. 1989;16(4):113-121.PubMedGoogle Scholar
82.
Osmers  R, Völksen  M, Schauer  A.  Vaginosonography for early detection of endometrial carcinoma?  Lancet. 1990;335(8705):1569-1571. doi:10.1016/0140-6736(90)91387-PPubMedGoogle ScholarCrossref
83.
Allen  DG, Correy  JF, Marsden  DE.  Abnormal uterine bleeding and cancer of the genital tract.  Aust N Z J Obstet Gynaecol. 1990;30(1):81-83. doi:10.1111/j.1479-828X.1990.tb03204.xPubMedGoogle ScholarCrossref
84.
Granberg  S, Wikland  M, Karlsson  B, Norström  A, Friberg  LG.  Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality.  Am J Obstet Gynecol. 1991;164(1 Pt 1):47-52. doi:10.1016/0002-9378(91)90622-XPubMedGoogle ScholarCrossref
85.
Goldstein  SR, Nachtigall  M, Snyder  JR, Nachtigall  L.  Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding.  Am J Obstet Gynecol. 1990;163(1, pt 1):119-123. doi:10.1016/S0002-9378(11)90683-8PubMedGoogle ScholarCrossref
86.
White  CD.  Post menopausal bleeding as a risk factor for endometrial carcinoma.  W V Med J. 1991;87(1):15-17.PubMedGoogle Scholar
87.
Dørum  A, Kristensen  GB, Langebrekke  A, Sørnes  T, Skaar  O.  Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1993;72(2):116-119. doi:10.3109/00016349309023423PubMedGoogle ScholarCrossref
88.
Lin  HH, Wu  MY, Shyu  MK, Chen  D, Tsai  JL, Hsieh  CY.  Clinical study of 381 postmenopausal bleeding patients.  J Formos Med Assoc. 1993;92(3):241-244.PubMedGoogle Scholar
89.
Auslender  R, Bornstein  J, Dirnfeld  M, Kogan  O, Atad  J, Abramovici  H.  Vaginal ultrasonography in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1993;3(6):426-428. doi:10.1046/j.1469-0705.1993.03060426.xPubMedGoogle ScholarCrossref
90.
Sladkevicius  P, Valentin  L, Marsál  K.  Endometrial thickness and Doppler velocimetry of the uterine arteries as discriminators of endometrial status in women with postmenopausal bleeding: a comparative study.  Am J Obstet Gynecol. 1994;171(3):722-728. doi:10.1016/0002-9378(94)90088-4PubMedGoogle ScholarCrossref
91.
Cacciatore  B, Ramsay  T, Lehtovirta  P, Ylöstalo  P.  Transvaginal sonography and hysteroscopy in postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1994;73(5):413-416. doi:10.3109/00016349409006254PubMedGoogle ScholarCrossref
92.
Chan  FY, Chau  MT, Pun  TC,  et al.  Limitations of transvaginal sonography and color Doppler imaging in the differentiation of endometrial carcinoma from benign lesions.  J Ultrasound Med. 1994;13(8):623-628. doi:10.7863/jum.1994.13.8.623PubMedGoogle ScholarCrossref
93.
Malinova  M, Pehlivanov  B.  Transvaginal sonography and endometrial thickness in patients with postmenopausal uterine bleeding.  Eur J Obstet Gynecol Reprod Biol. 1995;58(2):161-165. doi:10.1016/0028-2243(95)80017-MPubMedGoogle ScholarCrossref
94.
Conoscenti  G, Meir  YJ, Fischer-Tamaro  L,  et al.  Endometrial assessment by transvaginal sonography and histological findings after D & C in women with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1995;6(2):108-115. doi:10.1046/j.1469-0705.1995.06020108.xPubMedGoogle ScholarCrossref
95.
Emanuel  MH, Verdel  MJC, Stas  H, Wamsteker  K, Lammes  FB.  An audit of true prevalence of intra-uterine pathology: the hysteroscopical findings controlled for patient selection in 1202 patients with abnormal uterine bleeding.  Gynaecol Endosc. 1995;4(4):237-241.Google Scholar
96.
Karlsson  B, Granberg  S, Wikland  M,  et al.  Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: a Nordic multicenter study.  Am J Obstet Gynecol. 1995;172(5):1488-1494. doi:10.1016/0002-9378(95)90483-2PubMedGoogle ScholarCrossref
97.
Lee  WH, Tan  KH, Lee  YW.  The aetiology of postmenopausal bleeding—a study of 163 consecutive cases in Singapore.  Singapore Med J. 1995;36(2):164-168.PubMedGoogle Scholar
98.
Ferrazzi  E, Torri  V, Trio  D, Zannoni  E, Filiberto  S, Dordoni  D.  Sonographic endometrial thickness: a useful test to predict atrophy in patients with postmenopausal bleeding: an Italian multicenter study.  Ultrasound Obstet Gynecol. 1996;7(5):315-321. doi:10.1046/j.1469-0705.1996.07050315.xPubMedGoogle ScholarCrossref
99.
Haller  H, Matecjcić  N, Rukavina  B, Krasević  M, Rupcić  S, Mozetic  D.  Transvaginal sonography and hysteroscopy in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 1996;54(2):155-159. doi:10.1016/0020-7292(96)02677-XPubMedGoogle ScholarCrossref
100.
Cecchini  S, Ciatto  S, Bonardi  R, Grazzini  G, Mazzota  A.  Endometrial ultrasonography: an alternative to invasive assessment in women with postmenopausal vaginal bleeding.  Tumori. 1996;82(1):38-39. doi:10.1177/030089169608200107PubMedGoogle ScholarCrossref
101.
Wolman  I, Sagi  J, Ginat  S, Jaffa  AJ, Hartoov  J, Jedwab  G.  The sensitivity and specificity of vaginal sonography in detecting endometrial abnormalities in women with postmenopausal bleeding.  J Clin Ultrasound. 1996;24(2):79-82. doi:10.1002/(SICI)1097-0096(199602)24:2<79::AID-JCU5>3.0.CO;2-HPubMedGoogle ScholarCrossref
102.
Grigoriou  O, Kalovidouros  A, Papadias  C, Antoniou  G, Antonaki  V, Giannikos  L.  Transvaginal sonography of the endometrium in women with postmenopausal bleeding.  Maturitas. 1996;23(1):9-14. doi:10.1016/0378-5122(95)00945-0PubMedGoogle ScholarCrossref
103.
Nagele  F, O’Connor  H, Baskett  TF, Davies  A, Mohammed  H, Magos  AL.  Hysteroscopy in women with abnormal uterine bleeding on hormone replacement therapy: a comparison with postmenopausal bleeding.  Fertil Steril. 1996;65(6):1145-1150. doi:10.1016/S0015-0282(16)58329-0PubMedGoogle ScholarCrossref
104.
Fistonic  I, Hodek  B, Klaric  P, Jokanovic  L, Grubisic  G, Ivicevic-Bakulic  T.  Transvaginal sonographic assessment of premalignant and malignant changes in the endometrium in postmenopausal bleeding.  J Clin Ultrasound. 1997;25(8):431-435. doi:10.1002/(SICI)1097-0096(199710)25:8<431::AID-JCU4>3.0.CO;2-KPubMedGoogle ScholarCrossref
105.
Gruboeck  K, Jurkovic  D, Lawton  F, Savvas  M, Tailor  A, Campbell  S.  The diagnostic value of endometrial thickness and volume measurements by three-dimensional ultrasound in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1996;8(4):272-276. doi:10.1046/j.1469-0705.1996.08040272.xPubMedGoogle ScholarCrossref
106.
Kekre  AN, Jose  R, Seshadri  L.  Transvaginal sonography of the endometrium in south Indian postmenopausal women.  Aust N Z J Obstet Gynaecol. 1997;37(4):449-451. doi:10.1111/j.1479-828X.1997.tb02458.xPubMedGoogle ScholarCrossref
107.
Valli  E, Zupi  E, Marconi  D,  et al.  Vaginal ultrasonography and diagnostic hysteroscopy for women with abnormal uterine bleeding after menopause.  J Am Assoc Gynecol Laparosc. 1996;3(4)(suppl):S52.PubMedGoogle Scholar
108.
Güner  H, Tiras  MB, Karabacak  O, Sarikaya  H, Erdem  M, Yildirim  M.  Endometrial assessment by vaginal ultrasonography might reduce endometrial sampling in patients with postmenopausal bleeding: a prospective study.  Aust N Z J Obstet Gynaecol. 1996;36(2):175-178. doi:10.1111/j.1479-828X.1996.tb03280.xPubMedGoogle ScholarCrossref
109.
Bronz  L, Suter  T, Rusca  T.  The value of transvaginal sonography with and without saline instillation in the diagnosis of uterine pathology in pre- and postmenopausal women with abnormal bleeding or suspect sonographic findings.  Ultrasound Obstet Gynecol. 1997;9(1):53-58. doi:10.1046/j.1469-0705.1997.09010053.xPubMedGoogle ScholarCrossref
110.
Giusa-Chiferi  MG, Gonçalves  WJ, Baracat  EC, de Albuquerque Neto  LC, Bortoletto  CC, de Lima  GR.  Transvaginal ultrasound, uterine biopsy and hysteroscopy for postmenopausal bleeding.  Int J Gynaecol Obstet. 1996;55(1):39-44. doi:10.1016/0020-7292(96)02720-8PubMedGoogle ScholarCrossref
111.
Iatrakis  G, Diakakis  I, Kourounis  G,  et al.  Postmenopausal uterine bleeding.  Clin Exp Obstet Gynecol. 1997;24(3):157.PubMedGoogle Scholar
112.
Weber  G, Merz  E, Bahlmann  F, Rösch  B.  Evaluation of different transvaginal sonographic diagnostic parameters in women with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1998;12(4):265-270. doi:10.1046/j.1469-0705.1998.12040265.xPubMedGoogle ScholarCrossref
113.
Gemer  O, Segal  S.  Endometrial cancer in patients undergoing diagnostic curettage.  Arch Gynecol Obstet. 1998;261(2):79-81. doi:10.1007/s004040050203PubMedGoogle ScholarCrossref
114.
O’Connell  LP, Fries  MH, Zeringue  E, Brehm  W.  Triage of abnormal postmenopausal bleeding: a comparison of endometrial biopsy and transvaginal sonohysterography versus fractional curettage with hysteroscopy.  Am J Obstet Gynecol. 1998;178(5):956-961. doi:10.1016/S0002-9378(98)70530-7PubMedGoogle ScholarCrossref
115.
Büyük  E, Durmuşoğlu  F, Erenus  M, Karakoç  B.  Endometrial disease diagnosed by transvaginal ultrasound and dilatation and curettage.  Acta Obstet Gynecol Scand. 1999;78(5):419-422. doi:10.1080/j.1600-0412.1999.780514.xPubMedGoogle ScholarCrossref
116.
Briley  M, Lindsell  DR.  The role of transvaginal ultrasound in the investigation of women with post-menopausal bleeding.  Clin Radiol. 1998;53(7):502-505. doi:10.1016/S0009-9260(98)80169-4PubMedGoogle ScholarCrossref
117.
Bakour  SH, Dwarakanath  LS, Khan  KS, Newton  JR, Gupta  JK.  The diagnostic accuracy of ultrasound scan in predicting endometrial hyperplasia and cancer in postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1999;78(5):447-451. doi:10.1080/j.1600-0412.1999.780519.xPubMedGoogle ScholarCrossref
118.
Loverro  G, Bettocchi  S, Cormio  G,  et al.  Transvaginal sonography and hysteroscopy in postmenopausal uterine bleeding.  Maturitas. 1999;33(2):139-144. doi:10.1016/S0378-5122(99)00023-7PubMedGoogle ScholarCrossref
119.
Garuti  G, Sambruni  I, Cellani  F, Garzia  D, Alleva  P, Luerti  M.  Hysteroscopy and transvaginal ultrasonography in postmenopausal women with uterine bleeding.  Int J Gynaecol Obstet. 1999;65(1):25-33. doi:10.1016/S0020-7292(98)00224-0PubMedGoogle ScholarCrossref
120.
Sheikh  M, Sawhney  S, Khurana  A, Al-Yatama  M.  Alteration of sonographic texture of the endometrium in post-menopausal bleeding: a guide to further management.  Acta Obstet Gynecol Scand. 2000;79(11):1006-1010.PubMedGoogle Scholar
121.
Amit  A, Weiner  Z, Ganem  N,  et al.  The diagnostic value of power Doppler measurements in the endometrium of women with postmenopausal bleeding.  Gynecol Oncol. 2000;77(2):243-247. doi:10.1006/gyno.2000.5766PubMedGoogle ScholarCrossref
122.
Bree  RL, Bowerman  RA, Bohm-Velez  M,  et al.  US evaluation of the uterus in patients with postmenopausal bleeding: a positive effect on diagnostic decision making.  Radiology. 2000;216(1):260-264. doi:10.1148/radiology.216.1.r00jl37260PubMedGoogle ScholarCrossref
123.
Gull  B, Carlsson  S, Karlsson  B, Ylöstalo  P, Milsom  I, Granberg  S.  Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: is it always necessary to perform an endometrial biopsy?  Am J Obstet Gynecol. 2000;182(3):509-515. doi:10.1067/mob.2000.103092PubMedGoogle ScholarCrossref
124.
Dunn  TS, Stamm  CA, Delorit  M, Goldberg  G.  Clinical pathway for evaluating women with abnormal uterine bleeding.  J Reprod Med. 2001;46(9):831-834.PubMedGoogle Scholar
125.
Hunter  DC, McClure  N.  Abnormal uterine bleeding: an evaluation endometrial biopsy, vaginal ultrasound and outpatient hysteroscopy.  Ulster Med J. 2001;70(1):25-30.PubMedGoogle Scholar
126.
Cameron  ST, Walker  J, Chambers  S, Critchley  H.  Comparison of transvaginal ultrasound, saline infusion sonography and hysteroscopy to investigate postmenopausal bleeding and unscheduled bleeding on HRT.  Aust N Z J Obstet Gynaecol. 2001;41(3):291-294. doi:10.1111/j.1479-828X.2001.tb01230.xPubMedGoogle ScholarCrossref
127.
Jones  K, Bourne  T.  The feasibility of a “one stop” ultrasound-based clinic for the diagnosis and management of abnormal uterine bleeding.  Ultrasound Obstet Gynecol. 2001;17(6):517-521. doi:10.1046/j.1469-0705.2001.00445.xPubMedGoogle ScholarCrossref
128.
Sousa  R, Silvestre  M, Almeida e Sousa  L,  et al.  Transvaginal ultrasonography and hysteroscopy in postmenopausal bleeding: a prospective study.  Acta Obstet Gynecol Scand. 2001;80(9):856-862.PubMedGoogle Scholar
129.
Panda  JK.  One-stop clinic for postmenopausal bleeding.  J Reprod Med. 2002;47(9):761-766.PubMedGoogle Scholar
130.
Yaman  C, Ebner  T, Jesacher  K, Obermayr  G, Pölz  W, Tews  G.  Reproducibility of three-dimensional ultrasound endometrial volume measurements in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 2002;19(3):282-286. doi:10.1046/j.1469-0705.2002.00644.xPubMedGoogle ScholarCrossref
131.
Elliott  J, Connor  ME, Lashen  H.  The value of outpatient hysteroscopy in diagnosing endometrial pathology in postmenopausal women with and without hormone replacement therapy.  Acta Obstet Gynecol Scand. 2003;82(12):1112-1119. doi:10.1046/j.1600-0412.2003.00261.xPubMedGoogle ScholarCrossref
132.
Mossa  B, Imperato  F, Marziani  R,  et al.  Hormonal replacement therapy and evaluation of intrauterine pathology in postmenopausal women: a ten-year study.  Eur J Gynaecol Oncol. 2003;24(6):507-512.PubMedGoogle Scholar
133.
Arslan  M, Erdem  A, Erdem  M, Yazici  G, Himmetoglu  O, Gursoy  R.  Transvaginal color Doppler ultrasonography for prediction of pre-cancerous endometrial lesions.  Int J Gynaecol Obstet. 2003;80(3):299-306. doi:10.1016/S0020-7292(02)00374-0PubMedGoogle ScholarCrossref
134.
de Wit  AC, Vleugels  MP, de Kruif  JH.  Diagnostic hysteroscopy: a valuable diagnostic tool in the diagnosis of structural intra-cavital pathology and endometrial hyperplasia or carcinoma? six years of experience with non-clinical diagnostic hysteroscopy.  Eur J Obstet Gynecol Reprod Biol. 2003;110(1):79-82. doi:10.1016/S0301-2115(03)00165-9PubMedGoogle ScholarCrossref
135.
Bachmann  LM, ter Riet  G, Clark  TJ, Gupta  JK, Khan  KS.  Probability analysis for diagnosis of endometrial hyperplasia and cancer in postmenopausal bleeding: an approach for a rational diagnostic workup.  Acta Obstet Gynecol Scand. 2003;82(6):564-569. doi:10.1034/j.1600-0412.2003.00176.xPubMedGoogle ScholarCrossref
136.
Phillip  H, Dacosta  V, Fletcher  H, Kulkarni  S, Reid  M.  Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Afro-Caribbean Jamaican women with postmenopausal bleeding.  J Obstet Gynaecol. 2004;24(5):568-572. doi:10.1080/01443610410001722671PubMedGoogle ScholarCrossref
137.
Bruchim  I, Biron-Shental  T, Altaras  MM,  et al.  Combination of endometrial thickness and time since menopause in predicting endometrial cancer in women with postmenopausal bleeding.  J Clin Ultrasound. 2004;32(5):219-224. doi:10.1002/jcu.20020PubMedGoogle ScholarCrossref
138.
Minagawa  Y, Sato  S, Ito  M, Onohara  Y, Nakamoto  S, Kigawa  J.  Transvaginal ultrasonography and endometrial cytology as a diagnostic schema for endometrial cancer.  Gynecol Obstet Invest. 2005;59(3):149-154. doi:10.1159/000083089PubMedGoogle ScholarCrossref
139.
Litta  P, Merlin  F, Saccardi  C,  et al.  Role of hysteroscopy with endometrial biopsy to rule out endometrial cancer in postmenopausal women with abnormal uterine bleeding.  Maturitas. 2005;50(2):117-123. doi:10.1016/j.maturitas.2004.05.003PubMedGoogle ScholarCrossref
140.
Wilailak  S, Jirapinyo  M, Theppisai  U.  Transvaginal Doppler sonography: is there a role for this modality in the evaluation of women with postmenopausal bleeding?  Maturitas. 2005;50(2):111-116. doi:10.1016/j.maturitas.2004.04.004PubMedGoogle ScholarCrossref
141.
Taşkin  S, Bozaci  EA, Seval  MM, Unlü  C.  Transvaginal sonographic assessment of endometrial thickness and endometrial morphology in postmenopausal bleeding.  Int J Gynaecol Obstet. 2006;92(2):155-156. doi:10.1016/j.ijgo.2005.10.023PubMedGoogle ScholarCrossref
142.
Spicer  JM, Siebert  I, Kruger  TF.  Postmenopausal bleeding: a diagnostic approach for both private and public sectors.  Gynecol Obstet Invest. 2006;61(3):174-178. doi:10.1159/000091413PubMedGoogle ScholarCrossref
143.
Mansour  GM, El-Lamie  IK, El-Kady  MA, El-Mekkawi  SF, Laban  M, Abou-Gabal  AI.  Endometrial volume as predictor of malignancy in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 2007;99(3):206-210. doi:10.1016/j.ijgo.2007.07.024PubMedGoogle ScholarCrossref
144.
Yildirim  M, Bozkurt  N, Kurdoglu  M, Taskiran  C, Oktem  M, Dilek  KU.  Histopathologic findings in women with postmenopausal bleeding: implication for endometrial thickness and circulating levels of sex steroid hormones.  Arch Gynecol Obstet. 2007;276(4):305-310. doi:10.1007/s00404-007-0361-1PubMedGoogle ScholarCrossref
145.
Tinelli  R, Tinelli  FG, Cicinelli  E, Malvasi  A, Tinelli  A.  The role of hysteroscopy with eye-directed biopsy in postmenopausal women with uterine bleeding and endometrial atrophy.  Menopause. 2008;15(4, pt 1):737-742. doi:10.1097/gme.0b013e31815b644ePubMedGoogle ScholarCrossref
146.
Yaman  C, Habelsberger  A, Tews  G, Pölz  W, Ebner  T.  The role of three-dimensional volume measurement in diagnosing endometrial cancer in patients with postmenopausal bleeding.  Gynecol Oncol. 2008;110(3):390-395. doi:10.1016/j.ygyno.2008.04.029PubMedGoogle ScholarCrossref
147.
Sadoon  S, Salman  G, Smith  G, Henson  C, McCullough  W.  Ultrasonographic endometrial thickness for diagnosing endometrial pathology in postmenopausal bleeding.  J Obstet Gynaecol. 2007;27(4):406-408. doi:10.1080/01443610701327438PubMedGoogle ScholarCrossref
148.
Ewies  AA, Musonda  P.  Managing postmenopausal bleeding revisited: what is the best first line investigation and who should be seen within 2 weeks? a cross-sectional study of 326 women.  Eur J Obstet Gynecol Reprod Biol. 2010;153(1):67-71. doi:10.1016/j.ejogrb.2010.06.009PubMedGoogle ScholarCrossref
149.
Jillani  K, Khero  RB, Maqsood  S, Siddiqui  MA.  Prevalence of malignant disorders in 50 cases of postmenopausal bleeding.  J Pak Med Assoc. 2010;60(7):540-543.PubMedGoogle Scholar
150.
Liberis  V, Tsikouras  P, Christos  Z,  et al.  The contribution of hysteroscopy to the detection malignancy in symptomatic postmenopausal women.  Minim Invasive Ther Allied Technol. 2010;19(2):83-93. doi:10.3109/13645701003643881PubMedGoogle ScholarCrossref
151.
Menzies  R, Wallace  S, Ennis  M,  et al.  Significance of abnormal sonographic findings in postmenopausal women with and without bleeding.  J Obstet Gynaecol Can. 2011;33(9):944-951. doi:10.1016/S1701-2163(16)35020-4PubMedGoogle ScholarCrossref
152.
Zaki  A, Gaber  A, Ghanem  E, Moemen  M, Shehata  G.  Abdominal obesity and endometrial cancer in Egyptian females with postmenopausal bleeding.  Nutr Cancer. 2011;63(8):1272-1278. doi:10.1080/01635581.2011.615973PubMedGoogle ScholarCrossref
153.
Ragupathy  K, Cawley  N, Ridout  A, Iqbal  P, Alloub  M.  Non-assessable endometrium in women with post-menopausal bleeding: to investigate or ignore.  Arch Gynecol Obstet. 2013;288(2):375-378. doi:10.1007/s00404-013-2746-7PubMedGoogle ScholarCrossref
154.
Damle  RP, Dravid  NV, Suryawanshi  KH, Gadre  AS, Bagale  PS, Ahire  N.  Clinicopathological spectrum of endometrial changes in peri-menopausal and post-menopausal abnormal uterine bleeding: a 2 years study.  J Clin Diagn Res. 2013;7(12):2774-2776.PubMedGoogle Scholar
155.
Wong  AS, Lao  TT, Cheung  CW,  et al.  Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study.  BJOG. 2016;123(3):439-446. doi:10.1111/1471-0528.13342PubMedGoogle ScholarCrossref
156.
Cho  HJ, Lee  ES, Lee  JY,  et al.  Investigations for postmenopausal uterine bleeding: special considerations for endometrial volume.  Arch Iran Med. 2013;16(11):665-670.PubMedGoogle Scholar
157.
Abid  M, Hashmi  AA, Malik  B,  et al.  Clinical pattern and spectrum of endometrial pathologies in patients with abnormal uterine bleeding in Pakistan: need to adopt a more conservative approach to treatment.  BMC Womens Health. 2014;14:132. doi:10.1186/s12905-014-0132-7PubMedGoogle ScholarCrossref
158.
Loiacono  RM, Trojano  G, Del Gaudio  N,  et al.  Hysteroscopy as a valid tool for endometrial pathology in patients with postmenopausal bleeding or asymptomatic patients with a thickened endometrium: hysteroscopic and histological results.  Gynecol Obstet Invest. 2015;79(3):210-216. doi:10.1159/000371758PubMedGoogle ScholarCrossref
159.
Van den Bosch  T, Ameye  L, Van Schoubroeck  D, Bourne  T, Timmerman  D.  Intra-cavitary uterine pathology in women with abnormal uterine bleeding: a prospective study of 1220 women.  Facts Views Vis Obgyn. 2015;7(1):17-24.PubMedGoogle Scholar
160.
Kim  A, Lee  JY, Chun  S, Kim  HY.  Diagnostic utility of three-dimensional power Doppler ultrasound for postmenopausal bleeding.  Taiwan J Obstet Gynecol. 2015;54(3):221-226. doi:10.1016/j.tjog.2013.10.043PubMedGoogle ScholarCrossref
161.
Ozer  A, Ozer  S, Kanat-Pektas  M.  Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Turkish women with abnormal uterine bleeding.  J Obstet Gynaecol Res. 2016;42(5):573-578. doi:10.1111/jog.12937PubMedGoogle ScholarCrossref
162.
Seckin  B, Cicek  MN, Dikmen  AU, Bostancı  EI, Muftuoglu  KH.  Diagnostic value of sonography for detecting endometrial pathologies in postmenopausal women with and without bleeding.  J Clin Ultrasound. 2016;44(6):339-346. doi:10.1002/jcu.22329PubMedGoogle ScholarCrossref
163.
Trabert  B, Wentzensen  N, Yang  HP,  et al.  Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?  Int J Cancer. 2013;132(2):417-426. doi:10.1002/ijc.27623PubMedGoogle ScholarCrossref
164.
Lindenfeld  EA, Langer  RD.  Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial.  Obstet Gynecol. 2002;100(5, pt 1):853-863.PubMedGoogle Scholar
165.
Hickey  M, Ameratunga  D, Marino  JL.  Unscheduled bleeding in continuous combined hormone therapy users.  Maturitas. 2011;70(4):400-403. doi:10.1016/j.maturitas.2011.09.010PubMedGoogle ScholarCrossref
166.
van Hanegem  N, Prins  MM, Bongers  MY,  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;197:147-155. doi:10.1016/j.ejogrb.2015.12.008PubMedGoogle ScholarCrossref
167.
Timmermans  A, Opmeer  BC, Khan  KS,  et al.  Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis.  Obstet Gynecol. 2010;116(1):160-167. doi:10.1097/AOG.0b013e3181e3e7e8PubMedGoogle ScholarCrossref
168.
Lee  SC, Kaunitz  AM, Sanchez-Ramos  L, Rhatigan  RM.  The oncogenic potential of endometrial polyps: a systematic review and meta-analysis.  Obstet Gynecol. 2010;116(5):1197-1205. doi:10.1097/AOG.0b013e3181f74864PubMedGoogle ScholarCrossref
169.
Perri  T, Rahimi  K, Ramanakumar  AV,  et al.  Are endometrial polyps true cancer precursors?  Am J Obstet Gynecol. 2010;203(3):232.e1-232.e6. doi:10.1016/j.ajog.2010.03.036PubMedGoogle ScholarCrossref
170.
Kinde  I, Bettegowda  C, Wang  Y,  et al.  Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.  Sci Transl Med. 2013;5(167):167ra4. doi:10.1126/scitranslmed.3004952PubMedGoogle ScholarCrossref
171.
Fiegl  H, Gattringer  C, Widschwendter  A,  et al.  Methylated DNA collected by tampons: a new tool to detect endometrial cancer.  Cancer Epidemiol Biomarkers Prev. 2004;13(5):882-888.PubMedGoogle Scholar
172.
Arbyn  M, Xu  L, Verdoodt  F,  et al.  Genotyping for human papillomavirus types 16 and 18 in women with minor cervical lesions: a systematic review and meta-analysis.  Ann Intern Med. 2017;166(2):118-127. doi:10.7326/M15-2735PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    1 Comment for this article
    Endometrial Cancer Risks
    Leslee Jaeger, MD | North Clinic

    Although only 10% of post-menopausal bleeding is associated with endometrial cancer, the remainder of the cases that are benign or hyperplasia allow for education around the future risks for endometrial cancer and can contribute to lifestyle change when  weight, centripetal obesity, hypertension and diabetes are addressed. When patients are concerned about "cancer" they tend to be more motivated.

    CONFLICT OF INTEREST: None Reported
    Original Investigation
    September 2018

    Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
    • 2Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota
    • 3Unit of Cancer Epidemiology, Belgian Cancer Centre, Sciensano, Brussels, Belgium
    JAMA Intern Med. 2018;178(9):1210-1222. doi:10.1001/jamainternmed.2018.2820
    Key Points

    Question  What is the prevalence of postmenopausal bleeding in women with endometrial cancer and the risk of endometrial cancer in women with postmenopausal bleeding?

    Findings  This systematic review and meta-analysis of 40 790 unique patients in 129 unique studies suggests that postmenopausal bleeding occurs in approximately 90% of women with endometrial cancer; however, only 9% of women with postmenopausal bleeding were diagnosed with endometrial cancer. These estimates varied by geographic region, hormone use, and calendar time.

    Meaning  These findings provide a foundation for evaluating early detection strategies for endometrial cancer and can support risk-informed decision making in clinical management of postmenopausal bleeding.

    Abstract

    Importance  As the worldwide burden of endometrial cancer continues to rise, interest is growing in the evaluation of early detection and prevention strategies among women at increased risk. Focusing efforts on women with postmenopausal bleeding (PMB), a common symptom of endometrial cancer, may be a useful strategy; however, PMB is not specific for endometrial cancer and is often caused by benign conditions.

    Objective  To provide a reference of the prevalence of PMB in endometrial cancers and the risk of endometrial cancer in women with PMB.

    Data Sources  For this systematic review and meta-analysis, PubMed and Embase were searched for English-language studies published January 1, 1977, through January 31, 2017.

    Study Selection  Observational studies reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB in unselected populations were selected.

    Data Extraction and Synthesis  Two independent reviewers evaluated study quality and risk of bias using items from the Newcastle-Ottawa Quality Assessment Scale and the Quality Assessment of Diagnostic Accuracy Studies tool. Studies that included highly selected populations, lacked detailed inclusion criteria, and/or included 25 or fewer women were excluded.

    Main Outcomes and Measures  The pooled prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB.

    Results  A total of 129 unique studies, including 34 432 unique patients with PMB and 6358 with endometrial cancer (40 790 women), were analyzed. The pooled prevalence of PMB among women with endometrial cancer was 91% (95% CI, 87%-93%), irrespective of tumor stage. The pooled risk of endometrial cancer among women with PMB was 9% (95% CI, 8%-11%), with estimates varying by use of hormone therapy (range, 7% [95% CI, 6%-9%] to 12% [95% CI, 9%-15%]; P < .001 for heterogeneity) and geographic region (range, 5% [95% CI, 3%-11%] in North America to 13% [95% CI, 9%-19%] in Western Europe; P = .09 for heterogeneity).

    Conclusions and Relevance  Early detection strategies focused on women with PMB have the potential to capture as many as 90% of endometrial cancers; however, most women with PMB will not be diagnosed with endometrial cancer. These results can aid in the assessment of the potential clinical value of new early detection markers and clinical management strategies for endometrial cancer and will help to inform clinical and epidemiologic risk prediction models to support decision making.

    Introduction

    Endometrial cancer is the most common gynecologic cancer in developed countries and accounts for nearly 5% of cancer cases and more than 2% of deaths due to cancer in women worldwide.1 In regions such as North America and parts of Europe, the incidence of endometrial cancer is disproportionately higher than in other developed countries, which may be attributed to higher rates of obesity, as well as other important risk factors such as aging, early menarche, late menopause, nulliparity, and postmenopausal estrogen therapy use.2 Unlike most cancers, the incidence of endometrial cancer and associated mortality rates have increased in recent years3-7 and are projected to rise during the next 10 years.8-11

    Most endometrial cancers are diagnosed at a localized stage and are often curable with surgery, with a 5-year survival of approximately 95%. In contrast, 5-year survival for late-stage (stage IV) endometrial cancer ranges from 16% to 45%.12-14 However, studies evaluating early detection strategies for endometrial cancer are lacking, and at present no recommendation for population-based screening exists. In the era of precision prevention, emphasis on identifying individuals at high risk to maximize the positive outcomes of clinical interventions while avoiding unnecessary harms is growing.15-17 Rather than targeting the whole population, early detection strategies for endometrial cancer could focus on women at high risk of developing endometrial cancer, while excluding most women at low risk. Postmenopausal bleeding (PMB) is a common symptom of endometrial cancer and accounts for approximately two-thirds of all gynecologic visits among perimenopausal and postmenopausal women.18 Women presenting with PMB undergo additional clinical testing using a combination of transvaginal ultrasonography (TVUS), hysteroscopy, endometrial biopsy, and/or dilation and curettage, and workup varies widely among different settings.18-20 However, PMB is often associated with benign conditions such as endometrial polyps or may result from unscheduled bleeding in women using hormone therapy (HT).18,21 The risk of endometrial cancer in women with PMB varies widely in individual studies from 3% to 25%.22-27

    Accurate estimates of the prevalence of PMB in endometrial cancers (equal to the sensitivity of PMB for detecting endometrial cancer) and the risk of endometrial cancer in women with PMB (equal to the positive predictive value [PPV] of PMB for detecting endometrial cancer) are needed to evaluate whether targeting women with PMB for early detection is a useful strategy, particularly because endometrial cancer rates are increasing in the population. A high sensitivity of PMB would ensure that most cases of endometrial cancer are being captured by targeting this population. A high PPV of PMB, which translates into a low number needed to diagnose (1/PPV) to find 1 case of endometrial cancer, would support diagnostic workup of women with PMB, whereas a low PPV would signify the need for additional triage to improve performance of early detection. Furthermore, these estimates would provide the foundation for evaluating clinical and epidemiologic risk prediction models28 and are necessary for evaluating novel molecular markers that are currently under development against established methods.29-33

    We conducted a systematic review and meta-analysis to evaluate the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer among women with PMB. Our estimates could inform the evaluation of clinical scenarios to assess the utility of early detection strategies for endometrial cancer.

    Methods
    Search Strategy and Selection Criteria

    We conducted this systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (eFigure 1 in the Supplement).34 We included original studies with primary data reporting the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer among women with PMB. We searched English-language, peer-reviewed studies published before February 1, 2017, in the MEDLINE database via PubMed and Embase using search terms described in eMethods in the Supplement. We also reviewed the reference lists of articles identified in the primary search for additional relevant studies. Titles and abstracts were independently screened for inclusion by 3 investigators (M.A.C., A.D.M., and B.J.L.). Full-text versions of eligible articles were reviewed by 2 investigators (M.A.C. and B.J.L.) to determine eligibility; any questions regarding the inclusion of studies were resolved by the senior author (N.W.). We evaluated data on patient selection criteria, sample size, and exposure and outcome ascertainment to determine study quality and generalizability; we excluded studies that included special populations (eg, defined by comorbid conditions or specific histologic findings), lacked detailed inclusion criteria, and/or included 25 or fewer women.

    Data Extraction and Quality Assessment

    We extracted information on aggregate study-level participant characteristics (age, body mass index, years since menopause, parity, frequency of bleeding, HT use, tamoxifen use, and other comorbidities) and endometrial biopsy results, including stage and histologic data when available. Geographic regions were defined by the World Health Organization for those with 2 or more countries represented.1 Study designs were classified as retrospective or prospective if follow-up time was specified or as cross-sectional (or case series). We assessed study quality using items from the Newcastle-Ottawa Quality Assessment Scale35 and the Quality Assessment of Diagnostic Accuracy Studies tool36 (eMethods in the Supplement). We provide the detailed algorithms of how PMB was evaluated for each study in eTable 1 in the Supplement. Studies were classified as having potential verification bias if receipt or interpretation of the diagnostic test (eg, endometrial biopsy) depended on the results of a prior clinical test (eg, TVUS) (eMethods in the Supplement).

    Data Synthesis and Analysis

    We estimated pooled prevalence and 95% CIs using multilevel logistic-normal random-effects models to account for interstudy heterogeneity. Between-study variance was quantified using the τ2 statistic.37,38 We visualized variation in study-specific estimates using forest plots and performed subgroup analyses (described in eMethods in the Supplement) to evaluate the influence of (1) study exclusion criteria for HT use (analysis of risk of endometrial cancer in women with PMB only); (2) geographical region; and (3) study enrollment period, using the last year of study enrollment or publication date as a proxy, grouped as before 1990, 1990 to 1999, 2000 to 2009, and 2010 to 2017. We use the P value for heterogeneity to compare subgroup estimates, with significance at P < .05. The influence of continuous study-level (mean) characteristics, including age, years since menopause, and percentage using HT, was explored using multilevel logistic random-effects models for studies with available data. We conducted sensitivity analyses to assess the influence of clinical setting (tertiary center vs other), study design, and the potential for publication bias using Egger regression analyses.29 For the analysis of the prevalence of PMB in women with endometrial cancer, we excluded 2 studies39,40 that selected cases based on stage at diagnosis; however, these studies were included in the stage-specific analysis. For the analysis of the risk of endometrial cancer among women with PMB, we conducted a secondary analysis in a subset of 10 studies41-50 that excluded women with measurements below a minimum endometrial thickness determined by TVUS (range, 4-5 mm) and a separate subset of 7 studies51-57 that evaluated the risk of endometrial cancer in women with polyps.

    As an ancillary analysis, we simulated the performance of 2 approaches for early detection of endometrial cancer in a hypothetical population of 10 000 women with PMB to demonstrate how our results can be used to evaluate current testing strategies and the potential clinical value of early-stage biomarkers for endometrial cancer detection: TVUS (cutoff of ≤3 mm), which is a well-established, clinically validated test,18 and an experimental methylation marker assay31,32 (eMethods in the Supplement). All analyses were performed in Stata, version 13 (StataCorp). For pooling of proportions, we used the program metaprop_one.38

    Results

    We identified 2398 studies, of which 129 were eligible for our analysis,22-27,39-162 with 40 790 unique patients, including 1 study58 that was eligible for both analyses (overlap of 45 women with endometrial cancers and 45 women with PMB) (eFigure 1 in the Supplement). Studies were published from January 1, 1977, through January 1, 2017, and most were cross-sectional and conducted in Northern (26 [20.2%]) and Southern Europe (24 [18.6%]). Among eligible studies, 2139,40,58-72,74-77 were included for analysis of the prevalence of PMB in women with endometrial cancer (3792 cases of endometrial cancer, of which 3257 were in women with PMB, including the 2 studies restricted to stages III-IV cancers39,40) and 9222-27,58,78-162 were included for analysis of the risk of endometrial cancer in women with PMB (31 220 women with PMB and 2611 cases of endometrial cancer).

    Prevalence of PMB in Women With Endometrial Cancer

    Study-specific and pooled estimates of the prevalence of PMB in women with endometrial cancer are shown in Figure 1. The prevalence of PMB was 90% (95% CI, 84%-94%), with substantial between-study variance (τ2 = 1.14). Removal of a potential outlier74 resulted in a similar pooled prevalence of 91% (95% CI, 87%-93%), but strong reduction of variance between studies (τ2 = 0.47); therefore we excluded the outlier study from the remaining analyses. Among 5 studies66,70,72,75,76 with information on stage I tumors, the proportion of PMB was 94% (95% CI, 72%-99%; τ2 = 4.03). Among the 7 studies39,40,66,70,72,75,76 with information on stages II to IV tumors, the proportion of PMB was 84% (95% CI, 71%-92%; τ2 = 0.93). We found no significant difference in prevalence of PMB by stage (P = .20 for heterogeneity) (eFigure 2 in the Supplement).

    In an analysis stratified by geographic region, the prevalence of PMB ranged from 94% (95% CI, 84%-97%) in North America to 90% in Western Asia (95% CI, 85%-94%) and Eastern Asia (95% CI, 83%-94%) (P = .55 for heterogeneity) (eFigure 3 in the Supplement). The pooled prevalence of PMB among women with endometrial cancer varied significantly by study enrollment period (P < .001 for heterogeneity). The prevalence of PMB in women with endometrial cancer was higher in studies that enrolled women before 1990 (94%; 95% CI, 92%-95%) and in 1990 to 1999 (96%; 95% CI, 87%-99%) compared with studies that enrolled women in 2000 to 2009 (85%; 95% CI, 78%-90%) and in 2010 to 2017 (86%; 95% CI, 82%-90%) (eFigure 4 in the Supplement).

    In a sensitivity analysis restricted to 11 studies59,62,64,66-68,70-72,75,76 (67%) that ascertained PMB through retrospective medical record review, the pooled prevalence of PMB was 91% (95% CI, 85%-94%), similar to our overall findings. The prevalence of PMB did not vary significantly by clinical setting. No evidence of publication bias was found among studies reporting the prevalence of PMB in women with endometrial cancer (Egger regression intercept, 0.15; P = .90).

    Risk of Endometrial Cancer in Women With PMB

    Study-specific and pooled estimates of the risk of endometrial cancer in women with PMB are shown in Figures 2 and 3. In 92 studies,22-27,58,78-162 the risk of endometrial cancer ranged from 0% to 48%, yielding an overall pooled estimate of 9% (95% CI, 8%-11%), with moderate variability observed between studies (τ2 = 0.56).

    The pooled risk of endometrial cancer was significantly higher among the 41 studies22,24,58,82,89,92-94,98,99,101-106,112,115,116,118,120,121,127,133,136-138,140,141,143-147,149,150,152,158,160-162 that excluded women using HT (12%; 95% CI, 9%-15%; τ2 = 0.64) (Figure 4) compared with the 51 studies that included women using HT21,23,25-27,78-81,83-88,90,91,95-97,100,107-111,113,114,117,119,122-126,128-131,134,135,139,142,148,151,153-157,159 (7%; 95% CI, 6%-9%; τ2 = 0.38; P < .001 for heterogeneity) (eFigure 8 in the Supplement).

    The risk of endometrial cancer in women with PMB was lowest in North America (5%; 95% CI, 3%-11%; τ2 = 0.78) and Northern Europe (7%; 95% CI, 5%-8%; τ2 = 0.24) and highest in Western Europe (13%; 95% CI, 9%-19%; τ2 = 0.61) (P = .09 for heterogeneity) (eFigure 5 in the Supplement). In an analysis restricted to European countries only, the risk of endometrial cancer was significantly higher in Western Europe compared with Northern and Southern Europe (P = .03 for heterogeneity). After stratifying by exclusion of women who used HT, significant regional differences persisted in both strata (P = .02 for heterogeneity in studies that included women using HT; P < .001 for heterogeneity in studies that excluded women using HT).

    The risk of endometrial cancer was significantly higher in studies with enrollment periods before 1990 (13%; 95% CI, 10%-17%; τ2 = 0.18) and in 1990 to 1999 (11%; 95% CI, 8%-13%; τ2 = 0.57) compared with 2000 to 2009 (7%; 95% CI, 5%-9%; τ2 = 0.47) and 2010 to 2017 (8%; 95% CI, 5%-12%; τ2 = 0.59) (P < .001 for heterogeneity) (eFigure 6 in the Supplement). The risk of endometrial cancer was not significantly associated with mean age, number of years since menopause, and percentage of women using HT.

    The risk of endometrial cancer was significantly lower in prospective22,26,27,58,88,105,122-124,135,138-140,150 (6%; τ2 = 0.34) and retrospective23,25,83,94,97,113,125,131,134,147,148,151,153,155,158,161 (6%; τ2 = 0.37) studies compared with cross-sectional studies78-82,84-87,90-93,95,96,98-104,106-112,114-121,126-130,132,133,136,137,141-146,149,152,154,156,157,159,160,162 (11%; τ2 = 0.49; P < .001 for heterogeneity) and was significantly higher in 6 studies24,110,121,130,152,157 conducted in tertiary centers (23%; 95% CI, 17%-31%; τ2 = 0.18; P < .001 for heterogeneity), compared with studies conducted in other settings. Evidence of publication bias suggested that small studies may overestimate the risk of endometrial cancer in women with PMB (Egger regression intercept, 0.75; P = .001). In an analysis based on the assessment of study quality, verification bias could be excluded in 71 studies24-26,58,78,79,81-96,98-106,108,110-115,117-122,125,126,128,130-133,135-137,139-141,143-147,149,150,152,154,156-158,161,162 and was potentially present in 13 studies22,27,107,109,123,124,127,129,138,142,148,155,159 (8 were unclear). The risk of endometrial cancer was significantly lower in studies with potential verification bias (6%; 95% CI, 4%-9%) compared with those with no verification bias (10%; 95% CI, 8%-12%) (eTable 2 and eFigure 7 in the Supplement).

    In the 10 studies41-50 that included women with PMB and a minimum endometrial thickness (n = 2087), the pooled risk of endometrial cancer was 19% (95% CI, 14%-25%; τ2 = 0.28). In 7 studies51-57 restricted to women with PMB and polyps (n = 2801), the pooled risk of endometrial cancer was 3% (95% CI, 3%-4%; τ2 = 0).

    To demonstrate how the estimates from this meta-analysis can be used to evaluate strategies for endometrial cancer detection in women with PMB, we evaluated the performance of TVUS, a well-established clinical test for evaluating PMB18 and an experimental methylation assay for endometrial cancer detection31,32 in a hypothetical population of 10 000 women with PMB. We evaluated endometrial cancer risk estimates of 5%, 10%, and 15%, representing the range of risks observed in different geographic regions (Table). We show the magnitude of the increase in PPV of both tests with increasing risk of endometrial cancer in women with PMB, supporting the evaluation of early-detection strategies in various populations.

    Discussion

    The projected rise in endometrial cancer incidence and mortality underscores the importance of strategies for early detection and prevention. Focusing on women at highest risk of endometrial cancer can greatly improve the performance of a diagnostic test and avoid unnecessary testing and associated harms among women at low risk. Our systematic review and meta-analysis demonstrates that PMB is very sensitive for endometrial cancer detection, occurring in approximately 90% of cases. However, our findings indicate that among women with PMB, only approximately 9% will be diagnosed with endometrial cancer, with estimates varying substantially by HT use, geographic region, and the presence of endometrial polyps. Current practice guidelines recommend workup to rule out endometrial cancer among all women with PMB. Our findings support this recommendation by providing reassurance that targeting this high-risk group of women for early detection and prevention strategies will capture most endometrial cancers. However, the low PPV of PMB emphasizes the need for additional triage tests with high specificity to improve management of PMB and avoid unnecessary biopsies in low-risk women.

    The prevalence of PMB in endometrial cancer and the risk of endometrial cancer in women with PMB were higher before 2000 compared with after 2000. When interpreting these results, it is important to distinguish population risk, which has generally increased over time, from the risk in women with PMB. The number of endometrial cancers without PMB and the number of women with PMB with benign conditions may both have increased over time. This increase could be influenced by factors such as changes in HT use, changes in prevalence of obesity, or changes in clinical management thresholds for abnormal bleeding.

    The risk of endometrial cancer among women with PMB was notably lower in studies that included HT users compared with those that excluded these women. Use of HT may affect this association at multiple levels. Certain combined formulations of estrogen plus progestin therapy are established to have a protective effect on the endometrium.163 Furthermore, irregular uterine bleeding is a common adverse effect of HT, particularly within the first 6 months of use.164 The underlying causes of HT-induced bleeding is thought to involve changes in the size of endometrial blood vessels and regulation of vascular growth and integrity.165 Because this type of bleeding is generally not associated with abnormal endometrial histologic findings, most guidelines recommend against clinical workup of women using HT who experience irregular uterine bleeding within the first 6 months. However, little consensus exists about how to best treat these women if bleeding persists, and a considerable number of women with HT-associated bleeding will undergo procedures to rule out endometrial cancer.165 Our data emphasize the importance of considering a woman’s HT status to inform clinical decision making, potentially supporting a less aggressive management approach in HT users.

    We noted striking geographic differences in endometrial cancer risk among women with PMB, ranging from 13% in Western Europe to 5% in North America and 7% in Northern Europe. At present, consensus regarding the optimal approach for evaluating PMB is lacking. Practice may vary depending on resources, clinical expertise and judgment, and patient preferences. The threshold for evaluating PMB may be lower in North American countries compared with other countries in Europe and elsewhere. In many European countries, guidelines recommend TVUS as the first-line test, with histologic assessment indicated for women with a thickened endometrium based on cutoffs ranging from 3 to 5 mm.18,166,167 In the United States, guidelines recommend TVUS or endometrial biopsy as the first step in evaluating PMB.19 In sensitivity analyses, we observed a lower risk of endometrial cancer in studies with partial disease verification (ie, not all women received a biopsy) compared with studies with complete diagnostic verification, suggesting that disease may have been missed in women with negative findings for the first-line test (eg, TVUS). However, we cannot exclude that in some settings, women only received a first-line test such as TVUS if they had a lower risk of endometrial cancer. In the subset of studies included in our meta-analysis that included women with PMB and a minimum endometrial thickness, the pooled risk of endometrial cancer was 19%, more than double the risk observed in our main analysis.

    Our findings also suggest substantial variation in the risk of endometrial cancer depending on the underlying cause of PMB. Endometrial polyps are one of the most common causes of PMB. Although polyps have been associated with risk of endometrial cancer in women with PMB,168 other studies have suggested that this association is more likely attributed to detection bias, resulting from incidental findings during the diagnostic workup of PMB caused by endometrial polyps.169 Our meta-analysis confirms a lower risk of endometrial cancer among women with PMB and polyps.

    Strengths and Limitations

    To our knowledge, this systematic review and meta-analysis is the first to evaluate the prevalence of PMB in endometrial cancer and the risk of endometrial cancer in women with PMB, 2 important variables for evaluating the role of PMB in early detection of endometrial cancer. Our findings can support risk-informed decision making in clinical management of women with PMB. As an example, we simulated the performance of TVUS, an established diagnostic tool, and methylation markers, an early-phase biomarker, for early detection of endometrial cancer. We provided estimates of how many women would be referred for endometrial biopsy for combinations of endometrial cancer risk in women with PMB, and we showed how many women would need to undergo endometrial biopsy to identify 1 case.

    However, a few study limitations are worth noting. In general, data on study-level variables such as years since menopause and body mass index were inconsistently reported, limiting our ability to evaluate them. In addition, insufficient data were available to explore differences by histologic findings, stage, and grade. Whether cancers with more favorable histologic findings (eg, endometrioid type I tumors) are more likely to present with PMB compared with more aggressive histologic subtypes (eg, serous type II tumors) remains unknown. Our results suggest that approximately 10% of women diagnosed with endometrial cancer do not present with PMB. Given the cross-sectional nature of most studies included in this meta-analysis, additional studies linking clinical records with cancer registry data may be warranted to validate our findings. With respect to the analysis of the risk of endometrial cancer in women with PMB, most studies were cross-sectional, and few included prospective follow-up; thus, we were unable to evaluate long-term risk of endometrial cancer in these studies. Finally, our results suggested a lower prevalence of endometrial cancer in retrospective and prospective cohort studies compared with cross-sectional studies. Cross-sectional studies may have been more likely to include women with recurrent bleeding; however, few studies distinguished between incident vs recurrent PMB.

    Conclusions

    The widespread practice of referring all women with PMB for TVUS and/or endometrial biopsy carries a considerable burden and cost. Given the rise in endometrial cancer incidence and mortality, our findings raise the important question of how to best manage PMB to optimize the benefit of early detection approaches while avoiding unnecessary harms. Interest has increased in the use of biomarkers, such as DNA methylation, to improve early detection of endometrial cancer.31,32,170,171 To obtain reliable estimates of the clinical performance of molecular assays, diagnostic tests, and management algorithms, we must know the prior risk of endometrial cancer in the population.29,172

    Our study represents an important and timely evaluation of the risk of endometrial cancer in women with PMB and can serve as a reliable reference for the prevalence of PMB in women with endometrial cancer and the risk of endometrial cancer in women with PMB, 2 requisite prior probabilities for prediction of endometrial cancer risk and secondary and tertiary prevention. As new markers are discovered or new clinical management strategies are evaluated, our results can aid in the assessment of their potential clinical value and will help to inform clinical and epidemiologic risk prediction models to support clinical decision making.

    Back to top
    Article Information

    Accepted for Publication: May 3, 2018.

    Corresponding Author: Megan A. Clarke, PhD, MHS, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Room 6E552, Rockville, MD 20850 (megan.clarke@nih.gov).

    Published Online: August 6, 2018. doi:10.1001/jamainternmed.2018.2820

    Author Contributions: Dr Clarke had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Long, Bakkum-Gamez, Wentzensen.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Clarke, Bakkum-Gamez, Wentzensen.

    Critical revision of the manuscript for important intellectual content: Long, Del Mar Morillo, Arbyn, Bakkum-Gamez, Wentzensen.

    Statistical analysis: Clarke, Wentzensen.

    Administrative, technical, or material support: Wentzensen.

    Supervision: Bakkum-Gamez, Wentzensen.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was supported by grant 603019 via the COHEAHR Network, 7th Framework Programme of DG Research and Innovation, European Commission (Dr Arbyn).

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: Barbara Brandys, BASc, Office of Research Services, National Institutes of Health Library, assisted with the literature search. She was not compensated for this work.

    References
    1.
    Ferlay  J, Soerjomataram  I, Dikshit  R,  et al.  Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.  Int J Cancer. 2015;136(5):E359-E386. doi:10.1002/ijc.29210PubMedGoogle ScholarCrossref
    2.
    Setiawan  VW, Yang  HP, Pike  MC,  et al; Australian National Endometrial Cancer Study Group.  Type I and II endometrial cancers: have they different risk factors?  J Clin Oncol. 2013;31(20):2607-2618. doi:10.1200/JCO.2012.48.2596PubMedGoogle ScholarCrossref
    3.
    Jamison  PM, Noone  AM, Ries  LA, Lee  NC, Edwards  BK.  Trends in endometrial cancer incidence by race and histology with a correction for the prevalence of hysterectomy, SEER 1992 to 2008.  Cancer Epidemiol Biomarkers Prev. 2013;22(2):233-241. doi:10.1158/1055-9965.EPI-12-0996PubMedGoogle ScholarCrossref
    4.
    Torre  LA, Islami  F, Siegel  RL, Ward  EM, Jemal  A.  Global cancer in women: burden and trends.  Cancer Epidemiol Biomarkers Prev. 2017;26(4):444-457. doi:10.1158/1055-9965.EPI-16-0858PubMedGoogle ScholarCrossref
    5.
    Wartko  P, Sherman  ME, Yang  HP, Felix  AS, Brinton  LA, Trabert  B.  Recent changes in endometrial cancer trends among menopausal-age US women.  Cancer Epidemiol. 2013;37(4):374-377. doi:10.1016/j.canep.2013.03.008PubMedGoogle ScholarCrossref
    6.
    Siegel  RL, Miller  KD, Jemal  A.  Cancer Statistics, 2017.  CA Cancer J Clin. 2017;67(1):7-30. doi:10.3322/caac.21387PubMedGoogle ScholarCrossref
    7.
    Lortet-Tieulent  J, Ferlay  J, Bray  F, Jemal  A.  International patterns and trends in endometrial cancer incidence, 1978-2013.  J Natl Cancer Inst. 2018;110(4):354-361. doi:10.1093/jnci/djx214PubMedGoogle Scholar
    8.
    Lindemann  K, Eskild  A, Vatten  LJ, Bray  F.  Endometrial cancer incidence trends in Norway during 1953-2007 and predictions for 2008-2027.  Int J Cancer. 2010;127(11):2661-2668. doi:10.1002/ijc.25267PubMedGoogle ScholarCrossref
    9.
    Gaber  C, Meza  R, Ruterbusch  JJ, Cote  ML.  Endometrial cancer trends by race and histology in the USA: projecting the number of new cases from 2015 to 2040.  J Racial Ethn Health Disparities. Published online October 17, 2016.PubMedGoogle Scholar
    10.
    Sheikh  MA, Althouse  AD, Freese  KE,  et al.  USA endometrial cancer projections to 2030: should we be concerned?  Future Oncol. 2014;10(16):2561-2568. doi:10.2217/fon.14.192PubMedGoogle ScholarCrossref
    11.
    Smittenaar  CR, Petersen  KA, Stewart  K, Moitt  N.  Cancer incidence and mortality projections in the UK until 2035.  Br J Cancer. 2016;115(9):1147-1155. doi:10.1038/bjc.2016.304PubMedGoogle ScholarCrossref
    12.
    Weiderpass  E, Antoine  J, Bray  FI, Oh  JK, Arbyn  M.  Trends in corpus uteri cancer mortality in member states of the European Union.  Eur J Cancer. 2014;50(9):1675-1684. doi:10.1016/j.ejca.2014.02.020PubMedGoogle ScholarCrossref
    13.
    Creasman  WT, Odicino  F, Maisonneuve  P,  et al.  Carcinoma of the corpus uteri: FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer.  Int J Gynaecol Obstet. 2006;95(suppl 1):S105-S143. doi:10.1016/S0020-7292(06)60031-3PubMedGoogle ScholarCrossref
    14.
    UK CR. Uterine cancer statistics. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/uterine-cancer. Updated July 3, 2017. Accessed January 18, 2018.
    15.
    Kitson  SJ, Evans  DG, Crosbie  EJ.  Identifying high-risk women for endometrial cancer prevention strategies: proposal of an endometrial cancer risk prediction model.  Cancer Prev Res (Phila). 2017;10(1):1-13. doi:10.1158/1940-6207.CAPR-16-0224PubMedGoogle ScholarCrossref
    16.
    Castle  PE, Katki  HA.  Screening: a risk-based framework to decide who benefits from screening.  Nat Rev Clin Oncol. 2016;13(9):531-532. doi:10.1038/nrclinonc.2016.101PubMedGoogle ScholarCrossref
    17.
    Girschik  J, Miller  LJ, Addiscott  T,  et al.  Precision in setting cancer prevention priorities: synthesis of data, literature, and expert opinion.  Front Public Health. 2017;5:125. doi:10.3389/fpubh.2017.00125PubMedGoogle ScholarCrossref
    18.
    van Hanegem  N, Breijer  MC, Khan  KS,  et al.  Diagnostic evaluation of the endometrium in postmenopausal bleeding: an evidence-based approach.  Maturitas. 2011;68(2):155-164. doi:10.1016/j.maturitas.2010.11.010PubMedGoogle ScholarCrossref
    19.
    ACOG Committee opinion No. 734:  The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding.  Obstet Gynecol. 2018;131:e124-e129. doi:10.1097/AOG.0000000000002631PubMedGoogle ScholarCrossref
    20.
    Breijer  MC, Timmermans  A, van Doorn  HC, Mol  BW, Opmeer  BC.  Diagnostic strategies for postmenopausal bleeding.  Obstet Gynecol Int. 2010;2010:850812. doi:10.1155/2010/850812PubMedGoogle ScholarCrossref
    21.
    Burbos  N, Musonda  P, Duncan  TJ, Crocker  SG, Nieto  JJ, Morris  EP.  Postmenopausal vaginal bleeding in women using hormone replacement therapy.  Menopause Int. 2012;18(1):5-9. doi:10.1258/mi.2011.011111PubMedGoogle ScholarCrossref
    22.
    van Doorn  HC, Opmeer  BC, Jitze Duk  M, Kruitwagen  RF, Dijkhuizen  FP, Mol  BW.  The relation between age, time since menopause, and endometrial cancer in women with postmenopausal bleeding.  Int J Gynecol Cancer. 2007;17(5):1118-1123. doi:10.1111/j.1525-1438.2007.00925.xPubMedGoogle ScholarCrossref
    23.
    Schindler  AE, Schmidt  G.  Post-menopausal bleeding: a study of more than 1000 cases.  Maturitas. 1980;2(4):269-274. doi:10.1016/0378-5122(80)90028-6PubMedGoogle ScholarCrossref
    24.
    Randelzhofer  B, Prömpeler  HJ, Sauerbrei  W, Madjar  H, Emons  G.  Value of sonomorphological criteria of the endometrium in women with postmenopausal bleeding: a multivariate analysis.  Ultrasound Obstet Gynecol. 2002;19(1):62-68. doi:10.1046/j.0960-7692.2001.00618.xPubMedGoogle ScholarCrossref
    25.
    Mantalenakis  SJ, Papapostolou  MG.  Genital bleeding in women aged 50 and over.  Int Surg. 1977;62(2):103-105.PubMedGoogle Scholar
    26.
    Critchley  HO, Warner  P, Lee  AJ, Brechin  S, Guise  J, Graham  B.  Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.  Health Technol Assess. 2004;8(34):iii-iv, 1-139. doi:10.3310/hta8340PubMedGoogle ScholarCrossref
    27.
    Burbos  N, Musonda  P, Crocker  SG, Morris  EP, Nieto  JJ, Duncan  TJ.  Management of postmenopausal women with vaginal bleeding when the endometrium can not be visualized.  Acta Obstet Gynecol Scand. 2012;91(6):686-691. doi:10.1111/j.1600-0412.2012.01407.xPubMedGoogle ScholarCrossref
    28.
    van Hanegem  N, Breijer  MC, Opmeer  BC, Mol  BW, Timmermans  A.  Prediction models in women with postmenopausal bleeding: a systematic review.  Womens Health (Lond). 2012;8(3):251-262. doi:10.2217/WHE.12.10PubMedGoogle ScholarCrossref
    29.
    Wentzensen  N, Wacholder  S.  From differences in means between cases and controls to risk stratification: a business plan for biomarker development.  Cancer Discov. 2013;3(2):148-157. doi:10.1158/2159-8290.CD-12-0196PubMedGoogle ScholarCrossref
    30.
    Talhouk  A, McConechy  MK, Leung  S,  et al.  Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer.  Cancer. 2017;123(5):802-813. doi:10.1002/cncr.30496PubMedGoogle ScholarCrossref
    31.
    Wentzensen  N, Bakkum-Gamez  JN, Killian  JK,  et al.  Discovery and validation of methylation markers for endometrial cancer.  Int J Cancer. 2014;135(8):1860-1868. doi:10.1002/ijc.28843PubMedGoogle ScholarCrossref
    32.
    Bakkum-Gamez  JN, Wentzensen  N, Maurer  MJ,  et al.  Detection of endometrial cancer via molecular analysis of DNA collected with vaginal tampons.  Gynecol Oncol. 2015;137(1):14-22. doi:10.1016/j.ygyno.2015.01.552PubMedGoogle ScholarCrossref
    33.
    Stelloo  E, Bosse  T, Nout  RA,  et al.  Refining prognosis and identifying targetable pathways for high-risk endometrial cancer: a TransPORTEC initiative.  Mod Pathol. 2015;28(6):836-844. doi:10.1038/modpathol.2015.43PubMedGoogle ScholarCrossref
    34.
    Liberati  A, Altman  DG, Tetzlaff  J,  et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.  J Clin Epidemiol. 2009;62(10):e1-e34. doi:10.1016/j.jclinepi.2009.06.006PubMedGoogle ScholarCrossref
    35.
    Wells  G, Shea  B, O’Connell  D,  et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf. 2014. Accessed July 2017.
    36.
    Whiting  PF, Rutjes  AW, Westwood  ME,  et al; QUADAS-2 Group.  QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies.  Ann Intern Med. 2011;155(8):529-536. doi:10.7326/0003-4819-155-8-201110180-00009PubMedGoogle ScholarCrossref
    37.
    Higgins  JP, Thompson  SG, Spiegelhalter  DJ.  A re-evaluation of random-effects meta-analysis.  J R Stat Soc Ser A Stat Soc. 2009;172(1):137-159. doi:10.1111/j.1467-985X.2008.00552.xPubMedGoogle ScholarCrossref
    38.
    Nyaga  VN, Arbyn  M, Aerts  M.  Metaprop: a Stata command to perform meta-analysis of binomial data.  Arch Public Health. 2014;72(1):39. doi:10.1186/2049-3258-72-39PubMedGoogle ScholarCrossref
    39.
    Mackillop  WJ, Pringle  JF.  Stage III endometrial carcinoma: a review of 90 cases.  Cancer. 1985;56(10):2519-2523. doi:10.1002/1097-0142(19851115)56:10<2519::AID-CNCR2820561033>3.0.CO;2-MPubMedGoogle ScholarCrossref
    40.
    Pliskow  S, Penalver  M, Averette  HE.  Stage III and stage IV endometrial carcinoma: a review of 41 cases.  Gynecol Oncol. 1990;38(2):210-215. doi:10.1016/0090-8258(90)90043-KPubMedGoogle ScholarCrossref
    41.
    Williams  SC, Lopez  C, Yoong  A, McHugo  JM.  Developing a robust and efficient pathway for the referral and investigation of women with post-menopausal bleeding using a cut-off of < or =4 mm for normal thickness.  Br J Radiol. 2007;80(957):719-723. doi:10.1259/bjr/87219886PubMedGoogle ScholarCrossref
    42.
    de Kroon  CD, Hiemstra  E, Trimbos  JB, Jansen  FW.  Power Doppler area in the diagnosis of endometrial cancer.  Int J Gynecol Cancer. 2010;20(7):1160-1165. doi:10.1111/IGC.0b013e3181f0df98PubMedGoogle ScholarCrossref
    43.
    Alcazar  JL, Galvan  R.  Three-dimensional power Doppler ultrasound scanning for the prediction of endometrial cancer in women with postmenopausal bleeding and thickened endometrium.  Am J Obstet Gynecol. 2009;200(1):44.e1-44.e6. doi:10.1016/j.ajog.2008.08.027PubMedGoogle ScholarCrossref
    44.
    Opolskiene  G, Sladkevicius  P, Jokubkiene  L, Valentin  L.  Three-dimensional ultrasound imaging for discrimination between benign and malignant endometrium in women with postmenopausal bleeding and sonographic endometrial thickness of at least 4.5 mm.  Ultrasound Obstet Gynecol. 2010;35(1):94-102. doi:10.1002/uog.7445PubMedGoogle ScholarCrossref
    45.
    Elfayomy  AK, El Tarhouny  SA.  Ovarian volume assessment in relation to histologic findings and sex hormone levels in women with postmenopausal bleeding and thickened endometrium.  Ann Saudi Med. 2012;32(6):588-592. doi:10.5144/0256-4947.2012.588PubMedGoogle ScholarCrossref
    46.
    Rossi  A, Forzano  L, Romanello  I, Fachechi  G, Marchesoni  D.  Assessment of endometrial volume and vascularization using transvaginal 3D power Doppler angiography in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 2012;119(1):14-17. doi:10.1016/j.ijgo.2012.05.023PubMedGoogle ScholarCrossref
    47.
    Makled  AK, Elmekkawi  SF, El-Refaie  TA, El-Sherbiny  MA.  Three-dimensional power Doppler and endometrial volume as predictors of malignancy in patients with postmenopausal bleeding.  J Obstet Gynaecol Res. 2013;39(5):1045-1051. doi:10.1111/j.1447-0756.2012.02066.xPubMedGoogle ScholarCrossref
    48.
    Salman  MC, Bozdag  G, Dogan  S, Yuce  K.  Role of postmenopausal bleeding pattern and women’s age in the prediction of endometrial cancer.  Aust N Z J Obstet Gynaecol. 2013;53(5):484-488.PubMedGoogle Scholar
    49.
    Dueholm  M, Møller  C, Rydbjerg  S, Hansen  ES, Ørtoft  G.  An ultrasound algorithm for identification of endometrial cancer.  Ultrasound Obstet Gynecol. 2014;43(5):557-568. doi:10.1002/uog.13205PubMedGoogle ScholarCrossref
    50.
    Giannella  L, Mfuta  K, Setti  T, Cerami  LB, Bergamini  E, Boselli  F.  A risk-scoring model for the prediction of endometrial cancer among symptomatic postmenopausal women with endometrial thickness > 4 mm.  Biomed Res Int. 2014;2014:130569. doi:10.1155/2014/130569PubMedGoogle ScholarCrossref
    51.
    Fernández-Parra  J, Rodríguez Oliver  A, López Criado  S, Parrilla Fernández  F, Montoya Ventoso  F.  Hysteroscopic evaluation of endometrial polyps.  Int J Gynaecol Obstet. 2006;95(2):144-148. doi:10.1016/j.ijgo.2006.07.007PubMedGoogle ScholarCrossref
    52.
    Domingues  AP, Lopes  H, Dias  I, De Oliveira  CF.  Endometrial polyps in postmenopausal women.  Acta Obstet Gynecol Scand. 2009;88(5):618-620. doi:10.1080/00016340902818188PubMedGoogle ScholarCrossref
    53.
    Golan  A, Cohen-Sahar  B, Keidar  R, Condrea  A, Ginath  S, Sagiv  R.  Endometrial polyps: symptomatology, menopausal status and malignancy.  Gynecol Obstet Invest. 2010;70(2):107-112. doi:10.1159/000298767PubMedGoogle ScholarCrossref
    54.
    Mossa  B, Torcia  F, Avenoso  F, Tucci  S, Marziani  R.  Occurrence of malignancy in endometrial polyps during postmenopause.  Eur J Gynaecol Oncol. 2010;31(2):165-168.PubMedGoogle Scholar
    55.
    Ronghe  R, Gaudoin  M.  Women with recurrent postmenopausal bleeding should be re-investigated but are not more likely to have endometrial cancer.  Menopause Int. 2010;16(1):9-11. doi:10.1258/mi.2010.010008PubMedGoogle ScholarCrossref
    56.
    Wethington  SL, Herzog  TJ, Burke  WM,  et al.  Risk and predictors of malignancy in women with endometrial polyps.  Ann Surg Oncol. 2011;18(13):3819-3823. doi:10.1245/s10434-011-1815-zPubMedGoogle ScholarCrossref
    57.
    Cavkaytar  S, Kokanali  MK, Ceran  U, Topcu  HO, Sirvan  L, Doganay  M.  Roles of sonography and hysteroscopy in the detection of premalignant and malignant polyps in women presenting with postmenopausal bleeding and thickened endometrium.  Asian Pac J Cancer Prev. 2014;15(13):5355-5358. doi:10.7314/APJCP.2014.15.13.5355PubMedGoogle ScholarCrossref
    58.
    Ciatto  S, Cecchini  S, Gervasi  G, Landini  A, Zappa  M, Crocetti  E.  Association of endometrial thickness assessed at trans-vaginal ultrasonography to endometrial cancer in postmenopausal women asymptomatic or with abnormal uterine bleeding.  Radiol Med. 2002;104(5-6):437-442.PubMedGoogle Scholar
    59.
    Kodama  J, Seki  N, Ojima  Y, Nakamura  K, Hongo  A, Hiramatsu  Y.  Correlation of presenting symptoms and patient characteristics with endometrial cancer prognosis in Japanese women.  Int J Gynaecol Obstet. 2005;91(2):151-156. doi:10.1016/j.ijgo.2005.08.002PubMedGoogle ScholarCrossref
    60.
    Franceschi  S, La Vecchia  C, Gallus  G,  et al.  Delayed diagnosis of endometrial cancer in Italy.  Cancer. 1983;51(6):1176-1178. doi:10.1002/1097-0142(19830315)51:6<1176::AID-CNCR2820510634>3.0.CO;2-OPubMedGoogle ScholarCrossref
    61.
    Horwitz  RI, Feinstein  AR.  Alternative analytic methods for case-control studies of estrogens and endometrial cancer.  N Engl J Med. 1978;299(20):1089-1094. doi:10.1056/NEJM197811162992001PubMedGoogle ScholarCrossref
    62.
    Khunnarong  J, Tangjitgamol  S, Srijaipracharoen  S.  Other gynecologic pathology in endometrial cancer patients.  Asian Pac J Cancer Prev. 2016;17(2):713-717. doi:10.7314/APJCP.2016.17.2.713PubMedGoogle ScholarCrossref
    63.
    Le  T, Menard  C, Samant  R,  et al.  Longitudinal assessments of quality of life in endometrial cancer patients: effect of surgical approach and adjuvant radiotherapy.  Int J Radiat Oncol Biol Phys. 2009;75(3):795-802. doi:10.1016/j.ijrobp.2008.11.018PubMedGoogle ScholarCrossref
    64.
    Sharon  Z, Shani  M, Modan  B.  Clinicoepidemiologic study of uterine cancer: comparative aspects of the endometrial and cervical sites.  Obstet Gynecol. 1977;50(5):536-540.PubMedGoogle Scholar
    65.
    Hulka  BS, Grimson  RC, Greenberg  BG,  et al.  “Alternative” controls in a case-control study of endometrial cancer and exogenous estrogen.  Am J Epidemiol. 1980;112(3):376-387. doi:10.1093/oxfordjournals.aje.a113003PubMedGoogle ScholarCrossref
    66.
    Liu  JR, Conaway  M, Rodriguez  GC, Soper  JT, Clarke-Pearson  DL, Berchuck  A.  Relationship between race and interval to treatment in endometrial cancer.  Obstet Gynecol. 1995;86(4, pt 1):486-490. doi:10.1016/0029-7844(95)00238-MPubMedGoogle ScholarCrossref
    67.
    Piura  B, Bar-Dayan  A, Cohen  Y, Yanai-Inbar  I, Glezerman  M.  Endometrial carcinoma in the south of Israel: study of 231 cases.  J Surg Oncol. 1997;66(3):189-195. doi:10.1002/(SICI)1096-9098(199711)66:3<189::AID-JSO7>3.0.CO;2-8PubMedGoogle ScholarCrossref
    68.
    Schneider  D, Halperin  R, Langer  R, Bukovsky  I, Hermann  A.  Well-differentiated versus less-differentiated endometrial carcinoma.  Eur J Gynaecol Oncol. 1998;19(3):242-245.PubMedGoogle Scholar
    69.
    Tsuda  H, Kawabata  M, Yamamoto  K, Inoue  T, Umesaki  N.  Prospective study to compare endometrial cytology and transvaginal ultrasonography for identification of endometrial malignancies.  Gynecol Oncol. 1997;65(3):383-386. doi:10.1006/gyno.1997.4699PubMedGoogle ScholarCrossref
    70.
    Barak  F, Kalichman  L, Gdalevich  M,  et al.  The influence of early diagnosis of endometrioid endometrial cancer on disease stage and survival.  Arch Gynecol Obstet. 2013;288(6):1361-1364. doi:10.1007/s00404-013-2898-5PubMedGoogle ScholarCrossref
    71.
    Chandavarkar  U, Kuperman  JM, Muderspach  LI, Opper  N, Felix  JC, Roman  L.  Endometrial echo complex thickness in postmenopausal endometrial cancer.  Gynecol Oncol. 2013;131(1):109-112. doi:10.1016/j.ygyno.2013.07.109PubMedGoogle ScholarCrossref
    72.
    Seebacher  V, Schmid  M, Polterauer  S,  et al.  The presence of postmenopausal bleeding as prognostic parameter in patients with endometrial cancer: a retrospective multi-center study.  BMC Cancer. 2009;9:460. doi:10.1186/1471-2407-9-460PubMedGoogle ScholarCrossref
    73.
    Wang  J, Wieslander  C, Hansen  G, Cass  I, Vasilev  S, Holschneider  CH.  Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers.  Gynecol Oncol. 2006;101(1):120-125. doi:10.1016/j.ygyno.2005.09.042PubMedGoogle ScholarCrossref
    74.
    Dvalishvili  I, Charkviani  L, Turashvili  G, Burkadze  G.  Clinical characteristics of prognostic factors in uterine endometrioid adenocarcinoma of various grade.  Georgian Med News. 2006;(132):24-27.PubMedGoogle Scholar
    75.
    Kimura  T, Kamiura  S, Yamamoto  T, Seino-Noda  H, Ohira  H, Saji  F.  Abnormal uterine bleeding and prognosis of endometrial cancer.  Int J Gynaecol Obstet. 2004;85(2):145-150. doi:10.1016/j.ijgo.2003.12.001PubMedGoogle ScholarCrossref
    76.
    Krissi  H, Chetrit  A, Menczer  J.  Presenting symptoms of patients with endometrial carcinoma: effect on prognosis.  Eur J Gynaecol Oncol. 1996;17(1):25-28.PubMedGoogle Scholar
    77.
    Pakish  JB, Lu  KH, Sun  CC,  et al.  Endometrial cancer associated symptoms: a case-control study.  J Womens Health (Larchmt). 2016;25(11):1187-1192. doi:10.1089/jwh.2015.5657PubMedGoogle ScholarCrossref
    78.
    Swingler  GR, Cave  DG, Mitchard  P.  Diagnostic accuracy of the MiMark endometrial cell sampler in 101 patients with postmenopausal bleeding.  Br J Obstet Gynaecol. 1979;86(10):816-818. doi:10.1111/j.1471-0528.1979.tb10699.xPubMedGoogle ScholarCrossref
    79.
    Goldberg  GL, Tsalacopoulos  G, Davey  DA.  A comparison of endometrial sampling with the Accurette and Vabra aspirator and uterine curettage.  S Afr Med J. 1982;61(4):114-116.PubMedGoogle Scholar
    80.
    Nasri  MN, Coast  GJ.  Correlation of ultrasound findings and endometrial histopathology in postmenopausal women.  Br J Obstet Gynaecol. 1989;96(11):1333-1338. doi:10.1111/j.1471-0528.1989.tb03233.xPubMedGoogle ScholarCrossref
    81.
    Alberico  S, Conoscenti  G, Vegliò  P, Bogatti  P, Di Bonito  L, Mandruzzato  G.  A clinical and epidemiological study of 245 postmenopausal metrorrhagia patients.  Clin Exp Obstet Gynecol. 1989;16(4):113-121.PubMedGoogle Scholar
    82.
    Osmers  R, Völksen  M, Schauer  A.  Vaginosonography for early detection of endometrial carcinoma?  Lancet. 1990;335(8705):1569-1571. doi:10.1016/0140-6736(90)91387-PPubMedGoogle ScholarCrossref
    83.
    Allen  DG, Correy  JF, Marsden  DE.  Abnormal uterine bleeding and cancer of the genital tract.  Aust N Z J Obstet Gynaecol. 1990;30(1):81-83. doi:10.1111/j.1479-828X.1990.tb03204.xPubMedGoogle ScholarCrossref
    84.
    Granberg  S, Wikland  M, Karlsson  B, Norström  A, Friberg  LG.  Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality.  Am J Obstet Gynecol. 1991;164(1 Pt 1):47-52. doi:10.1016/0002-9378(91)90622-XPubMedGoogle ScholarCrossref
    85.
    Goldstein  SR, Nachtigall  M, Snyder  JR, Nachtigall  L.  Endometrial assessment by vaginal ultrasonography before endometrial sampling in patients with postmenopausal bleeding.  Am J Obstet Gynecol. 1990;163(1, pt 1):119-123. doi:10.1016/S0002-9378(11)90683-8PubMedGoogle ScholarCrossref
    86.
    White  CD.  Post menopausal bleeding as a risk factor for endometrial carcinoma.  W V Med J. 1991;87(1):15-17.PubMedGoogle Scholar
    87.
    Dørum  A, Kristensen  GB, Langebrekke  A, Sørnes  T, Skaar  O.  Evaluation of endometrial thickness measured by endovaginal ultrasound in women with postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1993;72(2):116-119. doi:10.3109/00016349309023423PubMedGoogle ScholarCrossref
    88.
    Lin  HH, Wu  MY, Shyu  MK, Chen  D, Tsai  JL, Hsieh  CY.  Clinical study of 381 postmenopausal bleeding patients.  J Formos Med Assoc. 1993;92(3):241-244.PubMedGoogle Scholar
    89.
    Auslender  R, Bornstein  J, Dirnfeld  M, Kogan  O, Atad  J, Abramovici  H.  Vaginal ultrasonography in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1993;3(6):426-428. doi:10.1046/j.1469-0705.1993.03060426.xPubMedGoogle ScholarCrossref
    90.
    Sladkevicius  P, Valentin  L, Marsál  K.  Endometrial thickness and Doppler velocimetry of the uterine arteries as discriminators of endometrial status in women with postmenopausal bleeding: a comparative study.  Am J Obstet Gynecol. 1994;171(3):722-728. doi:10.1016/0002-9378(94)90088-4PubMedGoogle ScholarCrossref
    91.
    Cacciatore  B, Ramsay  T, Lehtovirta  P, Ylöstalo  P.  Transvaginal sonography and hysteroscopy in postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1994;73(5):413-416. doi:10.3109/00016349409006254PubMedGoogle ScholarCrossref
    92.
    Chan  FY, Chau  MT, Pun  TC,  et al.  Limitations of transvaginal sonography and color Doppler imaging in the differentiation of endometrial carcinoma from benign lesions.  J Ultrasound Med. 1994;13(8):623-628. doi:10.7863/jum.1994.13.8.623PubMedGoogle ScholarCrossref
    93.
    Malinova  M, Pehlivanov  B.  Transvaginal sonography and endometrial thickness in patients with postmenopausal uterine bleeding.  Eur J Obstet Gynecol Reprod Biol. 1995;58(2):161-165. doi:10.1016/0028-2243(95)80017-MPubMedGoogle ScholarCrossref
    94.
    Conoscenti  G, Meir  YJ, Fischer-Tamaro  L,  et al.  Endometrial assessment by transvaginal sonography and histological findings after D & C in women with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1995;6(2):108-115. doi:10.1046/j.1469-0705.1995.06020108.xPubMedGoogle ScholarCrossref
    95.
    Emanuel  MH, Verdel  MJC, Stas  H, Wamsteker  K, Lammes  FB.  An audit of true prevalence of intra-uterine pathology: the hysteroscopical findings controlled for patient selection in 1202 patients with abnormal uterine bleeding.  Gynaecol Endosc. 1995;4(4):237-241.Google Scholar
    96.
    Karlsson  B, Granberg  S, Wikland  M,  et al.  Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: a Nordic multicenter study.  Am J Obstet Gynecol. 1995;172(5):1488-1494. doi:10.1016/0002-9378(95)90483-2PubMedGoogle ScholarCrossref
    97.
    Lee  WH, Tan  KH, Lee  YW.  The aetiology of postmenopausal bleeding—a study of 163 consecutive cases in Singapore.  Singapore Med J. 1995;36(2):164-168.PubMedGoogle Scholar
    98.
    Ferrazzi  E, Torri  V, Trio  D, Zannoni  E, Filiberto  S, Dordoni  D.  Sonographic endometrial thickness: a useful test to predict atrophy in patients with postmenopausal bleeding: an Italian multicenter study.  Ultrasound Obstet Gynecol. 1996;7(5):315-321. doi:10.1046/j.1469-0705.1996.07050315.xPubMedGoogle ScholarCrossref
    99.
    Haller  H, Matecjcić  N, Rukavina  B, Krasević  M, Rupcić  S, Mozetic  D.  Transvaginal sonography and hysteroscopy in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 1996;54(2):155-159. doi:10.1016/0020-7292(96)02677-XPubMedGoogle ScholarCrossref
    100.
    Cecchini  S, Ciatto  S, Bonardi  R, Grazzini  G, Mazzota  A.  Endometrial ultrasonography: an alternative to invasive assessment in women with postmenopausal vaginal bleeding.  Tumori. 1996;82(1):38-39. doi:10.1177/030089169608200107PubMedGoogle ScholarCrossref
    101.
    Wolman  I, Sagi  J, Ginat  S, Jaffa  AJ, Hartoov  J, Jedwab  G.  The sensitivity and specificity of vaginal sonography in detecting endometrial abnormalities in women with postmenopausal bleeding.  J Clin Ultrasound. 1996;24(2):79-82. doi:10.1002/(SICI)1097-0096(199602)24:2<79::AID-JCU5>3.0.CO;2-HPubMedGoogle ScholarCrossref
    102.
    Grigoriou  O, Kalovidouros  A, Papadias  C, Antoniou  G, Antonaki  V, Giannikos  L.  Transvaginal sonography of the endometrium in women with postmenopausal bleeding.  Maturitas. 1996;23(1):9-14. doi:10.1016/0378-5122(95)00945-0PubMedGoogle ScholarCrossref
    103.
    Nagele  F, O’Connor  H, Baskett  TF, Davies  A, Mohammed  H, Magos  AL.  Hysteroscopy in women with abnormal uterine bleeding on hormone replacement therapy: a comparison with postmenopausal bleeding.  Fertil Steril. 1996;65(6):1145-1150. doi:10.1016/S0015-0282(16)58329-0PubMedGoogle ScholarCrossref
    104.
    Fistonic  I, Hodek  B, Klaric  P, Jokanovic  L, Grubisic  G, Ivicevic-Bakulic  T.  Transvaginal sonographic assessment of premalignant and malignant changes in the endometrium in postmenopausal bleeding.  J Clin Ultrasound. 1997;25(8):431-435. doi:10.1002/(SICI)1097-0096(199710)25:8<431::AID-JCU4>3.0.CO;2-KPubMedGoogle ScholarCrossref
    105.
    Gruboeck  K, Jurkovic  D, Lawton  F, Savvas  M, Tailor  A, Campbell  S.  The diagnostic value of endometrial thickness and volume measurements by three-dimensional ultrasound in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1996;8(4):272-276. doi:10.1046/j.1469-0705.1996.08040272.xPubMedGoogle ScholarCrossref
    106.
    Kekre  AN, Jose  R, Seshadri  L.  Transvaginal sonography of the endometrium in south Indian postmenopausal women.  Aust N Z J Obstet Gynaecol. 1997;37(4):449-451. doi:10.1111/j.1479-828X.1997.tb02458.xPubMedGoogle ScholarCrossref
    107.
    Valli  E, Zupi  E, Marconi  D,  et al.  Vaginal ultrasonography and diagnostic hysteroscopy for women with abnormal uterine bleeding after menopause.  J Am Assoc Gynecol Laparosc. 1996;3(4)(suppl):S52.PubMedGoogle Scholar
    108.
    Güner  H, Tiras  MB, Karabacak  O, Sarikaya  H, Erdem  M, Yildirim  M.  Endometrial assessment by vaginal ultrasonography might reduce endometrial sampling in patients with postmenopausal bleeding: a prospective study.  Aust N Z J Obstet Gynaecol. 1996;36(2):175-178. doi:10.1111/j.1479-828X.1996.tb03280.xPubMedGoogle ScholarCrossref
    109.
    Bronz  L, Suter  T, Rusca  T.  The value of transvaginal sonography with and without saline instillation in the diagnosis of uterine pathology in pre- and postmenopausal women with abnormal bleeding or suspect sonographic findings.  Ultrasound Obstet Gynecol. 1997;9(1):53-58. doi:10.1046/j.1469-0705.1997.09010053.xPubMedGoogle ScholarCrossref
    110.
    Giusa-Chiferi  MG, Gonçalves  WJ, Baracat  EC, de Albuquerque Neto  LC, Bortoletto  CC, de Lima  GR.  Transvaginal ultrasound, uterine biopsy and hysteroscopy for postmenopausal bleeding.  Int J Gynaecol Obstet. 1996;55(1):39-44. doi:10.1016/0020-7292(96)02720-8PubMedGoogle ScholarCrossref
    111.
    Iatrakis  G, Diakakis  I, Kourounis  G,  et al.  Postmenopausal uterine bleeding.  Clin Exp Obstet Gynecol. 1997;24(3):157.PubMedGoogle Scholar
    112.
    Weber  G, Merz  E, Bahlmann  F, Rösch  B.  Evaluation of different transvaginal sonographic diagnostic parameters in women with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 1998;12(4):265-270. doi:10.1046/j.1469-0705.1998.12040265.xPubMedGoogle ScholarCrossref
    113.
    Gemer  O, Segal  S.  Endometrial cancer in patients undergoing diagnostic curettage.  Arch Gynecol Obstet. 1998;261(2):79-81. doi:10.1007/s004040050203PubMedGoogle ScholarCrossref
    114.
    O’Connell  LP, Fries  MH, Zeringue  E, Brehm  W.  Triage of abnormal postmenopausal bleeding: a comparison of endometrial biopsy and transvaginal sonohysterography versus fractional curettage with hysteroscopy.  Am J Obstet Gynecol. 1998;178(5):956-961. doi:10.1016/S0002-9378(98)70530-7PubMedGoogle ScholarCrossref
    115.
    Büyük  E, Durmuşoğlu  F, Erenus  M, Karakoç  B.  Endometrial disease diagnosed by transvaginal ultrasound and dilatation and curettage.  Acta Obstet Gynecol Scand. 1999;78(5):419-422. doi:10.1080/j.1600-0412.1999.780514.xPubMedGoogle ScholarCrossref
    116.
    Briley  M, Lindsell  DR.  The role of transvaginal ultrasound in the investigation of women with post-menopausal bleeding.  Clin Radiol. 1998;53(7):502-505. doi:10.1016/S0009-9260(98)80169-4PubMedGoogle ScholarCrossref
    117.
    Bakour  SH, Dwarakanath  LS, Khan  KS, Newton  JR, Gupta  JK.  The diagnostic accuracy of ultrasound scan in predicting endometrial hyperplasia and cancer in postmenopausal bleeding.  Acta Obstet Gynecol Scand. 1999;78(5):447-451. doi:10.1080/j.1600-0412.1999.780519.xPubMedGoogle ScholarCrossref
    118.
    Loverro  G, Bettocchi  S, Cormio  G,  et al.  Transvaginal sonography and hysteroscopy in postmenopausal uterine bleeding.  Maturitas. 1999;33(2):139-144. doi:10.1016/S0378-5122(99)00023-7PubMedGoogle ScholarCrossref
    119.
    Garuti  G, Sambruni  I, Cellani  F, Garzia  D, Alleva  P, Luerti  M.  Hysteroscopy and transvaginal ultrasonography in postmenopausal women with uterine bleeding.  Int J Gynaecol Obstet. 1999;65(1):25-33. doi:10.1016/S0020-7292(98)00224-0PubMedGoogle ScholarCrossref
    120.
    Sheikh  M, Sawhney  S, Khurana  A, Al-Yatama  M.  Alteration of sonographic texture of the endometrium in post-menopausal bleeding: a guide to further management.  Acta Obstet Gynecol Scand. 2000;79(11):1006-1010.PubMedGoogle Scholar
    121.
    Amit  A, Weiner  Z, Ganem  N,  et al.  The diagnostic value of power Doppler measurements in the endometrium of women with postmenopausal bleeding.  Gynecol Oncol. 2000;77(2):243-247. doi:10.1006/gyno.2000.5766PubMedGoogle ScholarCrossref
    122.
    Bree  RL, Bowerman  RA, Bohm-Velez  M,  et al.  US evaluation of the uterus in patients with postmenopausal bleeding: a positive effect on diagnostic decision making.  Radiology. 2000;216(1):260-264. doi:10.1148/radiology.216.1.r00jl37260PubMedGoogle ScholarCrossref
    123.
    Gull  B, Carlsson  S, Karlsson  B, Ylöstalo  P, Milsom  I, Granberg  S.  Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: is it always necessary to perform an endometrial biopsy?  Am J Obstet Gynecol. 2000;182(3):509-515. doi:10.1067/mob.2000.103092PubMedGoogle ScholarCrossref
    124.
    Dunn  TS, Stamm  CA, Delorit  M, Goldberg  G.  Clinical pathway for evaluating women with abnormal uterine bleeding.  J Reprod Med. 2001;46(9):831-834.PubMedGoogle Scholar
    125.
    Hunter  DC, McClure  N.  Abnormal uterine bleeding: an evaluation endometrial biopsy, vaginal ultrasound and outpatient hysteroscopy.  Ulster Med J. 2001;70(1):25-30.PubMedGoogle Scholar
    126.
    Cameron  ST, Walker  J, Chambers  S, Critchley  H.  Comparison of transvaginal ultrasound, saline infusion sonography and hysteroscopy to investigate postmenopausal bleeding and unscheduled bleeding on HRT.  Aust N Z J Obstet Gynaecol. 2001;41(3):291-294. doi:10.1111/j.1479-828X.2001.tb01230.xPubMedGoogle ScholarCrossref
    127.
    Jones  K, Bourne  T.  The feasibility of a “one stop” ultrasound-based clinic for the diagnosis and management of abnormal uterine bleeding.  Ultrasound Obstet Gynecol. 2001;17(6):517-521. doi:10.1046/j.1469-0705.2001.00445.xPubMedGoogle ScholarCrossref
    128.
    Sousa  R, Silvestre  M, Almeida e Sousa  L,  et al.  Transvaginal ultrasonography and hysteroscopy in postmenopausal bleeding: a prospective study.  Acta Obstet Gynecol Scand. 2001;80(9):856-862.PubMedGoogle Scholar
    129.
    Panda  JK.  One-stop clinic for postmenopausal bleeding.  J Reprod Med. 2002;47(9):761-766.PubMedGoogle Scholar
    130.
    Yaman  C, Ebner  T, Jesacher  K, Obermayr  G, Pölz  W, Tews  G.  Reproducibility of three-dimensional ultrasound endometrial volume measurements in patients with postmenopausal bleeding.  Ultrasound Obstet Gynecol. 2002;19(3):282-286. doi:10.1046/j.1469-0705.2002.00644.xPubMedGoogle ScholarCrossref
    131.
    Elliott  J, Connor  ME, Lashen  H.  The value of outpatient hysteroscopy in diagnosing endometrial pathology in postmenopausal women with and without hormone replacement therapy.  Acta Obstet Gynecol Scand. 2003;82(12):1112-1119. doi:10.1046/j.1600-0412.2003.00261.xPubMedGoogle ScholarCrossref
    132.
    Mossa  B, Imperato  F, Marziani  R,  et al.  Hormonal replacement therapy and evaluation of intrauterine pathology in postmenopausal women: a ten-year study.  Eur J Gynaecol Oncol. 2003;24(6):507-512.PubMedGoogle Scholar
    133.
    Arslan  M, Erdem  A, Erdem  M, Yazici  G, Himmetoglu  O, Gursoy  R.  Transvaginal color Doppler ultrasonography for prediction of pre-cancerous endometrial lesions.  Int J Gynaecol Obstet. 2003;80(3):299-306. doi:10.1016/S0020-7292(02)00374-0PubMedGoogle ScholarCrossref
    134.
    de Wit  AC, Vleugels  MP, de Kruif  JH.  Diagnostic hysteroscopy: a valuable diagnostic tool in the diagnosis of structural intra-cavital pathology and endometrial hyperplasia or carcinoma? six years of experience with non-clinical diagnostic hysteroscopy.  Eur J Obstet Gynecol Reprod Biol. 2003;110(1):79-82. doi:10.1016/S0301-2115(03)00165-9PubMedGoogle ScholarCrossref
    135.
    Bachmann  LM, ter Riet  G, Clark  TJ, Gupta  JK, Khan  KS.  Probability analysis for diagnosis of endometrial hyperplasia and cancer in postmenopausal bleeding: an approach for a rational diagnostic workup.  Acta Obstet Gynecol Scand. 2003;82(6):564-569. doi:10.1034/j.1600-0412.2003.00176.xPubMedGoogle ScholarCrossref
    136.
    Phillip  H, Dacosta  V, Fletcher  H, Kulkarni  S, Reid  M.  Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Afro-Caribbean Jamaican women with postmenopausal bleeding.  J Obstet Gynaecol. 2004;24(5):568-572. doi:10.1080/01443610410001722671PubMedGoogle ScholarCrossref
    137.
    Bruchim  I, Biron-Shental  T, Altaras  MM,  et al.  Combination of endometrial thickness and time since menopause in predicting endometrial cancer in women with postmenopausal bleeding.  J Clin Ultrasound. 2004;32(5):219-224. doi:10.1002/jcu.20020PubMedGoogle ScholarCrossref
    138.
    Minagawa  Y, Sato  S, Ito  M, Onohara  Y, Nakamoto  S, Kigawa  J.  Transvaginal ultrasonography and endometrial cytology as a diagnostic schema for endometrial cancer.  Gynecol Obstet Invest. 2005;59(3):149-154. doi:10.1159/000083089PubMedGoogle ScholarCrossref
    139.
    Litta  P, Merlin  F, Saccardi  C,  et al.  Role of hysteroscopy with endometrial biopsy to rule out endometrial cancer in postmenopausal women with abnormal uterine bleeding.  Maturitas. 2005;50(2):117-123. doi:10.1016/j.maturitas.2004.05.003PubMedGoogle ScholarCrossref
    140.
    Wilailak  S, Jirapinyo  M, Theppisai  U.  Transvaginal Doppler sonography: is there a role for this modality in the evaluation of women with postmenopausal bleeding?  Maturitas. 2005;50(2):111-116. doi:10.1016/j.maturitas.2004.04.004PubMedGoogle ScholarCrossref
    141.
    Taşkin  S, Bozaci  EA, Seval  MM, Unlü  C.  Transvaginal sonographic assessment of endometrial thickness and endometrial morphology in postmenopausal bleeding.  Int J Gynaecol Obstet. 2006;92(2):155-156. doi:10.1016/j.ijgo.2005.10.023PubMedGoogle ScholarCrossref
    142.
    Spicer  JM, Siebert  I, Kruger  TF.  Postmenopausal bleeding: a diagnostic approach for both private and public sectors.  Gynecol Obstet Invest. 2006;61(3):174-178. doi:10.1159/000091413PubMedGoogle ScholarCrossref
    143.
    Mansour  GM, El-Lamie  IK, El-Kady  MA, El-Mekkawi  SF, Laban  M, Abou-Gabal  AI.  Endometrial volume as predictor of malignancy in women with postmenopausal bleeding.  Int J Gynaecol Obstet. 2007;99(3):206-210. doi:10.1016/j.ijgo.2007.07.024PubMedGoogle ScholarCrossref
    144.
    Yildirim  M, Bozkurt  N, Kurdoglu  M, Taskiran  C, Oktem  M, Dilek  KU.  Histopathologic findings in women with postmenopausal bleeding: implication for endometrial thickness and circulating levels of sex steroid hormones.  Arch Gynecol Obstet. 2007;276(4):305-310. doi:10.1007/s00404-007-0361-1PubMedGoogle ScholarCrossref
    145.
    Tinelli  R, Tinelli  FG, Cicinelli  E, Malvasi  A, Tinelli  A.  The role of hysteroscopy with eye-directed biopsy in postmenopausal women with uterine bleeding and endometrial atrophy.  Menopause. 2008;15(4, pt 1):737-742. doi:10.1097/gme.0b013e31815b644ePubMedGoogle ScholarCrossref
    146.
    Yaman  C, Habelsberger  A, Tews  G, Pölz  W, Ebner  T.  The role of three-dimensional volume measurement in diagnosing endometrial cancer in patients with postmenopausal bleeding.  Gynecol Oncol. 2008;110(3):390-395. doi:10.1016/j.ygyno.2008.04.029PubMedGoogle ScholarCrossref
    147.
    Sadoon  S, Salman  G, Smith  G, Henson  C, McCullough  W.  Ultrasonographic endometrial thickness for diagnosing endometrial pathology in postmenopausal bleeding.  J Obstet Gynaecol. 2007;27(4):406-408. doi:10.1080/01443610701327438PubMedGoogle ScholarCrossref
    148.
    Ewies  AA, Musonda  P.  Managing postmenopausal bleeding revisited: what is the best first line investigation and who should be seen within 2 weeks? a cross-sectional study of 326 women.  Eur J Obstet Gynecol Reprod Biol. 2010;153(1):67-71. doi:10.1016/j.ejogrb.2010.06.009PubMedGoogle ScholarCrossref
    149.
    Jillani  K, Khero  RB, Maqsood  S, Siddiqui  MA.  Prevalence of malignant disorders in 50 cases of postmenopausal bleeding.  J Pak Med Assoc. 2010;60(7):540-543.PubMedGoogle Scholar
    150.
    Liberis  V, Tsikouras  P, Christos  Z,  et al.  The contribution of hysteroscopy to the detection malignancy in symptomatic postmenopausal women.  Minim Invasive Ther Allied Technol. 2010;19(2):83-93. doi:10.3109/13645701003643881PubMedGoogle ScholarCrossref
    151.
    Menzies  R, Wallace  S, Ennis  M,  et al.  Significance of abnormal sonographic findings in postmenopausal women with and without bleeding.  J Obstet Gynaecol Can. 2011;33(9):944-951. doi:10.1016/S1701-2163(16)35020-4PubMedGoogle ScholarCrossref
    152.
    Zaki  A, Gaber  A, Ghanem  E, Moemen  M, Shehata  G.  Abdominal obesity and endometrial cancer in Egyptian females with postmenopausal bleeding.  Nutr Cancer. 2011;63(8):1272-1278. doi:10.1080/01635581.2011.615973PubMedGoogle ScholarCrossref
    153.
    Ragupathy  K, Cawley  N, Ridout  A, Iqbal  P, Alloub  M.  Non-assessable endometrium in women with post-menopausal bleeding: to investigate or ignore.  Arch Gynecol Obstet. 2013;288(2):375-378. doi:10.1007/s00404-013-2746-7PubMedGoogle ScholarCrossref
    154.
    Damle  RP, Dravid  NV, Suryawanshi  KH, Gadre  AS, Bagale  PS, Ahire  N.  Clinicopathological spectrum of endometrial changes in peri-menopausal and post-menopausal abnormal uterine bleeding: a 2 years study.  J Clin Diagn Res. 2013;7(12):2774-2776.PubMedGoogle Scholar
    155.
    Wong  AS, Lao  TT, Cheung  CW,  et al.  Reappraisal of endometrial thickness for the detection of endometrial cancer in postmenopausal bleeding: a retrospective cohort study.  BJOG. 2016;123(3):439-446. doi:10.1111/1471-0528.13342PubMedGoogle ScholarCrossref
    156.
    Cho  HJ, Lee  ES, Lee  JY,  et al.  Investigations for postmenopausal uterine bleeding: special considerations for endometrial volume.  Arch Iran Med. 2013;16(11):665-670.PubMedGoogle Scholar
    157.
    Abid  M, Hashmi  AA, Malik  B,  et al.  Clinical pattern and spectrum of endometrial pathologies in patients with abnormal uterine bleeding in Pakistan: need to adopt a more conservative approach to treatment.  BMC Womens Health. 2014;14:132. doi:10.1186/s12905-014-0132-7PubMedGoogle ScholarCrossref
    158.
    Loiacono  RM, Trojano  G, Del Gaudio  N,  et al.  Hysteroscopy as a valid tool for endometrial pathology in patients with postmenopausal bleeding or asymptomatic patients with a thickened endometrium: hysteroscopic and histological results.  Gynecol Obstet Invest. 2015;79(3):210-216. doi:10.1159/000371758PubMedGoogle ScholarCrossref
    159.
    Van den Bosch  T, Ameye  L, Van Schoubroeck  D, Bourne  T, Timmerman  D.  Intra-cavitary uterine pathology in women with abnormal uterine bleeding: a prospective study of 1220 women.  Facts Views Vis Obgyn. 2015;7(1):17-24.PubMedGoogle Scholar
    160.
    Kim  A, Lee  JY, Chun  S, Kim  HY.  Diagnostic utility of three-dimensional power Doppler ultrasound for postmenopausal bleeding.  Taiwan J Obstet Gynecol. 2015;54(3):221-226. doi:10.1016/j.tjog.2013.10.043PubMedGoogle ScholarCrossref
    161.
    Ozer  A, Ozer  S, Kanat-Pektas  M.  Correlation between transvaginal ultrasound measured endometrial thickness and histopathological findings in Turkish women with abnormal uterine bleeding.  J Obstet Gynaecol Res. 2016;42(5):573-578. doi:10.1111/jog.12937PubMedGoogle ScholarCrossref
    162.
    Seckin  B, Cicek  MN, Dikmen  AU, Bostancı  EI, Muftuoglu  KH.  Diagnostic value of sonography for detecting endometrial pathologies in postmenopausal women with and without bleeding.  J Clin Ultrasound. 2016;44(6):339-346. doi:10.1002/jcu.22329PubMedGoogle ScholarCrossref
    163.
    Trabert  B, Wentzensen  N, Yang  HP,  et al.  Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?  Int J Cancer. 2013;132(2):417-426. doi:10.1002/ijc.27623PubMedGoogle ScholarCrossref
    164.
    Lindenfeld  EA, Langer  RD.  Bleeding patterns of the hormone replacement therapies in the postmenopausal estrogen and progestin interventions trial.  Obstet Gynecol. 2002;100(5, pt 1):853-863.PubMedGoogle Scholar
    165.
    Hickey  M, Ameratunga  D, Marino  JL.  Unscheduled bleeding in continuous combined hormone therapy users.  Maturitas. 2011;70(4):400-403. doi:10.1016/j.maturitas.2011.09.010PubMedGoogle ScholarCrossref
    166.
    van Hanegem  N, Prins  MM, Bongers  MY,  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;197:147-155. doi:10.1016/j.ejogrb.2015.12.008PubMedGoogle ScholarCrossref
    167.
    Timmermans  A, Opmeer  BC, Khan  KS,  et al.  Endometrial thickness measurement for detecting endometrial cancer in women with postmenopausal bleeding: a systematic review and meta-analysis.  Obstet Gynecol. 2010;116(1):160-167. doi:10.1097/AOG.0b013e3181e3e7e8PubMedGoogle ScholarCrossref
    168.
    Lee  SC, Kaunitz  AM, Sanchez-Ramos  L, Rhatigan  RM.  The oncogenic potential of endometrial polyps: a systematic review and meta-analysis.  Obstet Gynecol. 2010;116(5):1197-1205. doi:10.1097/AOG.0b013e3181f74864PubMedGoogle ScholarCrossref
    169.
    Perri  T, Rahimi  K, Ramanakumar  AV,  et al.  Are endometrial polyps true cancer precursors?  Am J Obstet Gynecol. 2010;203(3):232.e1-232.e6. doi:10.1016/j.ajog.2010.03.036PubMedGoogle ScholarCrossref
    170.
    Kinde  I, Bettegowda  C, Wang  Y,  et al.  Evaluation of DNA from the Papanicolaou test to detect ovarian and endometrial cancers.  Sci Transl Med. 2013;5(167):167ra4. doi:10.1126/scitranslmed.3004952PubMedGoogle ScholarCrossref
    171.
    Fiegl  H, Gattringer  C, Widschwendter  A,  et al.  Methylated DNA collected by tampons: a new tool to detect endometrial cancer.  Cancer Epidemiol Biomarkers Prev. 2004;13(5):882-888.PubMedGoogle Scholar
    172.
    Arbyn  M, Xu  L, Verdoodt  F,  et al.  Genotyping for human papillomavirus types 16 and 18 in women with minor cervical lesions: a systematic review and meta-analysis.  Ann Intern Med. 2017;166(2):118-127. doi:10.7326/M15-2735PubMedGoogle ScholarCrossref
    ×