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This disease is a frequent precursor to cases of endometrial carcinoma of the uterus. Both diseases present with abnormal uterine bleeding. The treating physician commonly performs a dilatation and curettage of the uterus yielding abundant tissue showing the characteristic histology. Pathologists have refined the diagnostic accuracy of this diagnosis stratifying endometrial hyperplasia by both histology and risk of progression to carcinoma.


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SYNONYMS Adenomatous hyperplasia
INCIDENCE 8/1000 of screened postmenopausal women



Estradiol-induced hyperplasia in endometrial biopsies from women on hormone replacement therapy.

Wright TC, Holinka CF, Ferenczy A, Gatsonis CA, Mutter GL, Nicosia S, Richart RM.

Am J Surg Pathol 2002 Oct;26(10):1269-75

Comparison of endometrial changes among symptomatic tamoxifen-treated and nontreated premenopausal and postmenopausal breast cancer patients.

Cheng WF, Lin HH, Torng PL, Huang SC.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Republic of China.

Gynecol Oncol 1997 Aug;66(2):233-7 Abstract quote

Breast cancer patients who received tamoxifen as adjuvant therapy have been reported to have more endometrial lesions such as polyps, hyperplasia, or carcinoma.

We conducted a prospective study to elucidate the endometrial changes of premenopausal and postmenopausal breast cancer patients with tamoxifen. Sixty-seven symptomatic breast cancer patients who had been on tamoxifen treatment, including 34 premenopausal and 33 postmenopausal patients, and another group of 48 patients who had not been on tamoxifen, including 25 premenopausal and 23 postmenopausal patients, were recruited. Symptomatic patients were defined as having hypermenorrhea or abnormal vaginal bleeding among premenopausal patients or postmenopausal bleeding among postmenopausal patients. Endometrial thickness and uterine size determined by vaginal ultrasonography, histologic findings, and risk factors for endometrial cancer were compared.

The mean endometrial thickness and uterine size showed no statistically significant difference in premenopausal patients with (n = 34) or without (n = 25) tamoxifen treatment, whereas there was a significant difference in the postmenopausal patients with (n = 33) or without (n = 23) tamoxifen treatment (12.11 +/- 12.38 mm vs 5.41 +/- 2.70 mm, P = 0.025; 234.71 +/- 76.36 cm3 vs 108.81 +/- 81.27 cm3, P = 0.0018, respectively).

The frequency of endometrial histopathologic findings was 23.5% (8/34) in tamoxifen-treated women compared with 12.0% (3/25) in nontreated women (P = 0.269) in the premenopausal groups. In contrast, it was remarkably high with 66.7% (22/33) in tamoxifen-treated women compared with 30.4% (7/23) in the nontreated women in the postmenopausal groups (P = 0.025). There were four postmenopausal patients with tamoxifen, including three with atypical endometrial hyperplasia and one endometrial carcinoma, in contrast to no postmenopausal nontreated patients, although this difference did not reach statistical significance in this study (P = 0.096).

There was a remarkably high prevalence of endometrial histopathologic findings in symptomatic tamoxifen-treated breast cancer patients, especially postmenopausal women. Tamoxifen might be associated with premalignant or malignant changes in postmenopausal endometrium. Thus timely, aggressive histologic assessment such as curettage or hysteroscope should be performed to detect the endometrial lesions when symptoms occur. Vaginal ultrasonography could be a useful tool to detect the endometrial lesions.

Endometrial cancer after tamoxifen treatment of breast cancer. Results of a retrospective cohort study.

Vrscaj MU, Bebar S, Djurisic A, Fras PA.

Institute of Oncology, Ljubljana, Slovenia.

Eur J Gynaecol Oncol 1999;20(1):20-5 Abstract quote

PURPOSE: The aim of the present retrospective study was to evaluate the relationship between the use of Tamoxifen (TAM) and development of endometrial carcinoma (EC) in Slovenia women patients (pts).

METHODS. This retrospective study included 408 pts, aged 55 years or more, treated for invasive breast cancer (285 pts were treated with TAM, 123 pts without it) at our Institute from 1988 to 1992. The pts who had had hysterectomy were not included. The observation period was 5 to 9 years. The Mantel-Haenszel chi2 test and Fisher p test were used. Survival was computed by Kaplan-Meier estimates.

RESULTS: As to the most common risk factors of EC no statistically significant difference was observed. The daily dose of TAM was 20 mg, median treatment period was 38 months (1-97). In 15% of pts, TAM-related side-effects were noted 30 months later; the most common was uterine bleeding. EC was detected in 10/30 pts with curettage, while others had polypous changes and cystic hyperplasia. In the group of pts without TAM, curettage was performed in 4 pts. In view of curettage, the difference between the two groups was statistically significant (p=0.014). In the group of pts without TAM, EC was detected in 2 pts. Evaluated relative risk (RR) was 2.16 (0.48-9.70). Between the TAM groups of pts with and without EC, the difference in survival was minimal, statistically nonsignificant (p=0.41).

CONCLUSION: Treatment with TAM increases the risk of benign endometrial changes and EC. In EC cases treatment with TAM does not influence the pts survival. Pts using TAM need to know what symptoms and signs should be reported.

Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and non-HRT-related endometrial pathology.

Kennedy MM, Baigrie CF, Manek S.

Nuffield Department of Pathology, John Radcliffe Hospital, Oxford, United Kingdom.

Int J Gynecol Pathol 1999 Apr;18(2):130-7 Abstract quote

Tamoxifen, a synthetic anti-estrogen that paradoxically acts as a partial estrogen agonist on the endometrium, is associated with an increased frequency of proliferative endometrial lesions, including hyperplasias, neoplasms, and polyps. Tamoxifen-related polyps are characteristically multiple and fibrotic. A variety of metaplasias and periglandular stromal condensation may be seen. Relatively few articles have focused on the descriptive morphology of the full range of tamoxifen-associated lesions.

The present study further defines the histologic features in both endometrial polyps and nonpolyp endometrium. One hundred and two specimens (including 50 polyps) were reviewed using hormone replacement therapy-related endometrial specimens and conventional polyps as the control groups.

The most characteristic findings of tamoxifen-associated lesions included polarized glands along the long axis of polyps (40%), a cambium layer (72%), frequent and diverse metaplasias, staghorn glands (36%), myxoid degeneration (12%), and small glands (36%). Similar morphologic features were identified in the hormone replacement therapy and control groups but to a variable, lesser extent. Overall, the tamoxifen group consisted of 18 cases of hyperplasia (11 complex, 7 simple) and one case each of adenofibroma, adenosarcoma, endometrial stromal sarcoma, and leiomyosarcoma.

Although none of the features is diagnostic, the presence of diverse metaplasias, polarized glands, staghorn glands, and a cambium layer strongly suggest tamoxifen exposure especially if a number of these features are present concurrently within the same material.

Significance of endovaginal ultrasonography in assessing tamoxifen-associated changes of the endometrium. A prospective study.

Strauss HG, Wolters M, Methfessel G, Buchmann J, Koelbl H.

Department of Gynecology, Martin-Luther-University Halle-Wittenberg, Germany.

Acta Obstet Gynecol Scand 2000 Aug;79(8):697-701 Abstract quote

BACKGROUND: A prospective study was conducted investigating the value of endovaginal ultrasound in the assessment of tamoxifen-associated changes of the endometrium in patients with breast cancer.

METHODS: Seventy postmenopausal patients with breast cancer treated with anti-estrogens for at least 6 months were entered. Those with bleeding disorders and/or an endometrial thickness of > or =10 mm found on ultrasonography underwent hysteroscopy and dilatation and curettage (D&C) for further histological evaluation. In 22 patients, positive ultrasound findings could be compared with histopathology.

RESULTS: 82% of the 22 patients with positive sonographic findings had a glandular-cystic hyperplasia or a glandular-cystic polyp. No adenomatous hyperplasia or endometrial cancer was observed in our series.

CONCLUSION: Vaginal ultrasound represents a useful diagnostic tool to detect tamoxifen-associated changes of the endometrium. A threshold of 10 mm endometrial thickness appears suitable to identify endometrial abnormalities while reducing the rate of false-positive findings to an acceptable level. However, the role of vaginal ultrasound in screening for endometrial cancer or premalignant lesions remains uncertain.

Endometrial histopathology in 700 patients treated with tamoxifen for breast cancer.

Deligdisch L, Kalir T, Cohen CJ, de Latour M, Le Bouedec G, Penault-Llorca F.

Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10029-6500, USA.

Gynecol Oncol 2000 Aug;78(2):181-6 Abstract quote

OBJECTIVE: The aim of this study was the evaluation of endometrial histopathologic findings from 700 patients treated with tamoxifen (Tx) for breast cancer from two medical centers (United States and France).

METHODS: A retrospective review of data including histologic slides from 134 hysterectomies and 566 endometrial biopsies from Tx-treated patients who presented with abnormal vaginal bleeding and/or abnormal sonograms was performed. Analysis of histologic characteristics included inactive/atrophic and functional endometria, endometrial polyps, hyperplasia and metaplasia, and endometrial cancer. Duration of Tx therapy was recorded when available, and its correlation with endometrial pathology was assessed.

RESULTS: The only statistically significant difference between the data from the United States and France was the number of hysterectomies, which was almost double in France (27% vs 13.7%). Nonpathologic endometria made up 61.14% (inactive/atrophic 46%, functional 15.14%). Pathologic changes were found in 39.86% cases, of which polyps were 23.14%, glandular hyperplasia 8%, and metaplasia 3%; endometrial cancer made up 4.71% (33 cases). Nine cancers were well-differentiated endometrioid adenocarcinomas, and 24 were moderately or poorly differentiated, of which 13 had nonendometrioid components (serous, clear cell, MMMT). Fifteen cancers were found in endometrial polyps; 12 were invasive to the myometrium and 4 to blood vessels. The weight of the uteri exceeded 300 g in 15 cases, with 4 exceeding 900 g. The average age of all patients was 60.91 years and of the cancer patients alone it was 69.26 years. The shortest average duration of Tx therapy (2.5 years) was found in patients with inactive/atrophic endometria and the longest (6.8 years) in patients with endometrial cancer. Patients with endometrial polyps and cancer presented more often with abnormal vaginal bleeding than those with inactive/atrophic endometrium.

CONCLUSIONS: Most Tx-treated patients had no pathologic endometrial changes. Endometrial polyps, hyperplasia, and metaplasia, consistent with an estrogen-agonist effect of Tx, were found in roughly one-third of all patients. The endometrial cancers were often high-grade and invasive tumors. Patients with endometrial pathology were more often symptomatic than patients with inactive/atrophic endometria.

Indication for histological examination of endometrium in breast carcinoma patients receiving tamoxifen therapy.

Ito T, Katagiri C, Murata Y, Hamazoe R, Morita K.

Department of Obstetrics and Gynecology, Hakuai Hospital, Yonago, Japan.

J Obstet Gynaecol Res 2001 Jun;27(3):141-5 Abstract quote

OBJECTIVE: To investigate the effects of tamoxifen on the uterine endometrium and define the indications for histological examination of endometrium on the thickness of uterine endometrium and on the duration of tamoxifen therapy.

METHODS: The endometrial thickness was measured on the transvaginal ultrasonogram in 40 postmenopausal breast carcinoma patients receiving tamoxifen (tamoxifen group), and control group. Endometrial histological examination was carried out. Receiver operating characteristic (ROC) curve analysis was carried out.

RESULTS: Endometrial thickness in the tamoxifen group was 11.2 +/- 5.1 mm, and that of the control group was 3.8 +/- 2.1 mm. The incidence of endometrial abnormalities in the tamoxifen group was greater than that in control group. The cut off values derived from the ROC curve analysis were 9 mm for endometrial thickness, and 24 months for duration of tamoxifen therapy.

CONCLUSION: The histological examination of endometrium should be carried out if the endometrial thickness is more than 9 mm, or the duration of tamoxifen therapy is more than 24 months even if the patients do not have any symptoms.

Risk factors of endometrial polyps resected from postmenopausal patients with breast carcinoma treated with tamoxifen.

Cohen I, Azaria R, Bernheim J, Shapira J, Beyth Y.

Department of Obstetrics and Gynecology, Sapir Medical Center, Kfar-Saba, Tel Aviv University, Israel.

Cancer 2001 Sep 1;92(5):1151-5 Abstract quote

BACKGROUND: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. Up to 3% of these polyps may show malignant changes. However, to the authors' knowledge no one has described any risk factor for the development of this pathology in postmenopausal patients with breast carcinoma treated with tamoxifen.

OBJECTIVE. The objective of this study was to evaluate whether risk factors can be identified for the development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen.

METHODS: The authors reviewed the medical records of 54 postmenopausal patients with breast carcinoma in whom endometrial polyps were resected by hysteroscopy after at least 6 months of tamoxifen treatment (Group I). Demographic characteristics, health habits, risk factors for endometrial carcinoma, and clinical factors related to the primary breast disease were examined. The results were compared with those obtained from 210 similar patients in whom hysteroscopy did not reveal any endometrial pathology (Group II).

RESULTS: Age at menopause was significantly older, duration of breast disease was significantly longer, and body weight was significantly heavier among Group I patients compared with Group II patients (P = 0.0162, P = 0.0026, and P = 0.0364, respectively). Endometrial thickness, measured by transvaginal ultrasonography, was significantly thicker in Group I patients (16.3 +/- 7.2 mm) compared with that detected in Group II patients (11.8 +/- 6.3; P = 0.0001).

CONCLUSIONS: Various factors, such as older age at menopause, longer duration of breast disease, heavier weight, and thicker endometrium may contribute to the prediction of increased risk of development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen.


Dissociated Expression of Bcl-2 and Ki-67 in Endometrial Lesions: Diagnostic and Histogenetic Implications

Björn Risberg, M.D., Ph.D.; Kerstin Karlsson, B.Sc.; Vera Abeler, M.D., Ph.D.; Anders Lagrelius, M.D., Ph.D.; Ben Davidson, M.D., Ph.D.; Mats G. Karlsson, M.D., Ph.D.

From the Department of Pathology, The Norwegian Radium Hospital (B.R., V.A., B.D.), Oslo, Norway; the Gynecological Clinic, Huddinge Hospital (A.L.), Karolinska Institute, Sweden; Astra-Zeneca Medical Development (K.K.), Södertälje, Sweden; and the Department of Pathology, Medical Center Hospital (M.G.K.), Örebro, Sweden.


Int J Gynecol Pathol 2002;21:155-160 Abstract quote

The objective of the present study was to analyze the expression of the proliferation marker, Ki-67, and the anti-apoptotic protein, bcl-2, in various endometrial lesions. Ki-67 and bcl-2 expressions were studied in 194 specimens of endometrial hyperplasia, polyps, carcinomas, and cyclic endometrium from a defined geographic area.

Results were statistically analyzed with respect to marker expression, localization to the stromal or glandular component, and intraglandular topography. The lowest glandular Ki-67 expression was seen in secretory endometrium, in polyps, and in atypical hyperplasia. The Ki-67 score was significantly higher and less heterogeneous in endometrial carcinomas than in hyperplasia (p<0.001). Endometrial hyperplasia of all types was characterized by a markedly heterogeneous glandular expression of Ki-67. The glandular expression of bcl-2 was highest in proliferative endometrium and polyps. Bcl-2 expression was significantly lower in adenocarcinomas than in hyperplastic lesions (p=0.002). Ki-67 and bcl-2 expression showed a significant association in proliferative endometrium (p=0.003). Endometrial polyps demonstrated a unique pattern of very low expression of Ki-67 and high bcl-2 expression in both stroma and glands.

Our findings indicate that an imbalance between proliferation and apoptosis may be an important factor in the development of different endometrial lesions, benign as well as malignant. The specific finding of inter- and intraglandular Ki-67 heterogeneity may be valuable as an adjunct to morphology in the differential diagnosis of endometrial hyperplasia.

Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules).

Brachtel EF, Sanchez-Estevez C, Moreno-Bueno G, Prat J, Palacios J, Oliva E.

From the *Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; daggerLaboratory of Breast and Gynecological Cancer, Molecular Pathology, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; and double daggerDepartment of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Supported in part by the Fondo de Investigaciones Sanitarias Grant No. FIS 02/0355.

Am J Surg Pathol. 2005 Oct;29(10):1322-1329. Abstract quote  

Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia.

In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease.

In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.

Atypical endometrial hyperplasia shares genomic abnormalities with endometrioid carcinoma by comparative genomic hybridization

Huseyin Baloglu, MD, Linda A. Cannizzaro, PhD, Joan Jones, MD, and Leopold G. Koss, MD

Hum Pathol 2001;32:615-622 Abstract quote

Endometrial hyperplasia is a common disorder that is now observed with increasing frequency in women treated with hormonal replacement therapy or with tamoxifen.

This study was undertaken to determine whether genomic features of various forms of endometrial hyperplasias would allow their classification as a benign, premalignant, or malignant abnormality.

Comparative genomic hybridization (CGH) was performed on endometrial glands microdissected by laser capture microscope from 19 archival endometrial samples, comprising 5 normal endometria, 1 polyp, 2 simple hyperplasias, 5 hyperplasias with nuclear abnormalities (atypical hyperplasias), and 4 low-grade and 2 high-grade endometrioid carcinomas, 1 with squamous component (adenoacanthoma). Genomic DNA, extracted from the glands and the squamous component in 1 case, was amplified by degenerate oligonucleotide—primed polymerase chain reaction (DOP-PCR) and compared with sex-matched DNA by CGH. No genomic imbalances were observed in the normal samples, the polyp, or the simple hyperplasias. However, in atypical hyperplasia, regardless of the level of cytologic atypia, genomic abnormalities were observed that also occurred in endometrioid carcinomas. Chromosomes 1, 8, and 10 were most often affected. The results are compared with molecular genetic abnormalities recently reported in these lesions.

This study strongly suggests that atypical endometrial hyperplasias are closely related to endometrioid carcinoma and should be considered precancerous lesions, contrary to simple hyperplasia, which is a benign disorder. The squamous component of one of the high-grade carcinomas showed genetic abnormalities similar to those of endometrioid carcinoma and therefore does not represent squamous metaplasia but is an integral part of the malignant process.


Tissue microarray immunohistochemical expression analysis of mismatch repair (hMLH1 and hMSH2 genes) in endometrial carcinoma and atypical endometrial hyperplasia: relationship with microsatellite instability.

Hardisson D, Moreno-Bueno G, Sanchez L, Sarrio D, Suarez A, Calero F, Palacios J.

Department of Pathology, Hospital Universitario La Paz, Spain.

Mod Pathol. 2003 Nov;16(11):1148-58 Abstract quote.  

Alterations in the mismatch repair genes (hMLH1 and hMSH2) play an important role in the development of microsatellite instability in sporadic endometrial cancer. Tissue microarray technology allows molecular profiling of tumor samples at the DNA, RNA, and protein levels.

We analyzed hMLH1 and hMSH2 expression by immunohistochemistry in a group of atypical endometrial hyperplasias (n = 10), endometrioid endometrial carcinomas (n = 58), and nonendometrioid endometrial carcinomas (n = 27) on tissue microarray. The results were correlated with microsatellite instability status as evaluated by BAT-25 and BAT-26. Overall, 29.4% of lesions showed microsatellite instability. Loss of nuclear hMLH1 and hMSH2 protein expression was seen in 22.3% and 6.5% of cases, respectively. Immunohistochemistry for hMLH1 and hMSH2 showed lack of protein expression in 64% and 16.6% of microsatellite instability-positive endometrial lesions, respectively. Taken together, hMLH1 or hMSH2 protein expression was absent in 18 of 24 microsatellite instability-positive cases (75% sensitivity).

A high level of concordance was found between immunohistochemistry for hMLH1 and hMSH2 and microsatellite instability status evaluated by BAT-25 and BAT-26 (kappa value of 0.7). Of the 57 cases found to be microsatellite instability negative, 53 showed normal expression of both proteins (93% specificity). The observed predictive value of absence of expression of hMLH1 for predicting microsatellite instability-positive status was 82%. The predictive value of normal expression of both proteins for predicting microsatellite instability-negative status was 90%. These results are consistent with those previously reported in whole tissue sections.

Therefore, immunohistochemical analysis of hMLH1 and hMSH2 expression on tissue microarray provides an accurate technique for screening for tumors with microsatellite instability. Tissue microarrays represent an ideal approach for comparing different diagnostic or predictive markers with one another in consecutive tissue microarray sections.



Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia: a systematic quantitative review.

Clark TJ, Voit D, Gupta JK, Hyde C, Song F, Khan KS.

Department of Obstetrics and Gynaecology, Birmingham Women's Hospital, Birmingham B15 2TG, England.

JAMA 2002 Oct 2;288(13):1610-21 Abstract quote

CONTEXT: Hysteroscopy (direct endoscopic visualization of the endometrial cavity) is used extensively in the evaluation of common gynecologic problems, such as menorrhagia and postmenopausal bleeding. However, there is a continuing debate about the value of this technology in the diagnosis of serious endometrial disease.

OBJECTIVE: To determine the accuracy of hysteroscopy in diagnosing endometrial cancer and hyperplasia in women with abnormal uterine bleeding.

DATA SOURCES: Relevant articles were identified through searches of the Cochrane Library, MEDLINE, and EMBASE (1984-2001), manual searches of bibliographies of known primary and review articles, and contact with manufacturers.

STUDY SELECTION: Studies were selected blindly, independently, and in duplicate if accuracy of hysteroscopy was estimated in women with abnormal uterine bleeding, using histopathologic findings as a reference standard. Our search identified 3486 articles; 208 of these were deemed to be potentially eligible and were retrieved for detailed data extraction. Sixty-five primary studies were analyzed, including 26 346 women.

DATA EXTRACTION: Data were abstracted on characteristics and quality from each study. Results for diagnostic accuracy were extracted to form 2 x 2 contingency tables separately for endometrial cancer and endometrial disease (cancer, hyperplasia, or both). Pooled likelihood ratios (LRs) were used as summary accuracy measures.

DATA SYNTHESIS: The pretest probability of endometrial cancer was 3.9% (95% confidence interval [CI], 3.7%-4.2%). A positive hysteroscopy result (pooled LR, 60.9; 95% CI, 51.2-72.5) increased the probability of cancer to 71.8% (95% CI, 67.0%-76.6%), whereas a negative hysteroscopy result (pooled LR, 0.15; 95% CI, 0.13-0.18) reduced the probability of cancer to 0.6% (95% CI, 0.5%-0.8%). There was statistical heterogeneity in pooling of LRs, but an explanation for this could not be found in spectrum composition and study quality. The overall accuracy for the diagnosis of endometrial disease was modest compared with that of cancer, and the results were heterogeneous. The accuracy tended to be higher among postmenopausal women and in the outpatient setting.

CONCLUSION: The diagnostic accuracy of hysteroscopy is high for endometrial cancer, but only moderate for endometrial disease (cancer or hyperplasia).


Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis.

Gupta J, Chien P, Voit D, Clark TJ, Khan K.

Acta Obstet Gynecol Scand 2002 Sep;81(9):799-816 Abstract quote

Our aim was to determine the diagnostic accuracy of endometrial thickness measurement by pelvic ultrasonography for predicting endometrial carcinoma and disease (hyperplasia and/or carcinoma) during an investigation of postmenopausal bleeding.

We performed a systematic quantitative review of the available published literature, which consisted of online searching the MEDLINE and EMBASE databases (1966-2000) coupled with scanning of bibliography of known primary and review articles. The selection of studies, assessment of study quality, and extraction of data were performed in duplicate under masked conditions. Included in the analyses were 57 studies with 9031 patients. Accuracy data were summarized using likelihood ratios for various cut-off levels of abnormal endometrial thickness. The commonest cut-offs were 4 mm (9 studies) and 5 mm (21 studies), measuring both endometrial layers. None of the nine studies using the </= 4 mm cut-off level were of good quality. Only four studies (out of the 21) used the </= 5 mm cut-off level, which employed the best-quality criteria. Using the pooled estimates from these four studies only, a positive test result raised the probability of carcinoma from 14.0% (95% CI 13.3-14.7) to 31.3% (95% CI 26.1-36.3), while a negative test reduced it to 2.5% (95% CI 0.9-6.4).

In conclusion, ultrasound measurement of endometrial thickness alone, using the best-quality studies cannot be used to accurately rule. However, a negative result at </= 5 mm cut-off level measuring both endometrial layers in the presence of endometrial pathology rules out endometrial pathology with good certainty.


Uterus The uterus may be enlarged and the endometrial lining thickened
May be diffuse or polypoid



Each category is further divided by the presence or absence of cytologic atypia

Atypia is defined as stratified cells with loss of polarity and increased nuclear:cytoplasmic ratio

Diagnosing Endometrial Hyperplasia: Why is it so Difficult to Agree?

Departments of *Pathology †Obstetrics and Gynecology ‡Epidemiology, University of Washington Medical Center §Public Health Sciences Division, Fred Hutchinson Cancer Research Center ∥Group Health Center for Health Studies, Seattle, WA.


Am J Surg Pathol. 2008 May;32(5):691-698. Abstract quote

Current World Health Organization classification of endometrial hyperplasia is problematic because of poor diagnostic reproducibility.

We sought to determine factors that cause diagnostic disagreement in a review of 2601 endometrial specimens. Blinded random specimens of normal endometrium, hyperplasias, and carcinoma were reviewed by 2 pathologists, with review by a third pathologist in cases with disagreement.

All cases of endometrial hyperplasia or carcinoma were scored for degree of glandular crowding, architectural complexity, and cytologic atypia. Sample adequacy, hyperplasia volume, presence of metaplasia, or endometrial polyp were also scored. The overall kappa for agreement was 0.71, with a lower kappa of 0.36 when cases called "no hyperplasia" were excluded. The percent specific agreement was 90.3% for no hyperplasia, 31.1% for simple hyperplasia, 51.1% for complex hyperplasia, 49.8% for atypical hyperplasia, and 57.5% for adenocarcinoma. Cases categorized as "low volume hyperplasia" had more diagnostic disagreement than "high volume," (62% vs. 39%, P=0.003). Similarly, cases called "scant" had more diagnostic disagreement than "not scant" (65% vs. 57%, P=0.013).

The histologic feature associated with the most diagnostic disagreement was cytologic atypia (P<0.0001). Architectural crowding, architectural complexity, or the presence of a polyp were all associated with diagnostic disagreement (P<0.0001).

High diagnostic disagreement in endometrial hyperplasia is related to both sample adequacy and interpretation of histologic features present. Although obtaining additional tissue may increase diagnostic reproducibility, differences in interpretation of key histologic features like cytologic atypia remain major factors contributing to diagnostic disagreement.

Prospective Multicenter Evaluation of the Morphometric D-Score for Prediction of the Outcome of Endometrial Hyperplasias

Jan P. A. Baak, M.D., Ph.D.; Anne Ørbo, M.D., Ph.D.; Paul J. van Diest, M.D., Ph.D.; Mehdi Jiwa, M.D., Ph.D.; Peter de Bruin, M.D., Ph.D.; Marc Broeckaert, B.Sc.; Wim Snijders, M.D.; P. Jan Boodt, M.D., Ph.D.; Guus Fons, M.D.; Curt Burger, M.D., Ph.D.; Renee H. M. Verheijen, M.D., Ph.D.; Paul W. H. Houben, M.D., Ph.D.; H. Sien The, M.D., Ph.D.; Peter Kenemans, M.D., Ph.D.

From the Departments of Pathology (J.P.A.B., P.J.v.D., M.B.) and Gynecology (C.B., R.H.M.V., P.K.), Free University Medical Center, Amsterdam; the Departments of Pathology (J.P.A.B., M.J., P.d.B.) and Gynecology (W.S., P.J.B., G.F.), Medical Center Alkmaar, Alkmaar; the Department of Gynecology (P.W.H.H., H.S.T.), Gemini Hospital, Den Helder, The Netherlands; and the Department of Pathology (A.O.), Institute of Medical Biology, University of Tromsø, 9037 Tromsø, Norway

Am J Surg Pathol 2001;25:930-935 Abstract quote

Prospective multicenter evaluation of the WHO classification and the morphometric D-score to predict endometrial hyperplasia cancer progression. In 132 endometrial hyperplasias WHO classification was performed by two experienced gynecologic pathologists. The D-score was assessed blindly by technicians in a routine diagnostic setting. Development of endometrial carcinoma during a 1–10-year follow-up was used as the end point. Eleven of 132 patients (8%), 10 of 61 (16%) atypical hyperplasias, and 1 of 71 (1%) nonatypical hyperplasias developed cancer. Twenty-six curettings had a D-score 0 (``unfavorable'' or endometrial intraepithelial neoplasia) of which 10 (38%) developed cancer. None of the 86 cases with a D-score >1 (``favorable'') and one of the 20 (5%) cases with 0 < D-score 1 (``uncertain'') developed cancer. Sensitivity of the D-score was 100%, specificity 82%, the positive and negative predictive values were 38% and 100%, respectively. These values are similar to those in three prior retrospective D-score studies but higher than the WHO values (which are 91%, 58%, 16%, and 99%, respectively).

The D-score in endometrial hyperplasias is a more sensitive and specific marker for cancer prediction than the WHO classification, can be assessed in a routine clinical setting on standard hematoxylin and eosin sections (15–30 minutes per case), and is highly reproducible and cost-effective (U.S. $50 per case).

Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial hyperplasia.

Clark TJ, Mann CH, Shah N, Khan KS, Song F, Gupta JK.

Academic Department of Obstetrics & Gynaecology, Birmingham Women's Hospital, Birmingham B15 2TG, U.K

Acta Obstet Gynecol Scand 2001 Sep;80(9):784-93 Abstract quote

BACKGROUND: To determine the accuracy of outpatient endometrial biopsy in diagnosing endometrial hyperplasia in women with abnormal uterine bleeding. DESIGN: Systematic quantitative review of published medical literature.

DATA SOURCES: Relevant papers were identified through electronic scanning of MEDLINE (1980-1999) and EMBASE (1980-1999), manual searching of bibliography of known primary and review articles and contact with manufacturers.

REVIEW METHODS: Studies were selected if accuracy of outpatient endometrial biopsy, in women with abnormal pre or postmenopausal uterine bleeding, was estimated compared to a reference standard, which was endometrial histology obtained by tissue sampling under anesthesia. Quality assessment and data extraction were performed in duplicate. Diagnostic accuracy was determined by pooled likelihood ratios (LR) for positive and negative test results for endometrial hyperplasia.

RESULTS: There were 881 subjects in 8 diagnostic evaluations reported in 6 primary studies. Postmenopausal women represented 25% of the participants studied. There were 43 patients in whom outpatient sampling was inadequate. A positive test result on outpatient biopsy diagnosed endometrial hyperplasia with a pooled LR of 12.0 (95% CI 7.8-18.6) while a negative test result had a pooled LR of 0.2 (95% CI 0.1-0.3). With a positive test result, the posttest probability of endometrial hyperplasia was 57.7% (95% CI 41.1%-72.7%) while it was 2.2% (95% CI 0.9%-4.1%) with a negative test.

CONCLUSION: Outpatient endometrial biopsy has modest accuracy in diagnosing endometrial hyperplasia. Therefore, additional endometrial assessment should be undertaken, especially if symptoms persist or intrauterine structural abnormalities are suspected.

Simple Increase in the glandular and stromal components with slight architectural abnormalities
Complex Crowded glands with little intervening stroma
Back to back glands and papillary intraluminal infoldings

Simple and Complex Hyperplastic Papillary Proliferations of the Endometrium A Clinicopathologic Study of Nine Cases of Apparently Localized Papillary Lesions With Fibrovascular Stromal Cores and Epithelial Metaplasia

Michael B. Lehman, M.D. ; William R. Hart, M.D.

From the Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine, Cleveland Clinic Foundation, Cleveland, Ohio, U.S.A.

Am J Surg Pathol 2001;25:1347-1354 Abstract quote

The clinicopathologic features of nine cases of papillary proliferation of the endometrium devoid of malignant nuclear features were studied.

The patients ranged in age from 33 to 71 years (median 57 years). All were postmenopausal, except the youngest. The most common symptom was postmenopausal bleeding. Two patients were receiving hormonal replacement therapy and two were taking megestrol acetate. Two lesions were incidental findings in a hysterectomy specimen. Seven were diagnosed in endometrial biopsy or curettage specimens. In six cases (67%) the lesion involved an endometrial polyp.

In all cases the papillae had fibrovascular stromal cores and variable degrees of branching. Two architectural patterns were found.

A simple papillary pattern with involvement of only a few glands and little epithelial proliferation occurred in five cases, including three that were entirely intracystic.

A complex papillary pattern with more extensive involvement of endometrial glands, a greater degree of branching of the papillae, and cellular tufting occurred in four cases. One or more metaplastic epithelial changes occurred in all cases, including endocervical-type mucinous metaplasia in nine cases (90%), eosinophilic cell change in eight (89%), ciliated cell change in seven (70%), focal squamous metaplasia in two cases (22%), and hobnail cell change in two (22%). Mitotic figures were found in three cases. In four lesions (44%), all with a complex papillary pattern, the proliferating cells had mild nuclear atypia. Three of these patients underwent hysterectomy within 5 months. Simple nonpapillary hyperplasia and two endometrial polyps were found in one patient, complex nonpapillary hyperplasia in one, and atrophic endometrium in the other. Two patients had additional endometrial samplings within 4 months that contained small residual simple papillary lesions. One of these had another biopsy at 16 months that showed only atrophy. One patient had no subsequent diagnostic or therapeutic procedures. One patient was a recent case. Of the three patients with intact uteri and appreciable follow-up, all were alive and well at 14, 96, and 102 months, respectively.

We conclude that these papillary proliferations are a form of hyperplasia that is closely associated with endometrial epithelial metaplasia. Polypectomy and/or curettage may be effective in removing them because they often are localized lesions. Although all of our patients had an uneventful outcome, the number of cases is small. Our findings question the validity of diagnosing endometrial lesions as well-differentiated carcinoma solely because of a complex papillary architectural pattern.


Tenascin Expression in Normal, Hyperplastic, and Neoplastic Endometrium

Murat edele, M.D.; eyda Karaveli, M.D.; Hadice Elif Petereli, M.D.; Tayyup imek, M.D.; Gökbay Elpek, M.D.; Mine Üner, M.D.; Canan Figen Sargin

From the Department of Pathology (M..), Antalya State Hospital; and the Departments of Pathology (.K., H.E.P.), Obstetrics and Gynaecology (T.., G.E., M.U.), and Biology (C.F.S.), School of Medicine, Akdeniz University, Antalya, Turkey.


Int J Gynecol Pathol 2002;21:161-166 Abstract quote

Tenascin (TN) is an extracellular matrix glycoprotein (ECM) that participates in embryogenesis and carcinogenesis.

The aim of this study was to investigate immunohistochemically the expression of TN in the normal, hyperplastic, and neoplastic endometrium (endometrial adenocarcinoma). In the adenocarcinomas, the results were correlated with patient age, menopausal status, stage, grade, myometrial invasion, and vascular invasion. TN expression was studied in the following cases: proliferative endometrium (10 cases), early secretory endometrium (10), secretory endometrium (10), simple hyperplasia (15), complex hyperplasia (15), atypical hyperplasia (15), and endometrial adenocarcinomas (25). Staining of basal membranes and the cytoplasm of the stromal and epithelial cells was evaluated semiquantitatively. Positive staining was observed in the vascular and glandular basal membranes, stromal cells, and epithelial cells of proliferative, hyperplastic, and neoplastic endometrium. The difference in percentage of stained stromal cells between the neoplastic and the nonneoplastic (proliferative and hyperplastic) endometrium was significant (p<0.005). However, the percentage of stained epithelial cell area in hyperplasia was significantly higher than that of adenocarcinoma and functional endometrium (p<0.005).

We conclude that TN is an extracellular matrix glycoprotein that plays a role in proliferation and possibly endometrial carcinogenesis.


Well differentiated carcinoma vs. endometrial hyperplasia For a diagnosis of carcinoma, must show stromal invasion-criteria for invasion as follows:
Irregular infiltration of glands associated with desmoplastic stroma
Confluent glandular pattern without intervening stroma
Extensive papillary pattern
Other Criteria
High architectural index in >/=30%
Labrinthine pattern
Exophytic coarse papillary pattern
Exophytic fine papillary pattern
Grade 3 nuclear pleomorphism
Grade 3 nucleolar prominence


Prognostic Factors

Cytologic atypia is one of the most important histological predictors of progression to carcinoma


Without cytologic atypia
<2% progress to carcinoma
With cytologic atypia
23% progress to carcinoma

Computerized Image Analysis of p53 and Proliferating Cell Nuclear Antigen Expression in Benign, Hyperplastic, and Malignant Endometrium

Ahmed S. Elhafey, MD, John C. Papadimitriou, MD, PhD, Mohamed S. El-Hakim, MD, Ahmed I. El-Said, MD, Bahaa B. Ghannam, MD, and Steven G. Silverberg, MD

From the Department of Pathology, University of Maryland Medical System, Baltimore, Md (Drs Elhafey, Papadimitriou, and Silverberg); and Faculty of Medicine, Al Azhar University, Cairo, Egypt (Drs El-Hakim, El-Said, and Ghannam).

Arch Pathol Lab Med 2001;125, No. 7: 872–879 Abstract quote

Context.—The endometrium is an intrinsically dynamic tissue with great capability for regeneration and proliferation; consequently, there is some overlap between features seen in benign, premalignant, and malignant lesions. This leads to marked intrabiopsy, interbiopsy, and interobserver variability.

Objective.—We studied the specificity and sensitivity of computerized image analysis of molecular markers to evaluate its potential use as a diagnostic tool.

Design.—Specimens from 100 patients were examined and the following histologic diagnoses were assigned: proliferative endometrium (n = 10), secretory endometrium (n = 10), endometrial hyperplasia (n = 40; 30 with no atypia, 10 with atypia), and carcinoma (n = 40; 20 endometrioid, 10 serous, and 10 clear cell). All cases were evaluated immunohistochemically for p53 and proliferating cell nuclear antigen (PCNA) expression. Computerized image analysis was performed with a CAS 200 digital analyzer.

Results.—Expression of p53 was found only in carcinomas (65%) and endometrial hyperplasia with atypia (30%). Expression of p53 was higher in the poor prognostic categories (serous carcinoma and clear cell carcinoma) than in endometrioid carcinoma. In endometrioid carcinoma, p53 expression correlated with grade. Proliferating cell nuclear antigen showed a similar pattern of results to p53 in the various carcinoma subtypes and endometrioid carcinoma grades. Endometrial hyperplasia PCNA values were the lowest among all the groups. Both carcinomas and proliferative endometrium showed higher glandular and stromal PCNA values, significantly different from endometrial hyperplasia with atypia. In proliferative endometrium, stromal PCNA was the highest among all of the groups. The p53 and PCNA results correlated with each other for carcinoma.

Conclusions.—Computerized image analysis correlates well with the established morphologic groups of endometrial pathology and yields results consistent with previous studies. Owing to its higher degree of sensitivity, computerized image analysis is of potential use in cases of diagnostic dilemmas and can help objectively allocate the case in the correct category (eg, proliferative endometrium vs endometrial hyperplasia, endometrial hyperplasia with atypia vs endometrioid carcinoma). It is particularly useful in the evaluation of stromal changes.


Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40.

Randall TC, Kurman RJ.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Obstet Gynecol 1997 Sep;90(3):434-40 Abstract quote

OBJECTIVE: To determine the efficacy of conservative management of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40.

METHODS: Pathology records were searched to identify women under age 40 diagnosed with atypical hyperplasia or well-differentiated carcinoma of the endometrium between January 1990 and January 1996. All available biopsy, curettage, and hysterectomy specimens were reviewed. Follow-up was obtained from the patients' gynecologists.

RESULTS: Sixty-seven records were identified. Atypical hyperplasia was found in 32 patients and well-differentiated carcinoma in 35 patients. Seven patients were excluded from analysis; four declined all treatment and follow-up, and three received no further treatment or tissue sampling from their physicians. Among 27 remaining patients with atypical hyperplasia, eight underwent hysterectomy, two were treated with ovulation induction, and 17 were treated with progestins, of whom 16 had regression of their lesions, and one had a persistent lesion. Among 33 women with well-differentiated carcinoma, 19 underwent hysterectomy, one was treated with bromocriptine, one was treated with oral contraceptives, and 12 were treated with progestins, of whom nine had regression of their lesions and three had persistent lesions. The median length of treatment required for a regression was 9 months. At a mean follow-up of 40 months, all patients were alive and well without evidence of progressive disease. Twenty-five women attempted to become pregnant, and five delivered healthy, full-term infants.

CONCLUSION: Treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium with progestins appears to be a safe alternative to hysterectomy in women under age 40.

Atypical endometrial hyperplasia treatment with progestogens and gonadotropin-releasing hormone analogues: long-term follow-up.

Perez-Medina T, Bajo J, Folgueira G, Haya J, Ortega P.

Department of Obstetrics and Gynecology, Department of Pathology, Getafe University Hospital, Getafe, Madrid, Spain.

Gynecol Oncol 1999 May;73(2):299-304 Abstract quote

OBJECTIVE: The aim of this study was to assess the long-term effect of gonadotropin-releasing hormone analogues (GnRH-a) in combination with high-dose progestogens in the treatment of atypical endometrial hyperplasia in selected surgical high-risk patients and in women desiring reproductive potential. We hypothesized that this therapy is effective for most couples.

METHODS: In the Department of Gynecology of a university hospital, a conservative treatment was offered to a series of 22 patients with atypical endometrial hyperplasia who had a surgical or anesthetic risk history or wished to preserve their fertility potential. After informed consent, they were treated with 500 mg norethisterone acetate weekly for 3 months and 3.75 mg Triptorelin depot every month for 6 months. Three patients failed to complete the study, so the group finally consisted of 19 subjects. They were prospectively followed for 5 years by hysteroscopy and multiple selected biopsies every 6 months.

RESULTS: At a 5-year follow-up, regression was noted in 16 patients (84.2%), persistence in 1 (5.1%), recurrence in 1 (5.1%), and progression in 1 (5.1%).

CONCLUSION: Consistent with our hypothesis, combined treatment with progestogens and GnRH-a is an effective alternative in selected patients with atypical endometrial hyperplasia.

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