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Endometrial carcinoma is cancer of the uterus, arising from the endometrial lining. It most commonly presents with irregular vaginal bleeding.


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SYNONYMS Uterine carcinoma, endometrial adenocarcinoma of the uterus, endometrioid adenocarcinomas
INCIDENCE 7% of all invasive cancer in women
5th leading cause of cancer in women
34,000 new cases/year in USA
150,000 new cases/year worldwide
4000 deaths/years
55-65 years
GEOGRAPHIC DISTRIBUTION Worldwide but higher in industrialized countries


Diabetes Abnormal glucose tolerance in >60%
Infertility More common in single and nulliparous women with history of menstrual irregularities
Endometrioid Carcinoma Simultaneously Involving the Uterus and the Fallopian Tube: A Clinicopathologic Study of 13 Cases.

Culton LK, Deavers MT, Silva EG, Liu J, Malpica A.

*Department of Pathology, The University of Texas Medical School at Houston, Houston, TX daggerDepartment of Pathology and Laboratory Medicine, M.D. Anderson Cancer Center, The University of Texas, Houston, TX.

Am J Surg Pathol. 2006 Jul;30(7):844-849. Abstract quote  

Although the simultaneous presentation of endometrial and ovarian carcinomas of the endometrioid type is well described, little is known about a similar phenomenon involving the endometrium and fallopian tube (FT).

We present the clinicopathologic features of 13 such cases seen in the Department of Pathology at The University of Texas M.D. Anderson Cancer Center over an 8 year period (1995 to 2002). FT tumors that could have represented luminal extension of the endometrial carcinoma or that represented an unequivocal metastasis to the FT were excluded. The patients' ages ranged from 34 to 77 years (median 54). The most common symptom was abnormal uterine/vaginal bleeding (11) and all of the patients were considered overweight or obese (mean body mass index was 41). The size of the endometrial carcinomas ranged from 0.3 to 8 cm. According to the FIGO grading of the endometrial endometrioid carcinomas, the cases were distributed as follows: Grade 1 (3) and Grade 2 (10). In 2 cases, there were also small areas of other histologic types, papillary serous carcinoma (1 case), and papillary endometrial carcinoma of intermediate grade (another case). The size of the fallopian tube carcinomas ranged from 0.2 to 17.5 cm. Seven of these tumors were located in the distal/fimbriated end of the FT. There was bilateral involvement in 2 cases. Three of the FT tumors were in situ. The grades of the fallopian tube carcinomas were as follows: Grade 1 (2), Grade 2 (6), and Grade 3 (2). In situ components were seen in all cases. One fallopian tube carcinoma was mixed with serous carcinoma. In 4 cases, there was also an endometrioid carcinoma involving the ovary, all of them with an intact ovarian capsule.

Patients were treated as follows: total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) (4), TAH/BSO/chemotherapy (chemo) (4), TAH/BSO/radiation (3), and TAH/BSO/chemo/radiation (2). Follow-up ranging from 6 to 54 months was available in 10 patients: 1 patient died of disease (at 38 mo), 1 patient is alive with disease (at 9 mo), 7 patients have no evidence of disease (6 to 54 mo), and 1 patient died of metastatic endometrial carcinoma (at 9 mo). Simultaneous endometrioid carcinomas of the uterus and FT are unusual and occur primarily in obese perimenopausal women.

The tumors are predominantly well or moderately differentiated with dissimilar endometrial and FT grades. The FT carcinoma is usually unilateral and located at the distal end of the tube.

Peritoneal keratin granulomas with carcinomas of endometrium and ovary and atypical polypoid adenomyoma of endometrium. A clinicopathological analysis of 22 cases.

Kim KR, Scully RE.

Department of Pathology, Harvard Medical School, Boston, Massachusetts

Am J Surg Pathol 1990 Oct;14(10):925-32 Abstract quote

Twenty-two cases of keratin granulomas of the peritoneum associated with endometrioid adenocarcinoma with squamous differentiation of the endometrium, the ovary, or both, and with an atypical polypoid adenomyoma of the endometrium were reviewed.

Follow-up data were available in 18 cases. Twelve patients were well and disease free 13 months to 15.2 years postoperatively; one patient died of unrelated disease 21 years postoperatively; three patients were tumor free with a short duration of follow-up; one patient, who had a stage Ic ovarian tumor, died of pulmonary embolism during the treatment of recurrent tumor 1 year after operation; and a final patient, who had been followed for 3 months after operation for stage IV disease, was alive with residual tumor. At least six patients with stage I carcinomas were treated with postoperative irradiation because the granulomas had raised a suspicion of advanced disease.

Follow-up data on the patients in this series suggest that peritoneal keratin granulomas have no prognostic significance and should be distinguished from viable tumor implants on microscopic examination.


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.

Apoptosis and apoptosis-associated parameters in relation to tamoxifen exposure in postmenopausal endometrium.

Mourits MJ, Hollema H, De Vries EG, Ten Hoor KA, Willemse PH, Van Der Zee AG.

Department of Obstetrics and Gynecology, University Hospital Groningen, The Netherlands.


Hum Pathol 2002 Mar;33(3):341-6 Abstract quote

Tamoxifen increases endometrial cell proliferation and the incidence of endometrial cancer in postmenopausal women.

The purpose of this study was to evaluate apoptosis and apoptosis-related factors in endometrium in relation to tamoxifen exposure. We analyzed benign postmenopausal endometrium from breast cancer patients receiving tamoxifen (n = 35) and from controls (n = 24), and endometrial cancer tissue from tamoxifen-treated breast cancer patients (n = 15) and endometrial cancer from women without tamoxifen exposure (n = 51). Apoptosis was examined morphologically, and the percentage of apoptotic epithelial cells was defined as the apoptotic index.

In the benign samples, the presence of apoptotic cells was also evaluated immunohistochemically by the expression of caspase-3 and the monoclonal antibody M30. The expression of Fas, FasL, and Bcl-2 was analyzed in all tissue samples. No differences were observed in the mean apoptotic index in benign endometrium in tamoxifen users (0.17%) versus controls (0.08%), or in tamoxifen-exposed (2.46%) versus nonexposed endometrial cancer (2.28%). However, the ratio of the apoptotic index with the previously reported proliferation index was lower in benign endometrium from tamoxifen users than in controls (0.02 +/- 0.026 vs. 0.05 +/- 0.03, Mann-Whitney U <0.005). In benign endometrium FasL was more frequently expressed in tamoxifen-users than in controls (chi(2) <0.05).

We conclude that the apoptosis/proliferation ratio in benign endometrium from tamoxifen users is lower than in controls, indicating that the tamoxifen-induced higher proliferation is not compensated for by increased apoptosis. An imbalance between cell proliferation and apoptosis, and possibly suppression of the antitumor immune response by FasL overexpression in tamoxifen-exposed endometrium might play a role in the development of endometrial cancer in tamoxifen users.


Two types of endometrial carcinoma  
Prolonged estrogen stimulation and endometrial hyperplasia
Linked to obesity and anovulatory cycles
Women with ovarian estrogen-secreting tumors
CA is rare in women with ovarian agenesis or castrated in early life
Estrogen replacement therapy associated with increased risk
Postmenopausal women have greater synthesis of estrogens in body fat from adrenal and ovarian androgen precursors
Minimal myometrial invasion
Atypical hyperplasia was distributed equally among all grades of cancer and present in 40% of cases
Second type unrelated to hyperestrinism or hyperplasia

Usually older age on onset
Tumors are usually poorly differentiated such as serous papillary carcinoma of the uterus
Linked to p53 overexpression
Deep myometrial invasion


Cellular apoptosis susceptibility gene expression in endometrial carcinoma: correlation with Bcl-2, Bax, and caspase-3 expression and outcome.

Peiro G, Diebold J, Baretton GB, Kimmig R, Lohrs U.

Institute of Pathology, Klinikum Grosshadern, Ludwig-Maximilians University Munich, Munchen, Germany.


Int J Gynecol Pathol 2001 Oct;20(4):359-67 Abstract quote

Deregulation of proliferation and apoptosis is known to contribute to neoplastic transformation and growth. Using specific antibodies for the cellular apoptosis susceptibility (CAS) gene, caspase-3, Bcl-2, and Bax, we examined the protein expression in 89 endometrial carcinomas and in 56 samples of nonneoplastic adjacent endometrium for comparison.

Immunostaining results were scored with regard to approximate percentage of positive tumor cells (< 10%, 10% to 50%, > 50%) and relative immunostaining intensity (1+, 2+, 3+). In nonneoplastic endometrium, CAS protein was expressed in 70.6%, Bax in 64%, caspase-3 in 52%, and Bcl-2 in 87%. In neoplastic tissue, CAS was present in 93% of the tumors, Bax in 88%, caspase-3 in 77%, and Bcl-2 in 51%. Bcl-2:Bax ratio was > 1 in 9 cases (10%).

In cases of atrophy (n = 24) and simple (n = 10) and complex (n = 22) hyperplasia in the adjacent endometrium, lower levels of expression compared with carcinoma were observed for CAS (p = 0.003), caspase-3 (p = 0.034), and Bax (p = 0.04) and higher levels for Bcl-2, although for this protein the results were not statistically significant (p = 0.32). There was no association between immunoscores and FIGO stage. High caspase-3 levels were seen in endometrioid tumor type (p = 0.017). CAS expression was higher in grade 3 tumors (p = 0.002) and older patients (p = 0.013). All tumors of younger patients (< 50 years) were Bcl-2 negative (p = 0.037). Caspase-3 correlated positively with CAS (p = 0.008), Bax (p = 0.04), and low Bcl-2:Bax ratio (p = 0.043), and inversely (as a trend) with Bcl-2 (p = 0.056). Survival analysis (Kaplan-Meier and Cox regression) established a strong association between prognosis and stage, grade, and histologic type (all p < or = 0.0036).

In addition, shorter survival was observed for patients whose tumors contained > 50% of positive cells for caspase-3 (p = 0.024) or for CAS (p = 0.04). Age, Bcl-2, Bax, and Bcl-2:Bax ratio did not provide prognostic information. Our results suggest a role of CAS, Bcl-2, Bax, and caspase-3, which are apparently involved in the progressive deregulation of proliferation and apoptosis leading from simple and complex hyperplasia to carcinoma. In addition, CAS and caspase-3 protein levels may be useful markers in predicting the outcome of the patients.


CTNNB1 mutations and beta-catenin expression in endometrial carcinomas.

Machin P, Catasus L, Pons C, Munoz J, Matias-Guiu X, Prat J.

Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.


Hum Pathol 2002 Feb;33(2):206-12 Abstract quote

Mutations in the beta-catenin gene (CTNNB 1) with abnormal nuclear accumulation of beta-catenin have recently been identified in endometrial carcinoma (EC). Their relationship with microsatellite instability (MI) is unclear.

It has been suggested that matrix metalloproteinase-7 (MMP-7) and cyclin D1 (cD) genes are targets for beta-catenin activation. DNA from 73 patients with EC was obtained from tumor and normal tissue (59 endometrioid and 14 nonendometrioid). CTNNB 1 mutations in exon 3 were assessed by single-strand conformation polymorphism and DNA sequencing. The results were correlated with immunostaining for beta-catenin, MMP-7, and cD. Three (CA)n repeats and mononucleotide tracts BAT 25 and BAT 26 had been previously used for MI analysis. CTNNB1 mutations were identified in 15 ECs (20.5%), all of them endometrioid carcinomas (15 of 59; 25.4%). They occurred in 6 of 19 MI-positive ECs (31.5%) and in 9 of 54 MI-negative ECs (16.6%). Eleven of the 15 CTNNB 1-mutated ECs showed beta-catenin nuclear immunostaining (P <.05). MMP-7 expression (>50% cells) was observed in 23 ECs, with 7 of these showing CTNNB 1 mutations. Significant expression of cD (>50% cells) was detected in 8 ECs, with 5 of these exhibiting CTNNB 1 mutations (P <.05).

The results confirm that beta-catenin plays a role in endometrial carcinogenesis, particularly in endometrioid carcinomas. The results also suggest that MMP-7 and particularly cD may be targets of beta-catenin activation in ECs.

beta-Catenin and E-Cadherin Expression Patterns in High-Grade Endometrial Carcinoma Are Associated with Histological Subtype.

Schlosshauer PW, Ellenson LH, Soslow RA.

Department of Pathology, Weill Medical College of Cornell University, New York, New York.

Mod Pathol 2002 Oct;15(10):1032-7 Abstract quote

Both beta-catenin and E-cadherin are epithelial cell adhesion molecules. In addition, beta-catenin is an important element of the Wnt signal transduction pathway, which has been implicated in embryogenesis and carcinogenesis, including the development of endometrial and ovarian endometrioid carcinomas.

We hypothesized that the expression pattern of these two adhesion molecules may depend upon the histological subtype of endometrial carcinomas. Therefore, we compared the immunohistochemical expression of beta-catenin and E-cadherin in a set of uterine adenocarcinomas matched for high histologic grade, that is, poorly differentiated (International Federation of Gynecology and Obstetrics [FIGO] Grade III) uterine endometrioid carcinomas and uterine serous carcinomas. Seventeen FIGO Grade III endometrioid adenocarcinomas and 17 serous carcinomas were evaluated histologically and immunohistochemically with commercially available monoclonal antibodies against beta-catenin and E-cadherin. Nuclear expression of beta-catenin was observed in 8 of 17 (47%) endometrioid adenocarcinomas but in none of the serous carcinomas (P =.003). Moderate or strong E-cadherin expression was identified in 7 of 17 (41%) serous carcinomas as opposed to in only 1 of 17 (6%) endometrioid adenocarcinomas (P =.02).

The majority of endometrioid adenocarcinomas showed strong beta-catenin expression coupled with weak E-cadherin expression; serous carcinomas did not exhibit a comparable trend.

Our results indicate that the expression of beta-catenin and E-cadherin in high-grade endometrial cancers is strongly associated with histological subtype. These data provide further support for the distinct molecular profiles of endometrioid adenocarcinoma and serous carcinoma. Notably, differences in cell adhesion molecule expression could account for variations in patterns of tumor dissemination. The immunohistochemical staining pattern may also be useful for diagnostic purposes.

Expression of COX-2, Ki-67, Cyclin D1, and P21 in Endometrial Endometrioid Carcinomas

Q. Jackie Cao, M.D., Ph.D.; Mark H. Einstein, M.D.; Patrick S. Anderson, M.D.; Carolyn D. Runowicz, M.D.; Raluca Balan, M.D.; Joan G. Jones, M.D.

From the Departments of Pathology (Q.J.C., R.B., J.G.J.), and the Department of Obstetrics & Gynecology and Women's Health (M.H.E., P.S.A., C.D.R.), Albert Einstein College of Medicine and Jack D. Weiler Hospital of Montefiore Medical Center, Bronx, New York.


Int J Gyn Pathol 2002;21:147-154 Abstract quote

COX-2, the isoform of cyclooxygenase inducible by cytokines, mitogens, and growth factors, appears to play an important role in inflammation and carcinogenesis. In the colon, COX-2 overexpression results in cell cycle alterations, and NSAIDs have proven effective in cancer chemoprevention. HNPCC (hereditary nonpolyposis colon cancer) is a clinically defined cancer susceptibility syndrome in which women are also at significantly increased risk for the development of endometrial carcinoma.

The purpose of this study was to evaluate expression of COX-2 in benign and malignant endometrium in the context of other cell cycle and proliferation markers, including Ki-67, cyclin D1, and the cyclin-dependent kinase inhibitor, p21. Immunostains with COX-2, Ki-67, cyclin D1, and p21 antibodies were performed on formalin-fixed and paraffin-embedded tissue sections from 40 cases: 10 benign (5 atrophic and 5 proliferative) endometria, 6 hyperplasias (complex without atypia), and 24 endometrioid carcinomas (9 well, 4 moderately, and 11 poorly differentiated). Ki-67 was positive in all proliferative and neoplastic endometria. Cyclin D1 and p21 were both overexpressed in endometrial hyperplasia and endometrioid carcinomas. COX-2 was negative in the nonneoplastic endometrium, stained minimally in the well-differentiated endometrioid carcinomas, and stained most strongly in the moderately and poorly differentiated endometrioid carcinomas. Because cyclin D1 may function as an oncogene, its effects may dominate the usual inhibitory effect of a rising p21. Alternatively, it has been shown that p21 can promote cell cycle function by stabilizing cell cycle complexes.

The overexpression of COX-2 in poorly differentiated endometrioid carcinoma and lack of expression in hyperplasia and well-differentiated carcinoma suggests that in this form of cancer, COX-2 may play a role in tumor progression rather than tumor initiation.

Cyclooxygenase-2 expression in endometrial cancer: Correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase.

Fujiwaki R, Iida K, Kanasaki H, Ozaki T, Hata K, Miyazaki K.

Department of Obstetrics and Gynecology, Shimane Medical University, Izumo, Japan.

Hum Pathol 2002 Feb;33(2):213-9 Abstract quote

Cyclooxygenase-2 (COX-2), known to be elevated in several human cancers, regulates angiogenesis by inducing production of angiogenic factors. These mechanisms require clarification in endometrial cancer. COX-2 expression was examined by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR) in endometrial cancer, endometrial hyperplasia, and normal endometrium in various phases.

We investigated the relationship between COX-2 expression and clinicopathologic variables, microvessel count, and expression of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). Immunohistochemistry demonstrated COX-2 protein in cancerous epithelial cells but not in stromal cells. COX-2 expression in epithelial cells was significantly greater in endometrial cancer (n = 63) and endometrial hyperplasia (n = 6) than in normal endometrium in any phase (n = 53). Although COX-2 did not correlate with any conventional clinicopathologic factor in patients with endometrial cancer, COX-2 expression was associated with high microvessel count, VEGF expression, and TP expression. By combined analysis of COX-2, VEGF, and TP, tumors with high expression of at least one factor had a significantly higher microvessel count than tumors expressing little of the three factors.

We confirmed upregulation of COX-2 mRNA expression by RT-PCR in endometrial cancer (n = 17) compared to normal endometrium (n = 12). COX-2 mRNA expression significantly correlated with VEGF mRNA expression in these tumors. COX-2 is upregulated in endometrial cancer and facilitates tumor growth via angiogenesis produced in associated with VEGF and TP. Specific inhibition of COX-2 may be a useful therapeutic intervention in endometrial cancer.

Insulin-like Growth Factor-I Receptor and PTEN Protein Expression in Endometrial Carcinoma
Correlation With bax and bcl-2 Expression, Microsatellite Instability Status, and Outcome

Gloria Peiró, MD,1 Peter Lohse, MD,2 Doris Mayr, MD,1 and Joachim Diebold, MD

Am J Clin Pathol 2003;120:78-85 Abstract quote

We immunohistochemically analyzed 89 endometrial carcinomas for insulin-like growth factor-I receptor (IGF-IR) and PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression. Results were compared with clinicopathologic factors, bcl-2 and bax expression, microsatellite instability (MSI) status, and prognosis. Increased expression of IGF-IR and bcl-2 (>50% cells) was seen in 60 cases (67%) and 15 cases (17%), respectively; loss of PTEN was seen in 13 cases (15%) and of bax in 11 cases (12%).

No significant correlation was observed between the proteins or with clinicopathologic factors. Loss of PTEN was more frequent in MSI-positive tumors (4/10 [40%]) than in negative tumors (9/79 [11%]; P = .016). Longer survival was observed for patients with endometrioid tumors, International Federation of Gynecology and Obstetrics stage I or II tumors, grade 1 tumors, superficial myometrial infiltration (£50%), less than 5% necrosis, no vascular invasion, or low level IGF-IR (<10% of cells) (P £ .05). Cox analysis showed independent value only for stage, grade, type, and lymph-vascular invasion (P < .05).

Our data demonstrate that IGF-IR overexpression occurs in a subset of endometrioid carcinomas, which has potential prognostic value, while loss of PTEN often is associated with the MSI phenotype.

Association of Mismatch Repair Deficiency With PTEN Frameshift Mutations in Endometrial Cancers and the Precursors in a Japanese Population

Taro Kanaya, MD, PhD, Satoru Kyo, MD, PhD, Junko Sakaguchi, Yoshiko Maida, MD, PhD, Mitsuhiro Nakamura, MD, PhD, Masahiro Takakura, MD, PhD, Manabu Hashimoto, MD, Yasunari Mizumoto, MD, and Masaki Inoue, MD, PhD
Am J Clin Pathol 2005;124:89-96 Abstract quote

We studied mismatch repair deficiency and PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutations in endometrial cancers and hyperplasias in a Japanese population. Methylation-sensitive restriction enzyme polymerase chain reaction revealed MLH1 hypermethylation in 21 (38%) of 56 endometrial cancers. Sequencing analysis revealed PTEN mutations in 22 patients with cancer (39%) in exons 5 and 8.

A PTEN frameshift mutation was associated significantly with MLH1 hypermethylation (P = .01) and a highly positive phenotype with microsatellite instability (P < .001) but not with a PTEN missense mutation. In hyperplasia, MLH1 hypermethylation was similarly observed (11/27 [41%]), but the PTEN mutation was less frequent (5/27 [19%]), observed only in atypical hyperplasias; among the 5 patients with a PTEN mutation, the 2 patients with frameshift mutations had MLH1 hypermethylation, but the 3 patients with missense mutations had unmethylated MLH1.

These findings indicate that MLH1 hypermethylation is an early event frequently occurring in hyperplasia without atypia, whereas the PTEN mutation occurs later, mostly in atypical hyperplasia, possibly caused by MLH1 hypermethylation.

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.

Occludin expression decreases with the progression of human endometrial carcinoma.

Tobioka H, Isomura H, Kokai Y, Tokunaga Y, Yamaguchi J, Sawada N.

Department of Pathology, Sapporo Medical University School of Medicine, Japan.
Hum Pathol. 2004 Feb;35(2):159-64 Abstract quote.

The tight junctions of the glandular epithelium are crucial for the maintenance of cell polarity, separating the plasma membrane into apical and basolateral domains. Thus abnormalities of the tight junctions may result in the structural disturbances of glandular epithelial neoplasia.

In this study we introduced an anti-occludin monoclonal antibody for semiquantitative assay of the occludin expression in tissue sections of human normal and neoplastic endometrial epithelia using the Adobe Photoshop and NIH Image programs. Normal endometrial glands and samples of endometrial hyperplasia and endometrioid carcinoma grade 1 fully expressed occludin at the apical cell border. In endometrioid carcinomas grades 2 and 3, however, occludin disappeared in solid areas of the carcinomatous tissues. Occludin was also found at the apical borders of the cancer cells that formed glandular structures.

Occludin expression decreased progressively in parallel with the increase in carcinoma grade, and the decreased occludin expression correlated with myometrial invasion and lymph node metastasis.

These results suggest that the loss of tight junctions has a close relationship with structural atypia in the progression of human endometrial carcinomas and their malignant potential.

Relationship between p53 pathway and estrogen receptor status in endometrioid-type endometrial cancer.

Maeda K, Tsuda H, Hashiguchi Y, Yamamoto K, Inoue T, Ishiko O, Ogita S.

Departments of Obstetrics and Gynecology, Osaka City University Graduate School of Medicine, and Departments of Obstetrics and Gynecology and Pathology, Osaka City General Hospital, Osaka 534-0021, Japan.

Hum Pathol 2002 Apr;33(4):386-91 Abstract quote

We analyzed the mechanism of estrogen receptor (ER) loss and status of the p53 pathway in 64 cases of endometrial cancer. 26.6% (17 of 64) of endometrial cancers lost ER. Methylation of the ER CpG island was significantly related to ER status (P = 0.0074). However, the methylation site of the ER CpG island differed between breast and endometrial cancers.

The abnormal expression rate of p14ARF, MDM2, p53, and the p53 pathway were 7.8% (5 of 64), 32.8% (21 of 64), 25.0% (16 of 64) and 53.1% (34 of 64), respectively. There was no significant difference in the overexpression of MDM2 between p53-positive cases (43.8%: 7 of 16) and p53-negative cases (29.2%; 14 of 48) (P = 0.3595). Abnormal p53 was higher in grade 3 tumors (55.6%; 5 of 9) than in grade 1 and 2 tumors (20.0%; 11 of 55) (P = 0.0364). The abnormality of the p53 pathway was higher in grade 3 tumors (88.9%; 8 of 9) than in grade 1 and 2 tumors (47.3%; 26 of 55) (P = 0.0294). However, there was no significant difference in abnormal p53 pathway between ER-negative and ER-positive cases.

In endometrial cancer, ER CpG island methylation was the important mechanism of ER loss. However, there was no significant relationship between the p53 pathway and ER status.


Am J Clin Pathol 2001;115-32-38
Also known as MMAC1 or TEP1
Isolated on the 10q23-24 region

Homology with conserved sequences of protein tyrosine phosphatases and tensin cytoskeletal proteins

Mouse embryos with disruption of this gene have increased cell proliferation and overgrowth of cephalic and caudal regions

PCR sequencing detected mutations in 14/57 carcinomas and 7/73 hyperplasias

Patients with PTEN mutation inactivation may have a better prognosis than those without

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.




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).

Endometrial Adenocarcinoma Associated With Elevated Serum Concentrations of the Free b Subunit of Human Chorionic Gonadotropin

David G. Grenache, PhD, Karen A. Moller, MD, and Pamela M. Groben, MD
Am J Clin Pathol 2004;121:748-753 Abstract quote

We report a case of a histologic grade II endometrial adenocarcinoma without trophoblastic differentiation in a 24-year-old woman with an elevated serum concentration of human chorionic gonadotropin (hCG) and with no evidence of pregnancy. Serum and urine specimens were used to study the hCG immunoreactivity.

Qualitative tests performed on serum and urine using 5 different assays produced conflicting results. The hCG concentration in serum and urine was quantified using assays designed to detect different molecular forms of the molecule; analysis revealed that serum hCG immunoreactivity was due entirely to the presence of the free b subunit. Immunohistochemical analysis performed on tissue samples showed strong cytoplasmic staining for hCG.

While hCG is a well-recognized tumor marker in gynecologic malignant neoplasms, immunoreactivity most often is due to the presence of both intact molecule and the free b subunit. To our knowledge, this is the first report of an endometrial adenocarcinoma producing only the free b subunit of hCG.

Significance of histiocytes in cervical smears from peri/postmenopausal women.

Tambouret R, Bell DA, Centeno BA.

James Homer Wright Laboratories, Massachusetts General Hospital, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02114, USA.

Diagn Cytopathol 2001 Apr;24(4):271-5 Abstract quote

Histiocytes in cervicovaginal smears from peri- or postmenopausal women have been viewed as a potential indicator of endometrial neoplasia, but recent studies have refuted that view.

This study further defines the clinical significance of such findings. All cervical smears were selected from women (< or = 50 yr) in whom the presence of histiocytes was mentioned; pertinent clinical history, follow-up information, and selected slides were reviewed.

Among 105,225 total cervicovaginal smears from a 3.5-yr period, 106 smears from 103 women were identified. Forty-two patients (41%) were on hormone replacement therapy (2 on tamoxifen), and 23 (22.3%) patients experienced vaginal bleeding, all of whom had biopsy or cytology follow-up. Ten (9.6%) patients had no follow-up, 35 (32%) had repeat smears only, and 58 (56.3%) had endometrial/endocervical sampling. In 28 patients, the index smear was categorized as other than within normal limits or benign cellular changes; of these, 24 had subsequent tissue sampling and 4 had cytology follow-up. Of the patients with tissue sampling, 51 (84%) had benign findings (including polyps), 2 (3.5%) had hyperplasia, and 5 (10%) had adenocarcinoma. All 5 patients with adenocarcinoma had endometrial glandular cells on the smear, and 4 had vaginal bleeding. One patient with hyperplasia had vaginal bleeding, and the other was on tamoxifen and had endometrial glandular cells on the smear. None of the patients having only histiocytes on their smears and no clinical symptoms or risk factors had endometrial adenocarcinoma or hyperplasia.

These findings support the conclusion that the presence of histiocytes alone on cervicovaginal smears from peri- or postmenopausal women is nonspecific and of no major clinical significance in the absence of other clinical or cytologic findings.


Value of preoperative CA 125 level in the management of uterine cancer and prediction of clinical outcome.

Sood AK, Buller RE, Burger RA, Dawson JD, Sorosky JI, Berman M.

Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, USA.

Obstet Gynecol 1997 Sep;90(3):441-7 Abstract quote

OBJECTIVE: To enhance cost-effective management of uterine cancer by predicting the likelihood of extrauterine disease and survival on the basis of preoperative parameters.

METHODS: A retrospective review of preoperative CA 125 levels from 210 women with endometrial carcinoma was performed. The relationship of preoperative CA 125 levels to various preoperative and postoperative histopathologic factors was investigated.

RESULTS: Elevated CA 125 (greater than 35 U/mL) correlated (P < .05) with higher stage, higher grade, increased depth of myometrial invasion, positive cytology, pelvic or para-aortic lymph node metastases, and reduced actuarial survival (P < .001). Multivariate analysis of preoperative factors showed that an elevated CA 125 level was the most important predictor for poor survival (P < .001). Moreover, a preoperative CA 125 level greater than 65 U/mL was the most significant predictor of extrauterine disease and carried a 6.5-fold higher risk (95% confidence interval 2.5, 17.1). A logistic model to predict extrauterine disease was developed. The model has a sensitivity of 62%, specificity of 91%, positive predictive value of 69%, and negative predictive value of 88%.

CONCLUSION: A CA 125 level should be included as part of the preoperative workup for all patients with uterine cancer. Patients with a preoperative CA 125 level less than or equal to 20 U/mL should be considered as candidates for vaginal hysterectomy unless unfavorable histology or a high-grade (grade II or III) tumor is present. In our series, this approach would have eliminated 24% of the abdominal staging procedures, with a risk of less than 3% for extrauterine disease, while lowering treatment-related morbidity and cutting costs in the treatment of this common female cancer.

Preoperative CA 125 in endometrial cancer: is it useful?

Dotters DJ.

Sacred Heart Medical Center, Eugene, OR 97405, USA.

Am J Obstet Gynecol 2000 Jun;182(6):1328-34 Abstract quote

OBJECTIVE: We sought to determine the clinical utility of preoperative CA 125 measurement in determining the need for lymphadenectomy in patients with endometrial carcinoma.Study Design: A prospective nonrandomized study was performed over a 2-year period. Patients referred with the diagnosis of endometrial carcinoma had CA 125 levels determined before surgical staging. Operative findings were then correlated with preoperative CA 125 values. Standard statistical calculations were used to determine sensitivity, specificity, positive predictive value, and false-positive and false-negative rates. The Student t test was used to determine differences between mean values.

RESULTS: Either a CA 125 level of >20 U/mL or a grade 3 tumor or both of these correctly predicted 87% of patients requiring surgical staging. In patients with a preoperative diagnosis of stage I, grade 1 or 2 tumors, a CA 125 level of >20 U/mL correctly identified 75% (9/12) of patients requiring lymphadenectomy compared with only 50% (6/12) identified when a CA 125 level of >35 U/mL was used. Two of 16 low-risk patients with preoperative grade 1 tumors and CA 125 levels of <20 U/mL had occult extrauterine disease at surgery.

CONCLUSION: Measurement of preoperative CA 125 is a clinically useful test in endometrial cancer. CA 125 levels of >35 U/mL strongly predicted extrauterine disease but lacked sensitivity in identifying patients needing staging. Either a CA 125 level of >20 U/mL or a grade 3 tumor or both of these correctly identified 75% to 87% of patients requiring lymphadenectomy. Until more data are collected, abdominal hysterectomy should be the procedure of choice for patients with grade 1 tumors and CA 125 levels of <20 U/mL.


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.


General May present as a localized polypoid tumor or diffuse tumor involving the entire surface
Synchronous endometrioid carcinomas of the uterine corpus and ovary: Alterations in the beta-catenin (CTNNB1) pathway are associated with independent primary tumors and favorable prognosis.

Irving JA, Catasus L, Gallardo A, Bussaglia E, Romero M, Matias-Guiu X, Prat J.

Hum Pathol. 2005 Jun;36(6):605-19 Abstract quote.  

Summary Diagnosis of synchronous endometrioid carcinomas of the uterine corpus and ovary as either separate independent primary or as metastatic tumors requires careful consideration of a number of gross and histological features. Although such assessment is often sufficient, recent evidence has suggested that molecular analysis may facilitate the diagnosis in problematic cases. Furthermore, as independent synchronous tumors limited to the uterus and ovary are generally associated with favorable outcome, determination of genetic alterations associated with this group of neoplasms may indicate molecular markers of less aggressive behavior.

We examined 12 cases of synchronous carcinomas of the uterus and ovary, correlating conventional gross and histological parameters with molecular genetic alterations common to single endometrioid carcinomas occurring in these sites.

We identified a frequency of molecular alterations in both independent and metastatic tumors, including microsatellite instability (uterine tumors, 50% and 67%, respectively; ovarian tumors, 33% and 67%) and PTEN mutations (uterine tumors, 38% and 100%; ovarian tumors, 33% and 83%) that is higher than that observed in single sporadic tumors. Loss of heterozygosity for chromosome 17p and 10q was also frequently observed. Nuclear immunoreactivities for beta -catenin and CTNNB1 mutations were restricted to independent uterine and ovarian tumors and were absent in all of the metastatic tumors, providing direct evidence for a divergence of molecular oncogenetic mechanisms in the subset of synchronous endometrioid carcinomas.

Furthermore, our data show that molecular genetic classification of synchronous independent versus metastatic tumors based on beta -catenin expression/mutation correlates with clinical outcome.

Genetics of synchronous uterine and ovarian endometrioid carcinoma: combined analyses of loss of heterozygosity, PTEN mutation, and microsatellite instability.

Fujii H, Matsumoto T, Yoshida M, Furugen Y, Takagaki T, Iwabuchi K, Nakata Y, Takagi Y, Moriya T, Ohtsuji N, Ohtsuji M, Hirose S, Shirai T.

Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.

Hum Pathol 2002 Apr;33(4):421-8 Abstract quote

Synchronous development of carcinomas in the endometrium and ovaries is a fairly common phenomenon, but distinction of a single clonal tumor with metastasis from 2 independent primary tumors may present diagnostic problems.

To determine clonality and the occurrence of progression, we microdissected multiple foci from 17 cases of synchronous endometrioid carcinomas and studied loss of heterozygosity (LOH), microsatellite instability (MI), and PTEN mutations. In 14 of the 17 cases, genetic alterations were either homogeneous or found in only some of the foci. LOH was detected for 10q (4 cases), 17p (2 cases), and 2p, 5q, 6q, 9p, 11q, 13q, and 16q (1 case each). Four cases had the MI phenotype with discordant MI patterns between both tumor sites, thus indicating a biclonal or triple clonal process. In 3 of 6 cases with PTEN mutations, identical mutations in both tumor sites indicated a single clonal neoplasm. Altogether, 14 synchronous tumors were genetically diagnosed as follows: single clonal tumor, characterized by concordant genetic alterations in both tumor sites, including identical LOH, identical PTEN mutations, and/or identical sporadic allelic instability patterns (4 cases); single clonal tumor with genetic progression, homogeneous LOH or identical PTEN mutations in both tumor sites and progressive LOH in ovarian metastatic foci (2 cases); and double (7 cases) or triple clonal tumors (1 case), determined by discordant PTEN mutations, heterogeneous LOH, and/or discordant MI patterns. Thus, 35% of synchronous tumors were monoclonal, 47% were polyclonal, and 18% were undetermined.

The favorable prognosis of synchronous endometrioid carcinomas may be due to the occurrence of PTEN mutations in both independent and metastatic tumors, the MI-positive independent primary tumors, and the low frequency of LOH.




Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial cancer: a systematic quantitative review.

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

Academic Department of Obstetrics and Gynaecology, Birmingham Women's Hospital, UK.

BJOG 2002 Mar;109(3):313-21 Abstract quote

OBJECTIVE: To determine the accuracy of outpatient endometrial biopsy in diagnosing endometrial cancer in women with abnormal uterine bleeding.

DESIGN: A systematic quantitative review of published research.

METHODS: Studies were selected if accuracy of outpatient endometrial biopsy was estimated compared with a reference standard. Diagnostic accuracy was determined by pooled likelihood ratios for positive and negative test results. There were 1013 subjects in 13 diagnostic evaluations reported in 11 primary studies.

RESULTS: A positive test result on outpatient biopsy diagnosed endometrial cancer with a pooled likelihood ratio of 66.48 (95% CI 30.04-147.13) while a negative test result had a pooled likelihood ratio of 0.14 (95% CI 0.08-0.27). The post test probability of endometrial cancer was 81.7% (95% CI 59.7%-92.9%) for a positive test and 0.9% (95% CI 0.4%-2.4%) for a negative test.

CONCLUSION: Outpatient endometrial biopsy has a high overall accuracy in diagnosing endometrial cancer when an adequate specimen is obtained. A positive test result is more accurate for ruling in disease than a negative test result is for ruling it out. Therefore, in cases of abnormal uterine bleeding where symptoms persist despite negative biopsy, further evaluation will be warranted.


85% of all endometrial carcinomas
By definition, these tumors do nost show more than 10% of squamous, serous, mucinous, or clear cell differentiation

FIGO Grade

Tumors may be graded well (G1) to poorly differentiated (G3)
G1 <5% of tumor composed of solid masses
G2 6-50% of tumor in solid masses
G3 >50% of tumor in solid masses

In general, if a tumor is G1 by architecture but there is marked nuclear atypia, should be upgraded to G2

Nuclear Grade
G1 Oval nuclei and evenly dispersed chromatin
G2 Nuclei with features between G1 and G3
G3 Markedly enlarged, pleomorphic nuclei wih irregular coarse chromatin and prominent, eosinophilic nucleoli

With squamous metaplasia 20% of all endometrial carcinomas
If the squamous component is malignant, termed adenosquamous carcinoma
If the squamous component is benign, termed adenoacanthoma

Diffusely infiltrative endometrial adenocarcinoma: an adenoma malignum pattern of myoinvasion.

Longacre TA, Hendrickson MR.

Department of Pathology, Stanford University Medical Center, California 94305, USA.


Am J Surg Pathol 1999 Jan;23(1):69-78 Abstract quote

The prognostic significance of a diffusely infiltrative intramyometrial growth pattern was evaluated in 110 cases of low-stage (stages I and II) endometrial adenocarcinoma.

Fifty cases were associated with diffuse infiltration (DI group), and 50 cases had more conventional granulation tissue type intramyometrial infiltration (GTT group). Ten cases with carcinomatous involvement of deeply situated adenomyosis (ADMY group) were also studied. The diffusely infiltrative "adenoma malignum" growth pattern featured typically round, regular individual glands, clearly within myometrium but with minimal or absent stromal or inflammatory cell response.

Myoinvasion of the conventional sort was characterized by irregular, sharply angulated abnormal glands within myometrium without interposed normal glands or endometrial stroma. The abnormal glands were surrounded, at least focally, by edematous stroma with granulation tissue type reaction and/or an inflammatory cell infiltrate. Mean follow-up was 77.8 months (range 3-219 months) for the patients with diffusely infiltrative myoinvasion and deep adenomyosis and 86.9 months (range 1-206 months) for the patients with conventional myoinvasion. Recurrence-free survival for patients with stage I disease and conventional myoinvasion (94%) was similar to that of patients with diffuse adenoma malignum infiltration (98%; p = 0.13).

Survival rates for both groups were also similar. Two (4%) of the 50 patients with diffusely infiltrative adenoma malignum pattern of myoinvasion died of endometrial carcinoma 36 and 72 months after hysterectomy, and 2 (4%) of the 50 patients with conventional myoinvasion died 34 and 67 months after hysterectomy (p = 0.41). Survival in these patients correlated with depth of myometrial invasion and stage. There were no recurrences in the patients with deep adenomyosis.

These results suggest that although endometrial carcinomas with diffuse myometrial infiltration are fully capable of aggressive clinical behavior, they do not appear to behave any more aggressively than those with conventional myometrial invasion. Prognostic indicators of clinically aggressive disease are similar to those that have been previously identified for endometrial carcinomas with the more conventional pattern of myometrial infiltration. They include cervical involvement, deep myometrial invasion, higher histologic grade, and lymph-vascular space invasion.

Endometrial carcinomas with extensive involvement of adenomyosis and adjacent foci of minimal myometrial infiltration appear to have very low malignant potential, but the number of cases with this finding and adequate clinical follow-up is limited. This finding needs to be confirmed in a much larger series of cases.

CILIATED Ciliated endometrial cells
Association with exogenous estrogen treatment
CLEAR CELL Older women with mean of 67 years
Solid, papillary, tubular, and cystic patterns composed of clear cells with hobnail-shaped cells with interspersed clear and eosinophilic cells
Psammoma bodies
Marked nuclear atypia
Precursors of Endometrial Clear Cell Carcinoma.

*Department of Pathology, Yale University School of Medicine, New Haven, CT daggerDepartment of Pathology, University Hospital, SUNY, Stony Brook, NY double daggerArizona Cancer Center section signDepartment of Pathology, College of Medicine, University of Arizona, Tucson, AZ parallelDepartment of Pathology, Shanghai Medical College, Fudan University, China.


Am J Surg Pathol. 2006 Dec;30(12):1519-1530. Abstract quote

The recognition of morphologically identifiable lesions which may confer an increased risk for subsequent development of an invasive malignancy offers an opportunity to investigate and better understand the molecular-genetic etiopathogenesis of the well-developed tumor, and potentially, to administer a therapeutic intervention before its development.

In contrast to uterine endometrioid and serous carcinomas, very little is known about the potential precursor lesions of endometrial clear cell carcinoma (ECCC). In our routine practice, we have noted the presence of a spectrum of atypical glandular changes in the endometria adjacent to ECCC or endometrial carcinomas with a clear cell component, which on the basis of current criteria, would not qualify for any specific designation.

We hypothesize that these lesions represent the earliest morphologically recognizable precursor lesions of ECCC and systematically characterize their clinicopathologic features herein. Thirty archived cases of pure ECCC (n=14) or mixed endometrial carcinomas with a >10% clear cell component (n=16) were retrieved and the "normal" endometria adjacent to the malignancies were evaluated in detail. Thirty-eight benign uteri and 30 uteri with classic endometrial endometrioid carcinoma (EEC) served as controls. All cases were reviewed in a blinded fashion. Putative precursor lesions (PPL) were searched for and identified microscopically. The lesions were typically isolated glands or surface epithelium (within an otherwise normal endometrial region) that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. Twenty-seven (90%) of the 30 cases had at least 1 PPL. In contrast, PPL were identified neither in the benign uteri nor in endometrioid carcinoma control groups (P<0.001). A total of 67 foci of PPL were identified in the 27 cases with an average of 2.5 foci per case.

The immunohistochemical expression of p53, mib-1, estrogen receptor (ERs), and progesterone receptor in the benign endometria, ECCC, and the PPL were evaluated on all 27 cases. The mean p53 scores for the benign endometria, PPL, and ECCC were 0, 4.5, and 6.2, respectively. Parallel values for mib-1 were 15%, 45%, and 63%. ER/progesterone receptor indices for benign endometria, PPL, and carcinoma were 90/80, 21.52/4.61, and 11/4, respectively.The PPL described herein have a morphologic and immunophenotypic profile which seems to be distinct from both the benign endometria in which they reside and the adjacent areas of ECCC. The high frequency of association of these lesions with ECCC, their frequent occurrence as isolated lesions within otherwise "benign-appearing" endometria, and their continuous spectrum of nuclear atypia from minimum (grade 1, cytologic atypia falls short of ECCC cells) to maximum (grade 3, cytologically identical to ECCC cells), argues in favor of our hypothesis that these may represent precursor lesions of ECCC.

Further studies are required to conclusively define the nature of these lesions. However, such studies can only be performed if diagnostic surgical pathologists recognize, highlight, and segregate these lesions for further analysis.
Molecular characterization of uterine clear cell carcinoma.

An HJ, Logani S, Isacson C, Ellenson LH.

Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA
Mod Pathol. 2004 May;17(5):530-7. Abstract quote  

Clinicopathological studies support a broad classification of endometrial carcinoma into two major types, designated as type I and type II, which correlate with their biological behavior. More recently, molecular studies have provided further insights into this classification scheme by elucidating the genetic events involved in the development and progression of endometrial carcinoma.

Microsatellite instability and mutations in the PTEN gene have been widely associated with type I (endometrioid) endometrial carcinoma, while p53 mutations have been identified in the majority of type II endometrial carcinoma, of which uterine serous carcinoma is the prototype. Uterine clear cell carcinoma (UCC) is an uncommon variant of endometrial carcinoma, and clinicopathological studies have produced conflicting results regarding its biological behavior with 5-year survival ranging from 21 to 75%. The molecular characteristics of endometrioid and serous carcinoma have been studied extensively; however, there have been few molecular genetic studies of the clear cell subtype. In this study, we evaluated 16 UCCs (11 pure and 5 mixed) for mutations in the p53 gene, PTEN gene and for microsatellite instability.

Although we found that these alterations were uncommon in pure clear cell carcinomas, all three were identified. In addition, two cases of mixed serous and clear cell carcinoma showed an identical mutation of the p53 gene in the histologically distinct components and one case of mixed clear cell and endometrioid carcinoma had identical mutations in the PTEN and p53 genes, and microsatellite instability in both components.

Our data suggest that UCC represent a heterogeneous group of tumors that arise via different pathogenetic pathways. Additional molecular studies of pure clear cell carcinoma are required to further elucidate the genetic pathways involved in its development and progression.

Low-stage clear-cell carcinoma of the endometrium.

Malpica A, Tornos C, Burke TW, Silva EG.

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Am J Surg Pathol 1995 Jul;19(7):769-74 Abstract quote

Clear-cell carcinoma (CCC) of the endometrium is a relatively rare malignancy that is considered to be one of the most aggressive types of endometrial carcinoma.

To evaluate the behavior of low-stage (stages I and II) CCC of the endometrium, we retrospectively reviewed 17 such cases seen at The University of Texas M.D. Anderson Cancer Center from 1963 to 1990. Patients' ages ranged from 52 to 81 years. Fifteen cases were pure CCC, and two cases were predominantly CCC with a focus of endometrioid adenocarcinoma FIGO grade I. All patients have been followed-up for at least 3 years. At the time of the study, six patients were alive without disease, one patient was alive with disease, five had died of other causes, and five had died of disease.

The estimated survival rate was 71%. Estimated 5-year survival rates for endometrioid adenocarcinoma FIGO grade III and uterine papillary serous carcinoma are 73 and 39%, respectively. We conclude that patients with low-stage CCC of the endometrium have a survival rate similar to that of patients with endometrioid adenocarcinoma FIGO grade III and better than that of patients with uterine papillary serous carcinoma of similar stages.

Prediction of endometrial carcinoma by subjective endometrial intraepithelial neoplasia diagnosis.

Hecht JL, Ince TA, Baak JP, Baker HE, Ogden MW, Mutter GL.

1Department of Pathology, Beth Israel Hospital, Boston, MA, USA.

Mod Pathol. 2005 Mar;18(3):324-30. Abstract quote  

Endometrial intraepithelial neoplasia (also known as 'EIN') is a precursor to endometrioid endometrial adenocarcinoma characterized by monoclonal growth of mutated cells, a distinctive histopathologic appearance, and 45-fold elevated cancer risk.

We have applied diagnostic criteria for EIN to 97 successive endometrial biopsies classified as hyperplastic according to World Health Organization criteria and correlated results with computer-assisted morphometry (D-score) and clinical cancer outcomes. Three pathologists separately reviewed all cases for presence or absence of EIN using published criteria (gland area>stromal area, cytologic change in focus of altered architecture, lesion size >1 mm, and exclusion of cancer and mimics). Discordant cases were resolved by a consensus review at a multiheaded scope.

Clinical outcomes were obtained in 84 patients from patient visit and pathology records. Diagnoses of presence or absence of EIN were unanimous among all three pathologists in 75% of cases, and intraobserver-reproducibility was very good (kappa 0.73-0.90). Cases rediagnosed as EIN encompassed hyperplasias previously diagnosed as atypical (n=18) or nonatypical (eight complex, two simple). Eight follow-up cancers were scattered between hyperplasia types (5/21 atypical, 3/63 nonatypical), but all classified as EIN (8/25) and D-score </=1 (8/38).

Subjective application of criteria for diagnosis of EIN correlates well with objective morphometry and successfully segregates patients into high and low cancer risk subgroups with better reproducibility than atypical hyperplasia diagnosis.
Endometrial Intraepithelial Carcinoma With Associated Peritoneal Carcinomatosis

Robert A. Soslow, M.D.; Edyta Pirog, M.D.; Christina Isacson, M.D.

From the Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University (NYPH-WMC).

Am J Surg Pathol 2000;24:726-732 Abstract quote

Endometrial intraepithelial carcinoma (EIC) is a recently described entity, defined as a noninvasive, cytologically malignant lesion that replaces the endometrial surface epithelium. EIC frequently coexists with uterine serous carcinoma (USC) and is hypothesized to be its precursor lesion. However, the clinical significance and biologic potential of finding EIC without USC is not known.

We report three postmenopausal women with EIC alone who were found to have multiple, synchronous foci of extrauterine serous carcinoma at presentation.

Because the clinical findings in these patients simulated primary peritoneal serous carcinoma (PSC), we compared the clinicopathologic features of these cases with a group of nine bona fide PSCs for which exhaustively sectioned endometria, fallopian tubes, and ovaries were available for review. The average age of the EIC patients was 73 years. Two patients presented with abdominal distention and one with vaginal bleeding. Hysterectomy in each case showed endometrial polyps with EIC, but without invasive USC, in a background of atrophic endometrium. Bilateral salpingo-oophorectomy and staging showed serous carcinoma involving the ovarian hilum, the surfaces of the fallopian tubes and ovaries, in addition to peritoneal carcinomatosis. p53 overexpression was observed in both EIC and the extrauterine deposits of serous carcinoma in each case. The average age of the PSC patients was 66 years. All nine patients presented with abdominal distention. EIC was not identified in any of the hysterectomy specimens. Bilateral salpingo-oophorectomies, omentectomies, and peritoneal biopsies showed peritoneal carcinomatosis, including bulky peritoneal tumor deposits, but only minimal ovarian surface involvement. p53 overexpression was observed in seven cases.

These findings indicate that EIC without coincident USC can be associated with invasive, extrauterine serous carcinomatosis. We did not, however, find any significant differences between the clinicopathologic features of primary extrauterine serous carcinomas (PSCs) and those associated with EIC.

We conclude that the finding of EIC in an endometrial curettage specimen should prompt a thorough search for an invasive uterine and/or extrauterine serous carcinoma. Conversely, an endometrial origin should be excluded in patients with peritoneal carcinomatosis.


Mesonephric Adenocarcinoma of the Uterine Corpus CD10 Expression as Evidence of Mesonephric Differentiation

Jaume Ordi, M.D. ; Francisco F. Nogales, M.D. ; Antonio Palacin, M.D. ; Manuel Márquez, M.D. ; Jaume Pahisa, M.D. ; Juan A. Vanrell, M.D. ; Antonio Cardesa, M.D.

From the Department of Pathology (J.O., A.P., M.M., A.C.) and Institut Clínic de Ginecologia, Obstetrícia i Neonatologia (J.P., J.A.V.), Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, School of Medicine, Barcelona, and University Hospital (F.F.N.), Granada, Spain.

Am J Surg Pathol 2001;25:1540-1545 Abstract quote

Mesonephric (wolffian) neoplasms of the female genital tract are infrequent and found in sites where embryonic remnants of wolffian origin are usually detected, such as the uterine cervix, broad ligament, mesosalpinx, and ovary. Their diagnosis is difficult because of the absence of specific immunohistochemical markers for mesonephric derivatives.

We present the first report of adenocarcinoma of mesonephric type arising as a purely myometrial mass without endometrial or cervical involvement in the uterine corpus of a 33-year-old woman. The tumor showed a combination of patterns, with retiform areas, ductal foci, and small tubules with eosinophilic secretion, which merged with solid sheets of cells with a sarcomatoid appearance. Immunohistochemically, neoplastic cells were diffusely positive for cytokeratin 7, epithelial membrane antigen, and CD15 and focally positive for BerEP4 and vimentin. A hitherto unreported feature was the positivity for CD10 in neoplastic cells, which was also present in a large number of control tissues obtained from male mesonephric derivatives and female mesonephric remnants and tumors. Furthermore, CD10 was negative in controls from müllerian epithelia of the female genital tract and in their corresponding tumors.

Therefore, the expression of CD10 by mesonephric remnants may be useful in establishing the diagnosis of tumors with mesonephric differentiation.


Microglandular adenocarcinoma of the uterus mimicking microglandular cervical hyperplasia.

Zamecnik M, Skalova A, Opatrny V.

Ann Diagn Pathol. 2003 Jun;7(3):180-6. Abstract quote

We present a rare case of microglandular carcinoma of the uterus occurring in 76-year-old woman. The tumor tissue in the curettage specimen showed strong similarity with microglandular hyperplasia of the cervix. Microglandular aggregates of glands with only mild nuclear atypia but without any structures of conventional endometrioid carcinoma were seen. Therefore, a microglandular hyperplasia of the cervix was seriously considered.

The following features were helpful in the differential diagnosis: numerous neutrophils and "dirty" amount within glandular lumens; very scarce (but nevertheless present) mitoses; isolated single glands with more endometrioid than endocervical appearance; and strong expression of vimentin, which is unusual for microglandular hyperplasia of the cervix.

In the resectate, a conventional well-differentiated endometrioid adenocarcinoma with microinvasion of the myometrium (under 1 mm of depth) was found. Microglandular differentiation has been, however, present in plaque-like proliferation replacing the endometrium and on the surface of conventional adenocarcinoma. Eleven months after the hysterectomy, the patient has no signs of recurrence or metastasis.

Our case shows the difficulties in the diagnosis of this lesion and confirms a low aggressiveness that was observed in all 10 cases described to date.

Microglandular adenocarcinoma of the endometrium: a form of mucinous adenocarcinoma that may be confused with microglandular hyperplasia of the cervix.

Zaloudek C, Hayashi GM, Ryan IP, Powell CB, Miller TR.

Department of Pathology, San Francisco General Hospital, California, USA.

Int J Gynecol Pathol 1997 Jan;16(1):52-9 Abstract quote

Microglandular adenocarcinoma of the endometrium may cause diagnostic problems because of its bland cytologic appearance and its histologic similarity to benign microglandular hyperplasia of the cervix.

We present two cases of microglandular adenocarcinoma and discuss the clinical, pathologic, and immunohistochemical findings. Both patients were postmenopausal women, one of whom was taking exogenous hormones. Endometrial biopsy specimens contained polypoid tissue fragments, within which were microcystic spaces lined by flattened, cuboidal, or columnar cells. Solid nests or sheets of tumor cells surrounded glands in some tissue fragments. The nuclei were uniform and bland, and mitotic figures, although readily identifiable, were infrequent (1 per 10 high-power fields). A majority of tumor cells contained intracytoplasmic mucin. Numerous neutrophils were present in gland lumens and tissues.

Immunohistochemical stains for carcinoembryonic antigen and TAG72 (B72.3) revealed focal moderate to intense apical and cytoplasmic staining; immunostains for p53 protein were negative. One carcinoma was confined to the endometrium, whereas the other invaded into the inner one-third of the myometrium.

Both patients were well after a limited follow-up of 1 year. Microglandular adenocarcinoma is a distinctive variant of endometrial carcinoma that is most likely a form of mucinous adenocarcinoma.


Minimal deviation endometrioid adenocarcinoma of cervix: a clinicopathological and immunohistochemical study of two cases.

Rahilly MA, Williams AR, al-Nafussi A.

Department of Pathology, University of Edinburgh, Scotland.

Histopathology 1992 Apr;20(4):351-4 Abstract quote

We describe the clinicopathological features of two cases of minimal deviation endometrioid adenocarcinoma of cervix. This is a rare tumour whose predominant pattern is one of bland endometrial-type glands infiltrating the cervical wall without a stromal response. Thus, it may be confused with benign conditions such as cervical endometriosis.

The two cases demonstrate that this tumour may behave aggressively despite its bland appearances. An immunohistochemical study was performed and showed only focal reactivity of neoplastic glands for carcinoembryonic antigen, which would limit its diagnostic use in small biopsy specimens.

Minimal-deviation endometrioid adenocarcinoma of the uterine cervix. A report of five cases of a distinctive neoplasm that may be misinterpreted as benign.

Young RH, Scully RE.

Department of Pathology, Harvard Medical School, Boston, Massachusetts.

Am J Surg Pathol 1993 Jul;17(7):660-5 Abstract quote

We describe five cervical adenocarcinomas with unusual, deceptively benign histological features that occurred in women 34 to 42 years of age and caused problems in interpretation.

The tumors were incidental findings in hysterectomy or cone-biopsy specimens in four patients; the fifth patient was investigated because abnormal glandular cells were found on a Papanicolaou smear. One patient had been exposed in utero to diethylstilbestrol. The cervix is known to have been abnormal on gross evaluation in only one case. Microscopic examination disclosed a deceptively benign-appearing proliferation of glands and cysts for the most part unassociated with a stromal reaction. Cilia were present in four neoplasms and apical snouts in three.

Features that indicated the neoplastic nature of the glandular proliferation in these cases, to varying extents in individual cases, included the number of glands and their distribution, the shapes of the glands, their presence deep in the cervical wall, the focal presence of a stromal reaction, and moderate cytologic atypicality with occasional mitotic figures. None of the tumors is known to have recurred or metastasized. In our opinion, these distinctive neoplasms represent minimal-deviation endometrioid adenocarcinomas of the cervix.

'Minimal deviation' endometrioid carcinoma with oncocytic change of the endometrium.

Mai KT, Yazdi HM, Boone SA.

Department of Laboratory Medicine, Ottawa Civic Hospital, Ontario, Canada.

Arch Pathol Lab Med 1995 Aug;119(8):751-4 Abstract quote

We report an unusual adenocarcinoma of the endometrium in an 80-year-old woman. The tumor diffusely involved the entire thickness of the myometrium. The cervix, ovaries, and fallopian tubes were unremarkable.

Microscopic examination revealed an extremely well-differentiated endometrioid adenocarcinoma with mild cytologic atypia and slightly distorted glands infiltrating almost the entire thickness of the myometrium. In addition, the neoplastic endometrioid cells showed extensive oncocytic change.

Endometrial curettings had been interpreted as simple endometrial hyperplasia with eosinophilic metaplasia. The significance of this lesion is discussed in terms of possible confusion with benign endometrial lesions as well as benign cervical lesions.

Endometrioid carcinoma of the endometrium with an invasive component of minimal deviation carcinoma.

Mai KT, Perkins DG, Yazdi HM, Thomas J.

Department of Laboratory Medicine, Division of Anatomical Pathology, The Ottawa Hospital-Civic Campus, and the Department of Pathology and Laboratory Medicine, University of Ottawa, Ontario, Canada.

Hum Pathol 2002 Aug;33(8):856-8 Abstract quote

Minimal deviation endometrioid adenocarcinoma is a rare pathological variant of endometrioid adenocarcinoma.

We describe a case representing another rare variant of endometrioid adenocarcinoma composed of both typical and minimal deviation endometrioid adenocarcinoma in a 45-year-old woman. Macroscopically, the cervix was of normal size but it had an indurated consistency. The myometrium was unremarkable.

Microscopically, in addition to the typical endometrioid adenocarcinoma that involved 75% of the endometrium, there was a proliferation of mildly atypical endometrial type glands sparsely distributed in the fibrovascular tissue, typical of minimal deviation endometrioid adenocarcinoma. The latter component extended downward from the endomyometrial junction and involved focal areas of the uterine body and isthmus, diffusely invaded the entire cervix and focally the cervical resection margins. Focal transitional areas between typical and minimal deviation endometrioid adenocarcinoma were identified.

Due to a relatively normal gross appearance and the microscopic deceptively benign looking appearance, minimal deviation endometrioid adenocarcinoma may pose problems of obtaining adequate sampling and evaluating the thickness of invasion of the endometrial carcinoma on gross, as well as microscopic, examination.

MUCINOUS More than half of the tumor cells much contain mucin
Often a focal finding in up to 42% of cancers
Papillary serous carcinoma  
SECRETORY Majority of cells exhibit subnuclear or supranuclear cytplasmic vacuoles resembling early secretory endometrium

Sertoliform endometrial adenocarcinoma: a study of four cases.

Eichhorn JH, Young RH, Clement PB.

James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Boston 02114, USA.

Int J Gynecol Pathol 1996 Apr;15(2):119-26 Abstract quote

We studied four endometrial carcinomas with a conspicuous component that resembled patterns in Sertoli cell tumors. The patients presented at age 44-83 years (mean 65 years), with abnormal or postmenopausal vaginal bleeding in three and abnormal cervical cytology in one. All were multiparous, moderately to markedly obese, and hypertensive, and three patients had non-insulin-dependent diabetes mellitus. One tumor was suspected to be an endometrial stromal sarcoma with sex-cord-like differentiation on biopsy.

Gross examination of the hysterectomy and bilateral salpingo-oophorectomy specimens showed solid polypoid endometrial tumors in each case. Light microscopic examination showed three to be superficially invasive of the myometrium and one to be confined to the endometrium; none of the tumors showed the tongue-like pattern of myoinvasion or the angiolymphatic invasion characteristic of low-grade endometrial stromal sarcomas. The sertoliform component, which predominated in one case and was only focal in the three others, was composed of uniform small hollow tubules lined by columnar cells with apical cytoplasm and of compact slender cords. The tubules and cords were often present between benign-appearing or carcinomatous glands. In the case with predominate sertoliform areas, the lesional cells had clear cytoplasm suggesting a lipid-rich variant; special stains of this case demonstrated cytoplasmic glycogen but no fat. In none of the cases was cytoplasmic mucin, argyrophil granules, or argentaffinity demonstrated. The nonsertoliform areas of the tumors consisted of typical endometrioid adenocarcinoma; concurrent endometrial hyperplasia was also present in each case. Squamous differentiation and minor foci of anaplastic carcinoma with bizarre tumor giant cells were present in three tumors.

Immunoperoxidase stains showed staining for two or more markers of epithelial or glandular differentiation in the sertoliform areas in all cases (keratin, epithelial membrane antigen, carcinoembryonic antigen, CA125, Tag72), with focal expression of vimentin in all cases. In none of the cases was desmin or actin staining observed.

The evidence indicates that tumors in this series are variants of endometrioid adenocarcinoma and are distinct from uterine tumors resembling ovarian sex-cord tumors and stromal sarcomas with sex-cord-like differentiation.

Endometrioid Carcinomas of the Uterine Corpus With Sex Cord-like Formations, Hyalinization, and Other Unusual Morphologic Features: A Report of 31 Cases of a Neoplasm That May Be Confused With Carcinosarcoma and Other Uterine Neoplasms.

Murray SK, Clement PB, Young RH.

From the *Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada; daggerDepartment of Pathology, Vancouver Hospital Health Sciences Centre, University of British Columbia, Vancouver, British Columbia, Canada; and the double daggerJames Homer Wright, Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA.

Am J Surg Pathol. 2005 Feb;29(2):157-166. Abstract quote

We describe a series of unusual endometrioid carcinomas (ECs) of the uterine corpus characterized in significant part by cords of epithelioid cells, spindle cells, and a hyalinized stroma that sometimes formed osteoid. These features, particularly when prominent, produced an appearance strikingly different from that of conventional EC, sometimes resulting in problems in differential diagnosis, especially with a malignant mullerian mixed tumor (carcinosarcoma).

The 31 patients ranged in age from 25 to 83 years (mean, 52 years). The proportion within each stage were as follows: stage Ia, 9.7%, stage Ib, 45.2%, stage Ic, 9.7%, stage IIb, 16.1%, stage IIIc 3.2%, and stage IV, 3.2%. In 4 patients (12.9%), staging information was not available. On microscopic examination, typical EC, which accounted for 10% to 90% of the tumor, was admixed in 90% of cases with cords of epithelioid or spindle cells within a hyalinized stroma. In 3 cases, the tumor contained cords of cells without a hyalinized stroma. Areas with a diffuse growth of fusiform cells suggesting endometrial stromal cells were also occasionally seen in minor amounts. Seventy percent of the tumors exhibited squamous differentiation, and in 50% of the tumors there was a background of endometrial hyperplasia. Two thirds of the tumors were grade 2 and the remainder were grade 1. Vascular space invasion was identified in seven tumors.

On immunohistochemical analysis, the typical EC component was strongly positive for keratin, whereas the keratin staining was more focal and variable in the epithelial cells in the cords. Muscle markers (desmin, actin), CD10, and inhibin were negative in the latter. Overexpression of p53 was found in only 1 case. Eighty-three percent of the patients were alive with no evidence of disease on follow-up (range, 2-115 months; mean, 34.4 months). The clinical features, including a typically low stage and generally good prognosis, and histologic findings are different from those of malignant mullerian mixed tumors that are characterized by both high-grade carcinomatous and sarcomatous components and an aggressive clinical course. Confusion with other neoplasms, particularly those with sex cord-like growth, such as uterine tumors resembling ovarian sex cord tumors and epithelioid smooth muscle tumors, may also arise.

We refer to tumors with the features described herein as "corded and hyalinized endometrioid carcinomas," a designation that reflects their two most striking and consistent features. Corded and hyalinized endometrioid carcinomas are yet another example of the protean phenotype of endometrioid adenocarcinomas of the female genital tract that has been appreciated only in the last two decades.

Must satisfy three criteria:
Adencarcinoma is not present in the endometrium
Squamous carcinoma has no connection to the cervical squamous epithelium
Squamous carcinoma is not present in the cervix

May have connection to cervical stenosis, pyometria, and chronic inflammation

Undifferentiated Carcinoma of the Endometrium.

Altrabulsi B, Malpica A, Deavers MT, Bodurka DC, Broaddus R, Silva EG.

From the *Department of Pathology, Baylor University, Dallas, TX; and the Departments of daggerPathology and double daggerGynecologic Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, TX.

Am J Surg Pathol. 2005 Oct;29(10):1316-1321. Abstract quote  

Undifferentiated carcinoma arising in the endometrium is considered a rare neoplasm with only a few studies published thus far. This limited number of studies is most likely a reflection of the underrecognition of this tumor because of a lack of diagnostic criteria to separate it from endometrial endometrioid adenocarcinoma, FIGO grade 3.

In this study, we present the clinicopathologic features of 16 cases of endometrial undifferentiated carcinoma. In addition, we review the clinicopathologic features of 33 cases of endometrial endometrioid adenocarcinoma, FIGO grade 3, and compare them with the undifferentiated cases. The age of the 16 patients with undifferentiated carcinoma of the endometrium ranged from 40 and 69 years (mean, 59 years). Stage was known in 13 patients. Six (46%) patients presented with early stage disease (4 stage I and 2 stage II). Seven (54%) patients presented with advanced stage disease (2 stage III and 5 stage IV). Staging information was not available for 3 patients.

Undifferentiated carcinoma was characterized by a proliferation of medium-sized, monotonous, epithelial cells growing in solid sheets with no specific pattern. Glands were not identified. Keratin immunostaining was focally positive in 11 of 12 cases, and EMA was focally positive in all 12 cases. The age of the 33 patients with endometrial endometrioid carcinoma, FIGO grade 3, ranged from 40 to 90 years (mean, 68 years). Twenty-three (70%) patients presented with early stage disease (21 stage I and 2 stage II), and 10 (30%) patients presented with advanced stage disease (8 stage III and 2 stage IV). Focal glandular differentiation was seen in all cases. The solid component was different from the one seen in the undifferentiated carcinomas because well demarcated trabeculae, cords, or groups of cells were identified in all cases. The tumor cells in the solid areas resembled the cells in the glandular component of the tumor. Immunoperoxidase studies for keratin and EMA were positive in 23 of 23 cases. Twelve of the 16 (75%) patients with undifferentiated carcinoma died of disease; 10 (62.5%) of them within 5 years after diagnosis. In contrast, 13 of 33 (39.4%) patients with endometrial endometrioid carcinoma, FIGO grade 3, died of disease. Twelve (36.4%) died within 5 years after diagnosis.

In summary, undifferentiated carcinoma of the endometrium appears to be more aggressive than endometrial endometrioid adenocarcinoma, FIGO grade 3. Its proper recognition is important for prognosis and potentially for therapy.
VILLOGLANDULAR Papillary fronds with fibrovascular core lined by cells having grade 1-2 nuclei
Low grade carcinomas

Significance of papillary (villoglandular) differentiation in endometrioid carcinoma of the uterus.

Ambros RA, Ballouk F, Malfetano JH, Ross JS.

Department of Pathology, Albany Medical College, NY 12208.

Am J Surg Pathol 1994 Jun;18(6):569-75 Abstract quote

The frequency, topography, and significance of papillary (villoglandular) differentiation were examined in 142 cases of endometrioid (typical) carcinoma of the endometrium. Forty-four (31%) of the 142 cases showed papillary differentiation, including eight carcinomas limited to the endometrium and 36 cases with myometrial invasion. In 24 (67%) of the 36 cases with myometrial invasion, papillary differentiation was found in both the endometrial component of the carcinoma and in tumor invading the myometrium. In the remaining 12 cases, papillary differentiation was found in the endometrial component but not in tumor invading the myometrium, which showed either glandular or solid growth patterns.

When patients were divided into two groups based on the presence or absence of papillary differentiation, regardless of its location, the two groups did not differ in prognosis or frequency of pathologic changes associated with outcome.

In the subgroup of patients with tumors showing myometrial invasion, however, endometrioid carcinomas displaying papillary differentiation in the myometrium were associated with a higher frequency of vascular invasion (p = 0.007), a higher rate of lymph node metastasis (p = 0.001), and worse outcome (p = 0.05) compared with carcinomas showing myometrial invasion in the form of glandular or solid patterns regardless of the presence or absence of papillary differentiation in the endometrium. The results of the present study suggest that papillary differentiation is of significance in endometrioid carcinoma.

If these findings can be confirmed, a separate designation for these tumors as "papillary endometrioid carcinomas" or "villoglandular endometrial carcinomas" would be helpful if use of these terms was limited to endometrioid carcinomas manifesting papillary differentiation in the myometrium.


Villoglandular adenocarcinoma of the endometrium: a clinicopathologic study of 61 cases: a gynecologic oncology group study.

Zaino RJ, Kurman RJ, Brunetto VL, Morrow CP, Bentley RC, Cappellari JO, Bitterman P.

Department of Pathology, The Milton S. Hershey Medical Center of Pennsylvania State University, Hershey 17033, USA.

Am J Surg Pathol 1998 Nov;22(11):1379-85 Abstract quote

Papillary endometrioid or villoglandular adenocarcinoma (VGA) is a relatively common type of endometrial adenocarcinoma, but studies describing its behavior have yielded conflicting results. Patients with a component of VGA were identified in a review of 819 women entered in a Gynecology Oncology Group Study (Protocol 33) of clinical stages I and II endometrial adenocarcinoma. Cases with coexisting foci of serous or clear cell carcinoma were excluded from further consideration.

Of the 61 cases that formed the study sample, there were 24 with pure villoglandular differentiation and 37 who were admixed with typical endometrioid adenocarcinoma (EA). The general clinicopathologic features of patients with pure and mixed VGA are compared with 469 patients with pure EA. The VGAs were better differentiated (grade 1 or 2--97% of VGA versus 74% EA, p = 0.001). but they were not significantly different with respect to median age, depth of invasion, or frequency of nodal spread. Six of the 61 patients with VGA died of their tumor. The disease-specific survival rate at 3 years for VGA is 94% (95% confidence interval: 0.88-0.99) compared with 88% (95% CI: 0.86-0.91) for EA. Two of the patients who died had pure villoglandular tumors and four had mixed villoglandular and endometrioid carcinoma.

In view of the frequent admixture of VGA and EA and their generally similar biological characteristics, with a prognosis similar to that of typical EA, we conclude that VGA should be considered a variant of EA.


Immunophenotypic diversity of endometrial adenocarcinomas: implications for differential diagnosis.

Reid-Nicholson M, etal.

1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.


Mod Pathol. 2006 Aug;19(8):1091-100. Abstract quote

Many endometrial adenocarcinomas, particularly those of endometrioid type, express estrogen receptors (ERs), progesterone receptors (PRs), and vimentin. This typical immunophenotype is frequently considered a standard against which others are compared when immunohistochemistry is used for differential diagnosis.

We tested large numbers of endometrial cancers, enriched for high-grade tumors, to determine whether this reported immunophenotype was valid and whether expression differences between types of endometrial carcinoma could be exploited for diagnostic purposes.

Immunohistochemical stains were performed on the following types of endometrial cancers using established methodology: International Federation of Gynecology and Obstetrics (FIGO) grades 1 and 2 endometrioid-42; FIGO grade 3 endometrioid-40; serous-24; clear cell-11; carcinosarcoma-9. In total, 92% of serous carcinomas expressed p16 strongly compared to weak-to-moderate expression of p16 in 7-67% of other tumors (FIGO grades 1 and 2 carcinoma and carcinosarcoma, respectively). A total of 84% of FIGO grades 1 and 2 carcinomas expressed ER compared to 9-54% of other tumors (clear cell and serous carcinomas respectively); 83% of FIGO grades 1 and 2 expressed PR compared to 11-54% of other carcinomas (carcinosarcoma and serous carcinoma, respectively). Most carcinomas were negative for monoclonal carcinoembryonic antigen (mCEA), and those that were positive showed mostly only focal membrane expression. Vimentin was expressed in nearly every tumor. Most tumors were diffusely vimentin positive, but a large range of expression patterns, from focal to diffuse and from weak to strong, was noted. Only 70% of FIGO grades 1 and 2 endometrioid carcinomas and 26% of grade 3 endometrioid carcinomas possessed the reportedly characteristic endometrial cancer immunophenotype p16 (-), ER (+), PR (+), mCEA (-), and vimentin (+).

Endometrial cancers demonstrate substantial immunophenotypic diversity that remained apparent even within groups of similar histologic subtype and grade. ER, PR, and p16 expression was more illustrative of tumor type and degree of differentiation than they were of endometrial origin. In contrast, the vimentin-positive/CEA-negative phenotype remained the most constant among all endometrial cancers.

A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas.

McCluggage WG, Sumathi VP, McBride HA, Patterson A.

Department of Pathology, Royal Group of Hospitals Trust, Belfast, Northern Ireland.


Int J Gynecol Pathol 2002 Jan;21(1):11-5 Abstract quote

The histological distinction between a primary endometrial and a primary endocervical adenocarcinoma is often difficult, especially in small biopsy specimens. A preoperative distinction is important because primary surgical management differs between the two tumors. Cases of primary endometrioid endometrial (n=30) and primary endocervical (n=26) adenocarcinoma of endocervical type were stained immunohistochemically with the monoclonal antibodies against carcinoembryonic antigen (CEA), vimentin, estrogen receptor (ER), and 34 beta E12. In all cases the origin of the adenocarcinoma was confirmed by examination of the definitive pathology specimen.

There was diffuse positive nuclear staining for ER in 28 of 30 (93%) endometrial adenocarcinomas. ER was negative in 16 of 26 endocervical adenocarcinomas, and there was focal weak nuclear staining in the other cases. Vimentin was positive in 29 of 30 (97%) endometrial adenocarcinomas but in only 2 of 26 (8%) endocervical adenocarcinomas. CEA was positive in 25 of 26 (96%) endocervical adenocarcinomas, mostly with diffuse membranous and cytoplasmic staining. Positivity with CEA was present in 21 of 30 (70%) endometrial adenocarcinomas but was largely confined to squamoid areas with only 12 tumors exhibiting focal membranous staining of the glandular component. 34 beta E12 was diffusely positive in all except one cervical adenocarcinoma.

In endometrial carcinomas, positivity was strongest in squamoid areas but there was positive staining, either focally or diffusely, of the glandular component in 27 cases. In summary, primary endometrioid endometrial adenocarcinomas are characterized by diffuse, strong, positive staining for vimentin and ER and negative or very focal, positive staining of the glandular component for CEA. In contrast, primary endocervical adenocarcinomas are characterized by CEA positivity, which is usually but not always diffuse, negativity for vimentin, and negativity or focal weak positivity for ER. 34 beta E12 is of no value in the distinction between endometrial and endocervical adenocarcinomas.

A panel of immunohistochemical stains, comprising CEA, vimentin, and ER, generally allows confident preoperative distinction between a primary endometrial and endocervical adenocarcinoma.

Immunohistochemical Staining in the Distinction Between Primary Endometrial and Endocervical Adenocarcinomas: Another Viewpoint

Seiryu Kamoi, M.D.; Muna I. AlJuboury, M.D.; Marie-Rose Akin, M.D.; Steven G. Silverberg, M.D.

From the Departments of Pathology, University of Maryland School of Medicine and Medical Center, Baltimore, Maryland (S.K., M.I.A, S.G.S.), Loma Linda University School of Medicine, California (M.R.A.), Riyadh Armed Forces Hospital, Saudi Arabia (M.I.A.), and the Department of Obstetrics and Gynecology, Nippon Medical School Chiba Hokusoh Hospital, Japan (S.K.).


Int J Gynecol Pathol 2002 Jul;21(3):217-23 Abstract quote

Several studies have reported on the use of antibodies to monoclonal carcinoembryonic antigen (CEA) and vimentin (VIM) to distinguish between adenocarcinomas of endometrial (EM) and endocervical (EC) origin, with variably enthusiastic results. It is still unclear whether site of origin or pathway of differentiation (endometrioid [em] versus mucinous [m]) is more important in predicting immunohistochemical differences.

In the present study, paraffin blocks from adenocarcinomas of known origin were retrieved and immunostained with monoclonal antibodies to VIM and CEA, as well as cytokeratins (CK) 4, 18, and 20, estrogen receptor (ER), and progesterone receptor (PR). Positivity was scored on a scale from 0 to 12, with emphasis on the pattern of differentiation (tumors with mixed patterns received separate scores for the em and m foci). Mean CEA scores for emEM (n = 27), mEM (17), mEC (10), and emEC (6) were 0.4, 0.9, 5.1, and 1.2, respectively. VIM scores were 6.9, 1.3, 0, 4.4; ER, 5.7, 4.2, 0, 1.6; PR, 7.6, 2.8, 0.1, 6.0; CK4, 9.2, 4.4, 8.5, 10.6; CK18, 6.4, 3.4, 5.5, 8.4; CK20, 0.7, 0, 0.5, 0.4. Both site and differentiation influenced these results, with the latter more important for VIM and PR, the former for ER, both for CEA (only mEC was frequently strongly positive), and neither for the CKs studied. No one stain or combination reliably distinguished endometrial from endocervical origin.

The only immunostaining pattern that might identify a site of origin with more accuracy than hematoxylin & eosin evaluation alone is the combination of high VIM and ER scores in an endometrioid carcinoma, suggesting with about 95% accuracy in this series an endometrial origin of the tumor.

Immunohistochemical analysis of PTEN in endometrial carcinoma: a tissue microarray study with a comparison of four commercial antibodies in correlation with molecular abnormalities.

Pallares J, Bussaglia E, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Sanchez-Verde L, Palacios J, Prat J, Matias-Guiu X.

1Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, Spain.

Mod Pathol. 2005;18:719-727 Abstract quote


The tumor suppressor gene PTEN/MMAC1 is located on chromosome 10q23.3. Inactivation of PTEN, either by mutations, deletions, or promoter hypermethylation, has been identified in a wide variety of tumors. Inactivation of the two alleles of PTEN is required, because it is a tumor suppressor gene. Immunohistochemical staining may be an effective screening method to demonstrate the absence of the protein in tumors exhibiting PTEN inactivation.

We studied a tissue microarray, constructed from paraffin-embedded blocks of 95 endometrial carcinomas, 38 of them previously evaluated for alterations in PTEN. We also studied cell blocks obtained from one PTEN-defective endometrial cancer cell line, after transfection with either a plasmid encoding wild-type PTEN or the empty vector. The tumor samples were tested with four different anti-PTEN commercial antibodies: a polyclonal antibody, the monoclonal antibody 28H6, the monoclonal antibody 10P03, and the monoclonal antibody 6.H2.1. Results were correlated with the presence of abnormalities in PTEN, as well as with the immunohistochemical expression of phosphorylated AKT. Antibody 28H6 produced a predominant nuclear staining, while the other three antibodies produced a predominant cytoplasmic staining.

There was no significant correlation between the results obtained with the four antibodies. The monoclonal antibody 6.H2.1 was the only one that exhibited a correlation with the presence of molecular alterations in PTEN, and a statistically significant association with immunostaining for phosphorylated AKT (r=-0.249, P=0.037). The monoclonal antibody 10P03 exhibited an association with phospho-AKT that did not have statistical significance. Both 6.H2.1 and 10P03 antibodies stained PTEN-transfected cells, and were negative in the PTEN-deficient cell line blocks.

The polyclonal antibody and the monoclonal antibody 28H6 produced positive staining in PTEN-deficient cell line blocks, suggesting nonspecific staining. The results indicate that monoclonal antibody 6.H2.1 may be a suitable alternative for tumors with inactivation of PTEN.



CD10 Immunostaining Does Not Distinguish Endometrial Carcinoma Invading Myometrium From Carcinoma Involving Adenomyosis.

Srodon M, Klein WM, Kurman RJ.

Am J Surg Pathol. 2003 Jun;27(6):786-9. Abstract quote

The distinction of involvement of adenomyosis by endometrial carcinoma from endometrial carcinoma invading the myometrium can at times be difficult. This distinction, however, is important from the standpoint of staging, treatment, and prognosis because the outcome of carcinoma invading the myometrium as compared with involving adenomyosis is significantly worse. CD10 has been recently reported to be expressed by normal and neoplastic endometrial stromal cells. We therefore hypothesized that CD10 may be helpful in distinguishing carcinoma within adenomyosis from endometrial carcinoma directly invading the myometrium.

Twenty-two cases of invasive endometrioid adenocarcinoma were identified from the surgical pathology files of the Johns Hopkins Hospital and consultation files of one of the authors (R.J.K.) and immunostained for CD10, desmin, and caldesmon. The pattern of staining was compared with five cases in which carcinoma was confined to adenomyosis. As a control, 14 cases of adenomyosis unassociated with carcinoma were included in the analysis.

All 22 endometrial carcinomas that invaded the myometrium expressed CD10 to some extent in cells immediately surrounding the neoplastic glands. In 18, all of the invasive nests displayed CD10 in surrounding cells, but in four cases the staining was patchier, involving the surrounding cells of approximately 50-75% of the invasive nests. In four cases of myoinvasive carcinoma, the CD10-positive cells surrounding the nests of invasive carcinoma were also positive for desmin and caldesmon. In the remaining 18 cases with myoinvasive carcinoma, the cells surrounding the carcinomas failed to react with desmin and caldesmon. All five endometrial carcinomas involving adenomyosis displayed CD10 positivity in what appeared to be endometrial stromal cells surrounding the neoplastic glands. The stromal cells were negative for desmin and caldesmon. The control cases of adenomyosis were all positive for CD10, although in four cases the staining was patchy compared with 10 cases in which it was diffuse. Desmin and caldesmon were negative in all of these cases.

Although CD10 identifies endometrial stromal cells in the endometrium and in adenomyosis and endometriosis, this study demonstrates that CD10 does not aid in distinguishing myometrial invasion of endometrial carcinoma from involvement of adenomyosis by endometrial carcinoma because the cells surrounding the tumor in the myoinvasive group express CD10.

The Role of CD10 Staining in Distinguishing Invasive Endometrial Adenocarcinoma from Adenocarcinoma Involving Adenomyosis.

Nascimento AF, Hirsch MS, Cviko A, Quade BJ, Nucci MR.

Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.


Mod Pathol 2003 Jan;16(1):22-7 Abstract quote

Adenomyosis may be involved by endometrial adenocarcinoma, but in contrast to true myometrial invasion, the depth of an adenomyotic focus involved by carcinoma does not alter pathologic tumor staging. Therefore, distinction from carcinoma invading myometrium is clinically relevant.

We hypothesized that CD10, a marker of non-neoplastic and neoplastic endometrial stroma, would highlight the stromal component of adenomyotic foci and be useful in this distinction. Thirty-nine cases of endometrial adenocarcinoma were analyzed and divided into three groups: I, invasive endometrial adenocarcinoma (n = 14); II, endometrial adenocarcinoma involving adenomyosis but without myometrial invasion (n = 18); and III, adenomyosis involved by endometrial adenocarcinoma with concomitant invasive component (n = 7). All cases of adenomyosis involved by endometrial adenocarcinoma demonstrated CD10 expression in the stromal cells of adenomyotic foci. Eleven of 21 cases (52%) of invasive adenocarcinoma also showed CD10 expression, at least focally, in cells immediately surrounding the infiltrating glands. Of these, two cases (from Group III) also had associated adenomyotic involvement by carcinoma. The remaining cases of invasive carcinoma were negative for CD10.

Therefore, presence of CD10 staining immediately surrounding neoplastic glands does not equate with involvement of adenomyosis by endometrial adenocarcinoma. In contrast, absence of CD10 expression excludes involvement of adenomyosis by adenocarcinoma.


Distinction of Endocervical and Endometrial Adenocarcinomas: Immunohistochemical p16 Expression Correlated With Human Papillomavirus (HPV) DNA Detection

Ansari-Lari, M Ali MD*; Staebler, Annette MD*; Zaino, Richard J MD‡; Shah, Keerti V MD, DRPH§; Ronnett, Brigitte M MD*†

From the Departments of *Pathology and †Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD; ‡Department of Pathology, Pennsylvania State University College of Medicine, Hershey, PA; and §Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. The current affiliation of Dr. Staebler is Institute of Pathology, University of Muenster, Muenster, Germany.


The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 160-167 Abstract quote

Determining the origin of uterine adenocarcinomas can be difficult in biopsy and curettage specimens because the morphologic spectrum of endocervical and endometrial adenocarcinomas overlaps. In hysterectomy specimens, the primary site is often equivocal for tumors that involve the lower uterine segment and endocervix and lack identifiable precursor lesions. Most endocervical adenocarcinomas (ECAs) contain high-risk human papillomavirus (HPV) DNA, whereas endometrial adenocarcinomas (EMAs) rarely do. p16 is an inhibitor of cyclin-dependent kinases, and overexpression of p16 has been observed in cervical intraepithelial lesions and invasive carcinomas associated with high-risk HPV types.

We evaluated the utility of immunohistochemistry for p16 in the distinction of ECAs and EMAs. p16 expression was assessed in 24 unequivocal EMAs and 19 unequivocal ECAs and correlated with HPV DNA detection by in situ hybridization and polymerase chain reaction. These assays were then used to assist in the classification of four lower uterine segment/upper endocervical adenocarcinomas (LUS/EC-A) of equivocal origin. p16 expression was moderate-strong and diffuse in 18 ECAs (median 90% of tumor cells positive, range 90%-100%), and weak and diffuse in one. Fourteen of these were positive for HPV DNA, whereas 5 lacked detectable HPV DNA by in situ hybridization; one of these 5 was positive by polymerase chain reaction. In contrast, EMAs displayed weaker staining with patchy distribution (median 30% of tumor cells positive, range 5%-70%) and none contained HPV DNA by in situ hybridization. Two LUS/EC-As, which were positive for HPV, exhibited strong, diffuse p16 expression, consistent with endocervical origin of the tumors. The remaining 2 LUS/EC-As showed patchy p16 staining and did not contain detectable HPV DNA, consistent with the endometrial origin of the tumors.

The p16 expression pattern can distinguish ECAs from EMAs. Compared with HPV DNA detection by in situ hybridization, p16 immunohistochemistry appears to be a more sensitive and easier to perform method for distinguishing ECAs from EMAs, can be used to assist in the classification of LUS/EC-As of equivocal origin, and should be evaluated for its utility in the prospective classification of uterine adenocarcinomas in curettage specimens prior to hysterectomy.

Endometrial endometrioid adenocarcinoma with a deceptive pattern of spread to the uterine cervix: a manifestation of stage IIb endometrial carcinoma liable to be misinterpreted as an independent carcinoma or a benign lesion.

Tambouret R, Clement PB, Young RH.


Am J Surg Pathol. 2003 Aug;27(8):1080-8. Abstract quote

The prognosis of endometrial endometrioid adenocarcinoma is determined in part by stage; endocervical stromal involvement (stage IIB) imparts a worsened prognosis.

We describe a deceptive pattern of stage IIB disease that mimics a primary endocervical glandular proliferation and may lead to understaging of endometrial endometrioid adenocarcinoma. Fifteen cases of endometrial endometrioid adenocarcinoma with a peculiar pattern of cervical involvement were identified from our consultation files. All cases were referred in consultation because of doubt about the nature of the cervical process and its relation to the corpus tumor; in a few instances, the cervical proliferation was considered possibly benign and in one case was misinterpreted as mesonephric hyperplasia. The patients ranged from 49 to 84 years in age (mean age 64.9 years). There was usually a grossly evident endometrial tumor. The cervix was unremarkable grossly in at least 11 patients. The cervical tumors were composed of variably shaped, often tubular glands with little or no stromal response and mainly invaded as widely spaced glands that often appeared deceptively benign. In 14 cases luminal secretions, mainly eosinophilic, were identified, often leading to consideration of a mesonephric lesion. Ten of the endometrial tumors were grade 1, four grade 2, and one grade 3. One was noninvasive, nine superficially invasive, and five deeply invasive. In four cases myoinvasion had, at least in part, a diffusely infiltrative pattern. The tumors in the cervix showed no in situ component and no definite surface involvement. Continuity with the corpus tumor could be demonstrated in 12 cases. Ten of the cervical tumors invaded more deeply than the endometrial tumor, four invaded to a similar depth, and only one was more superficial than its endometrial counterpart. The cervical and corpus tumors had a similar immunoprofile in nine cases: all were vimentin positive, eight estrogen positive and one negative, four carcinoembryonic antigen negative, and five with focal apical or rare cytoplasmic staining.

This immunoprofile in conjunction with routine morphologic similarity between the two tumors and the usual documented continuity between them indicate that the cervical process represents spread from the endometrial endometrioid adenocarcinoma.

It is important for both therapeutic and prognostic reasons that the cervical abnormality is not misinterpreted as a benign or malignant primary endocervical glandular process.

Hormone Receptor Immunohistochemistry and Human Papillomavirus In Situ Hybridization Are Useful for Distinguishing Endocervical and Endometrial Adenocarcinomas

Annette Staebler, M.D.; Mark E. Sherman, M.D.; Richard J. Zaino, M.D.; Brigitte M. Ronnett, M.D.
Am J Surg Pathol 2002; 26(8):998-1006 Abstract quote

Determining the origin of uterine adenocarcinomas can be difficult in biopsy and curettage specimens because the morphologic spectrum of endocervical and endometrial adenocarcinomas overlaps. In addition, in hysterectomy specimens the primary site is often equivocal for tumors that involve predominantly the lower uterine segment and endocervix and lack identifiable precursor lesions.

We assessed the value of immunohistochemistry for estrogen and progesterone receptors and in situ hybridization for human papillomavirus DNA detection in making this clinically relevant distinction. We evaluated a set of 48 adenocarcinomas of unequivocal origin (24 endocervical carcinomas and 24 endometrial endometrioid carcinomas without cervical extension) and then tested seven lower uterine segment/endocervical carcinomas of equivocal origin to determine whether patterns established in the initial set would permit definitive assignment of primary site for the equivocal set. Only one (4.2%) of 24 endocervical carcinomas was positive for both estrogen receptor and progesterone receptor, whereas 18 (75%) of 24 endometrial carcinomas were positive for estrogen receptor and 23 (95.8%) of 24 endometrial carcinomas were positive for progesterone receptor (p <0.001, ?2 test). Human papillomavirus DNA was detected in 16 (66.7%) of 24 endocervical carcinomas and in none of 24 endometrial carcinomas (p <0.001, ?2 test). Of the seven tumors of equivocal origin, five could be definitively classified as either endocervical or endometrial in origin based on their demonstration of a characteristic profile with these assays (either estrogen receptor/progesterone receptor-negative/human papillomavirus-positive, consistent with endocervical origin or estrogen receptor/progesterone receptor-positive/human papillomavirus-negative, consistent with endometrial origin).

We conclude that hormone receptor immunohistochemistry and human papillomavirus in situ hybridization are useful for distinguishing endocervical and endometrial adenocarcinomas. The clinical utility of these techniques should be evaluated in studies that include curettage and biopsy specimens.
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

Invasive micropapillary carcinoma of the breast metastatic to the urinary bladder and endometrium: Diagnostic pitfalls and review of the literature of tumors with micropapillary features.

Ramalingam P, Middleton LP, Tamboli P, Troncoso P, Silva EG, Ayala AG.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.


Ann Diagn Pathol 2003 Apr;7(2):112-9 Abstract quote

Carcinomas with micropapillary features have been described in the breast, urinary bladder, lung, and ovary. They are characterized by the presence of micropapillary tufts in clear spaces. Unequivocal vascular invasion is usually present at the periphery of the tumor. Consequently, these tumors have a high propensity for lymph node metastases and high-stage disease. The metastatic carcinoma can consist exclusively of the micropapillary component, which may elicit an erroneous diagnosis if located in the bladder or lung, as in the patient presented herein.

We present a case of a 59-year-old woman with a history of bilateral breast carcinoma status post-bilateral mastectomy, chemotherapy, and tamoxifen therapy. She presented with urinary frequency, and a pelvic mass was noted. A biopsy of the endometrium revealed a poorly differentiated carcinoma. Urinary bladder biopsies showed a carcinoma with micropapillary features diagnosed as micropapillary transitional cell carcinoma. She presented to M.D. Anderson Cancer Center (Houston, TX) for further treatment recommendations.

The urinary bladder and endometrial biopsies both contained carcinomas with micropapillary features. The mastectomy specimen showed an invasive ductal carcinoma with a significant micropapillary component. The tumor cells from the breast, endometrium, and urinary bladder were positive for cytokeratin (CK) 7 and estrogen receptor and negative for CK20. In view of the morphologic and immunohistochemical profile, the carcinoma in the endometrium and urinary bladder were interpreted as metastatic lesions from the breast primary.

Carcinomas with a micropapillary component are morphologically identical in the breast, urinary bladder, and lung. However, micropapillary serous carcinoma has a different appearance more akin to borderline tumors of the ovary. Immunohistochemical stains are useful in distinguishing these lesions in that thyroid transcription factor-1 positivity suggests a lung primary, CK7 and estrogen receptor suggest a breast primary, and both CK7 and CK20 positivity suggest a urinary bladder primary. It is important to exclude metastatic carcinomas with micropapillary features before making a definite diagnosis of a primary tumor.

Carcinomas with micropapillary features have a propensity for lymph node metastases and advanced stage disease. This article discusses the differential diagnosis of carcinomas with micropapillary features in different organs.

Nodular histiocytic hyperplasia of the endometrium.

Fukunaga M, Iwaki S.

Department of Pathology, Jikei University School of Medicine, Tokyo, Japan.
Arch Pathol Lab Med. 2004 Sep;128(9):1032-4. Abstract quote  

A case of nodular histiocytic hyperplasia of the endometrium is described. A 45-year-old Japanese woman was found to have an enlarged uterus during her annual checkup. Hysterectomy and bilateral salpingo-oophorectomy specimens revealed uterine leiomyomas, adenomyosis, and acute salpingitis.

A 5-mm, well-demarcated, elevated endometrial nodule (an incidental finding) was present and consisted of round or polygonal histiocytic cells with eccentric nuclei and pale or granular cytoplasm. The nuclei were ovoid, reniform, or crescent-shaped and had fine chromatin and inconspicuous nucleoli, and the cytoplasm contained single or multiple vacuoles. Immunohistochemically, the histiocytic cells were positive for vimentin, CD68, and lysozyme and were negative for cytokeratin, S100 protein, estrogen and progesterone receptors, and CD10.

Nodular histiocytic hyperplasia in the endometrium is considered to be a reactive process. Differentiation from neoplasms, including signet-ring cell carcinoma, in curettage specimens is critical to avoid unnecessary surgical resection.

Am J Clin Pathol 2001;115:249-25

5 patients (mean age, 50 years; all had uterine bleeding) whose routine endometrial biopsy and curettage specimens contained prominent signet-ring cells

Each specimen contained loose aggregates of signet-ring cells scattered within the endometrial stroma that were characterized by peripherally displaced, small, uniform nuclei with indistinct nucleoli and showed no mitotic activity. The central portion of the cytoplasm was occupied by single or multiple cytoplasmic vacuoles.

In all cases, the signet-ring cells were reactive for vimentin and negative for epithelial membrane antigen and cytokeratin
Four cases were focally positive for muscle-specific actin or smooth muscle actin and negative for CD68, Mac387, periodic acid–Schiff, mucicarmine, and alcian blue. In these 4 cases, the surrounding endometrial stroma showed decidual changes, and the signet-ring cells demonstrated a morphologic continuum with more typical decidualized stroma. As such, the signet-ring cells in these cases were vacuolated, decidualized endometrial stromal cells

In the remaining case, the vacuolar contents of the signet-ring cells were periodic acid–Schiff–positive and resistant to diastase predigestion, and the cells reacted with Mac387 and CD68. The surrounding stroma showed no decidual reaction. Thus, the signet-ring cells in this case were of histiocytic differentiation

At least 2 directions of differentiation, decidual and histiocytic, are possible.


Prognostic Factors

Stage is the most important
80% present in stage I, limited to the uterus

In general, if there is extrauterine disease, cervical involvement, or vascular invasion, patients are at high risk for recurrence ranging from 20% with one factor to 63% with all three factors

Prognostic Factors-Uterine
Histological type
Depth of myometrial invasion
Cervical involvement
Vascular invasion
Presence of atypical endometrial hyperplasia
Progesterone receptor status
DNA ploidy and S-phase fraction
Prognostic Factors-Extrauterine
Adnexal involvement
Intraperitoneal metastasis
Positive peritoneal cytology
Pelvic and para-arotic lymph node metastases
Prognostic parameters of endometrial carcinoma.

Prat J.

Hum Pathol. 2004 Jun;35(6):649-62. Abstract quote  

Endometrial carcinoma is the most common malignant tumor of the female genital tract in the Western world. Approximately 80% of cases are well- to moderately differentiated (endometrioid) adenocarcinomas, which are confined to the uterine corpus at diagnosis, and thus most can be cured. Conversely, high-grade (ie, clear cell and serous) carcinomas account for only 15% to 20% of cases and show marked nuclear atypia. These tumors usually invade the myometrium and may extend beyond the uterus at the time of hysterectomy. In addition to clinical and morphological differences, these 2 groups of endometrial carcinomas differ in their pathogenesis. Whereas prognosis in the latter group is generally poor, the pathologist's role in establishing the outcome in the former group is crucial. Furthermore, it has become progressively apparent that both groups overlap to some extent, making the dualistic model a guideline at best.

Over the last 2 decades, several studies have demonstrated the prognostic importance of various key surgical and pathological parameters, including histological type, histological grade, surgical-pathological stage, depth of myometrial invasion, vascular invasion, and cervical involvement.

This review presents the most important prognostic factors of endometrial carcinomas from the pathologist's viewpoint, and attempts to clarify existing conflicts in the classification and diagnosis of these tumors.
Expression of Aurora kinases A and B in normal, hyperplastic, and malignant human endometrium: Aurora B as a predictor for poor prognosis in endometrial carcinoma.

Kurai M, Shiozawa T, Shih HC, Miyamoto T, Feng YZ, Kashima H, Suzuki A, Konishi I.

Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Hum Pathol. 2005 Dec;36(12):1281-8 Abstract quote.  

Aurora kinases such as Aurora A and Aurora B are key regulators of mitosis and have been reported to be overexpressed in various malignancies. However, the expression and localization of Aurora kinases in normal and neoplastic endometrial tissues remain undetermined.

In the present study, immunohistochemical expression of Aurora A and B was examined in 40 normal, 30 hyperplastic, and 73 malignant endometria. The data were compared with the expression of Ki-67 and patient survivals. The expression of Aurora A and B at protein and messenger RNA levels was also examined using Western blotting and the reverse transcriptase polymerase chain reaction. The expression of Aurora A in normal endometrium was observed mainly in the proliferative phase and was decreased in the secretory phase. The Aurora A expression was significantly increased in carcinomas compared with normal proliferative endometrium; however, there was no correlation of Aurora A expression with Ki-67 expression or patient survival.

The expression of Aurora B in normal endometrium was significantly higher in the proliferative phase than in the secretory phase. In endometrial carcinomas, the expression of Aurora B was correlated with Ki-67 expression and was significantly increased in high-grade tumors. In addition, patients with Aurora B-positive carcinoma showed poor prognosis compared with those with Aurora B-negative carcinoma (P = .0135).

Accordingly, the present study indicates the aberrant expression of Aurora A and Aurora B in endometrial carcinomas and the clinical importance of Aurora B expression in relationship to patient prognosis.
Clinicopathologic Analysis of 187 High-grade Endometrial Carcinomas of Different Histologic Subtypes: Similar Outcomes Belie Distinctive Biologic Differences.

Departments of *Pathology ‡Epidemiology and Biostatistics ∥Radiation Oncology §Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY †Pathology Department ¶Gillette Center for Womenʼs Cancer, Massachusetts General Hospital, Boston, MA.


Am J Surg Pathol. 2007 Jul;31(7):979-987. Abstract quote

The clinical and histopathologic features of 187 high-grade endometrial cancers [FIGO grade 3 endometrioid (EC-3), serous (SC), and clear cell (CC)] were studied to determine whether clinicopathologic differences between these various histologic subtypes existed. The study group consisted of 89 EC-3s, 61 SCs, and 37 CCs.

Treatment regimens were individualized. SCs and CCs were significantly more likely than EC-3s to occur in patients older than 65 years (P=0.03), and SCs tended to occur more frequently in patients of African descent than EC-3s and CCs (P=0.07), although this was not statistically significant. EC-3s had the highest rate of associated endometrial hyperplasia (P=0.05). SCs were most likely to have high-stage disease at presentation (>/=stage IIB; P=0.01), with peritoneal dissemination at diagnosis being much more common compared with EC-3s and CCs (P=0.004). Median follow-up was 39 months, and median overall survival was 47 months. Five-year survivals were 45% (EC-3), 36% (SC), and 50% (CC)-differences that were not statistically significant. In contrast, the impact of stage on survival was significant (P<0.001). Among all other factors evaluated, only age greater than 65 years was a negative predictor (risk ratio, 2.23; P<0.001), whereas a family history of cancer reduced the risk of death when controlling for stage (risk ratio, 0.54; P=0.005). When controlling for stage, race, reproductive history, personal history of cancer, histologic subtype, depth of myometrial invasion, lymphovascular invasion, presence of an endometrial polyp, presence of hyperplasia, or staging adequacy did not affect prognosis.

High-grade endometrial cancers of different histologic subtypes treated in an individualized manner are associated with similar clinical outcomes, but differences in age at presentation, race distribution, association with hyperplasia, stage, and sites of tumor dissemination support the idea that these represent distinct disease entities as defined by traditional histopathologic classification of endometrial cancers.
Description of a Novel System for Grading of Endometrial Carcinoma and Comparison With Existing Grading Systems.

Alkushi A, Abdul-Rahman ZH, Lim P, Schulzer M, Coldman A, Kalloger SE, Miller D, Gilks CB.

From the *Genetic Pathology Evaluation Centre of the Prostate Centre and Departments of Pathology, Vancouver General Hospital, British Columbia Cancer Agency and University of British Columbia; daggerDepartment of Radiation Oncology, British Columbia Cancer Agency; double daggerDepartments of Medicine and Statistics, University of British Columbia; section signPopulation and Preventive Oncology, British Columbia Cancer Agency; and parallelDepartment of Gynecologic Oncology and Gynecology Tumour Group, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Am J Surg Pathol. 2005 Mar;29(3):295-304. Abstract quote  

The most widely used system for grading of endometrial carcinoma is the International Federation of Gynecology and Obstetrics (FIGO) grading system. This grading system requires evaluation of histologic features that are difficult to assess reproducibly.

Two hundred and two cases of endometrial carcinoma, treated by hysterectomy, were retrieved from the archives of Vancouver General Hospital (1983-1998). For each tumor, the architectural pattern, nuclear grade, and mitotic index were assessed. The tumor architectural pattern, nuclear grade, and mitotic index were significant predictors of patient outcome (P < 0.0001 for each, by univariate analysis). There were no prognostic differences between patients having predominantly solid versus papillary tumors, or tumors with mild versus moderate nuclear atypia. The tumors were then classified into high and low grade based on assessment of these three features.

The presence of at least two criteria of these three: 1) predominantly papillary or solid growth pattern, 2) mitotic index >/=6/10 high power fields, or 3) severe nuclear atypia, resulted in a tumor being considered high grade. Low-grade tumors satisfied at most one of those criteria. The proposed grading system was found to be an independent predictor of patient outcome when patient survival was adjusted for FIGO stage, patient age, and tumor cell type. It also had more prognostic power than other grading systems tested when it was applied to all tumors, regardless of their cell type; however, the FIGO grading system was superior for prognostication when only carcinomas of endometrioid type were considered.

With the FIGO grading system, no significant difference in survival was observed between patients with grade 1 and grade 2 tumors. Combining FIGO grades 1 and 2 results in a binary system (grades 1 and 2 vs. grade 3) that was the most prognostically significant grading system tested, with the additional advantages of being highly reproducible and familiar to practicing pathologists.

A Binary Architectural Grading System for Uterine Endometrial Endometrioid Carcinoma Has Superior Reproducibility Compared With FIGO Grading and Identifies Subsets of Advance-Stage Tumors With Favorable and Unfavorable Prognosis

Sigurd F. Lax, M.D.; Robert J. Kurman, M.D.; Ellen S. Pizer, M.D., Ph.D.; Lee Wu, Ph.D.; Brigitte M. Ronnett, M.D. Kurman RJ, ed.

From the Departments of Pathology (S.F.L., R.J.K., E.S.P., B.M.R.) and Gynecology and Obstetrics (R.J.K., B.M.R.), The Johns Hopkins University School of Medicine and Division of Biostatistics (L.W.), The Johns Hopkins University School of Public Health, Baltimore, Maryland, U.S.A.; and the Department of Pathology (S.F.L.), University of Graz, Austria.

Am J Surg Pathol 2000;24:1201-1208 Abstract quote

The International Federation of Gynecology and Obstetrics (FIGO) grading of uterine endometrial endometrioid carcinoma requires evaluation of histologic features that can be difficult to assess, including recognition of small amounts of solid growth, distinction of squamous from nonsquamous solid growth, and assessment of degree of nuclear atypia.

The authors describe a novel, binary architectural grading system that uses low-magnification assessment of amount of solid growth, pattern of invasion, and presence of necrosis to divide endometrioid carcinomas into low-and high-grade tumors. The authors analyzed its performance for predicting prognosis and with respect to intra-and interobserver reproducibility.

A total of 141 endometrioid carcinomas from hysterectomy specimens were graded according to the FIGO system, nuclear grading, and the binary architectural system. A tumor was classified as high grade if at least two of the following three criteria were present: (1) more than 50% solid growth (without distinction of squamous from nonsquamous epithelium); (2) a diffusely infiltrative, rather than expansive, growth pattern; and (3) tumor cell necrosis. For tumors that were confined to the endometrium, only percent solid growth and necrosis were evaluated, and those with both solid growth of more than 50% and necrosis were considered high grade. All tumors were graded independently by three pathologists on two separate occasions. Both inter-and intraobserver agreement using the binary grading system ( = 0.65 and 0.79) were superior compared with FIGO ( = 0.55 and 0.67) and nuclear grading ( = 0.22 and 0.41). The binary grading system stratified patients into three distinct prognostic groups. Patients with stage I low-grade tumors with invasion confined to the inner half of the myometrium (stages IA and IB) had a 100% 5-year survival rate. Patients with low-grade tumors that invaded beyond the outer half of the myometrium (stage IC and stages II–IV) and those with high-grade tumors with invasion confined to the myometrium (stages IB and IC) had a 5-year survival rate of 67% to 76%. In striking contrast to patients with advance-stage low-grade tumors, patients with advance-stage high-grade tumors had a 26% 5-year survival rate.

This binary grading system has advantages over FIGO and nuclear grading that permit greater interobserver and intraobserver reproducibility and should be tested in other studies of endometrial endometrioid carcinomas to validate its reproducibility and use for segregating patients into different prognostic groups.


Immunohistochemical expression of cyclins, cyclin-dependent kinases, tumor-suppressor gene products, Ki-67, and sex steroid receptors in endometrial carcinoma: Positive staining for cyclin A as a poor prognostic indicator.

Shih HC, Shiozawa T, Kato K, Imai T, Miyamoto T, Uchikawa J, Nikaido T, Konishi I.


Hum Pathol. 2003 May;34(5):471-8. Abstract quote

Although aberrant expression of several cell-cycle regulators has been reported in endometrial carcinoma, correlations among these factors and their prognostic significance have not fully been elucidated.

In the present study, expression of cyclins (D1, E, A, and B1), cyclin-dependent kinases (cdk2, cdk4, and cdc2), and tumor-suppressor gene products (p53, p21, and p27) were systematically examined by immunohistochemistry in 82 cases of endometrial carcinoma and 20 normal endometria. Results were compared with the expression of Ki-67, sex steroid receptor status, clinicopathological parameters, and patient outcomes. Positive staining for cyclin D1, cyclin E, cyclin A, cyclin B1, cdk2, cdk4, cdc2, p53, p21, and p27 was observed in 63%, 66%, 31%, 32%, 51%, 77%, 71%, 43%, 35%, and 60% of the 82 carcinomas, respectively.

Among these factors, positive staining for cyclin D1, cdk4, and p53 was significantly frequent in advanced-stage tumors, and that for cyclin D1, cyclin A, cdk4, p21, and p53 was more frequent in higher-grade tumors. High correlation was found between cyclin A and p53 expression, between cyclin D1 and cdk4 expression, between cdk4 and Ki-67 expression, and between p21 and Ki-67 expression. Multivariate analysis showed that the factors for poor prognosis were advanced stage and cyclin A positivity.

These findings suggest that various cell-cycle regulators are involved in activated cell growth of endometrial carcinoma, and that positive staining for cyclin A could be a useful marker for unfavorable patient prognosis.

Ezrin expression is related to poor prognosis in FIGO stage I endometrioid carcinomas.

Kobel M, Langhammer T, Huttelmaier S, Schmitt WD, Kriese K, Dittmer J, Strauss HG, Thomssen C, Hauptmann S.

1Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
Mod Pathol. 2006 Apr;19(4):581-7. Abstract quote  

As a cortical cytoskeletal protein, ezrin adapts the cytoplasmic tail of CD44 to the actin-based cytoskeleton and is functionally involved in migration and adhesion that are prerequisites for metastasis.

To assess the importance of ezrin and its associated protein osteopontin for the progression of endometrioid carcinoma in FIGO stage I, we analyzed paraffin-embedded tissue from 164 patients by immunohistochemistry and correlated these data with clinicopathological parameters. Ezrin was expressed in normal proliferating endometrial glands, as was confirmed by quantitative PCR and immunohistochemistry. In endometrioid carcinoma, enhanced ezrin expression correlated with a reduced overall survival in univariate analysis (P=0.041). In contrast, no significant correlation was found for osteopontin. In multivariate survival analysis, among FIGO grade 3 and age, ezrin was still found to be an independent risk factor (relative risk 2.2, confidence interval 1.0-5.4, P=0.047).

Hence, elevated ezrin expression is a new independent prognostic marker in FIGO stage I endometrioid carcinoma, and thus provides further evidence for an important role of ezrin in tumor progression.

Analysis of HER-2/neu amplification in endometrial carcinoma by chromogenic in situ hybridization. Correlation with fluorescence in situ hybridization, HER-2/neu, p53 and Ki-67 protein expression, and outcome.

Peiro G, Mayr D, Hillemanns P, Lohrs U, Diebold J.

1Institute of Pathology, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Munchen, Germany.
Mod Pathol. 2004 Jan 30 [Epub ahead of print] Abstract quote

Fluorescence in situ hybridization (FISH) is the most widely used technique to detect HER-2/neu gene amplification; however, it is only available in some institutions. In contrast, chromogenic in situ hybridization (CISH) can be evaluated by routine light microscopy. In endometrial carcinoma there are few data concerning HER-2/neu status and prognosis.

Therefore, we determined HER-2/neu gene status by CISH using a digoxigenin-labelled probe on 60 formalin-fixed paraffin-embedded endometrial carcinomas. The data were compared with the immunohistochemistry of HER-2/neu (A0485, TAB250), p53, Ki-67, clinicopathological factors, and survival. By conventional light microscopy, HER-2/neu amplification (>/=6 copies >50% cancer cells) was detected in 14% (8/59) tumours, HER-2/neu overexpression (>10% cells moderate/strong complete membrane staining) in 22% (13/60) for A0485, and 18% (11/60) for TAB250, p53 (>10% +cells) in 61% (36/59), and Ki-67 (>50% +cells) in 50% (30/60). Discordant cases for CISH and immunohistochemistry, as well as all (2+) were further analysed by FISH (Vysis). Among 10 cases (2+) and not amplified by CISH, two showed low-level amplification by FISH. Significant correlation was found between amplification and protein overexpression (P</=0.001), and a trend with nonendometrioid type, higher grade, and older age. A better outcome (Kaplan-Meier) was observed for patients with nonamplified (1-5 copies per nucleus) or low-level (6-10 copies) amplification tumours, low Ki-67 expression, age <50 years, endometrioid type, low FIGO (International Federation of Obstetrics and Gynaecology) grade and stage, superficial myometrial infiltration, and no lymph-vascular invasion (P</=0.036), but only as a trend for HER-2/neu protein negative (P=0.13). Cox analysis revealed age, FIGO grade and stage, myometrial infiltration, and lymph-vascular invasion to be independent prognostic factors (P</=0.05), and a trend for HER-2/neu gene copy number (0.18).

In endometrial carcinoma, HER-2/neu gene status can be readily assessed by CISH in routine clinical practice, and it gives more prognostic information than HER-2/neu by immunohistochemistry. FISH analysis in (2+) cases but negative by CISH may detect additional tumours with low-level amplification.

Markers of proliferative activity are predictors of patient outcome for low-grade endometrioid adenocarcinoma but not papillary serous carcinoma of endometrium.

Al Kushi A, Lim P, Aquino-Parsons C, Gilks CB.

Department of Pathology, Vancouver General Hospital and British Columbia Cancer Agency, Vancouver, British Columbia, Canada.


Mod Pathol 2002 Apr;15(4):365-71 Abstract quote

On the basis of pathogenesis, two types of endometrial cancer can be recognized. Type 1 endometrial carcinomas are relatively indolent tumors that develop after prolonged estrogen stimulation, on a background of endometrial hyperplasia. Type 2 endometrial carcinomas are aggressive tumors that are not associated with hyperplasia or estrogen excess.

The aim of this study is to evaluate the prognostic significance of tumor proliferative activity in early-stage endometrial cancer by using mitotic index and immunostaining, comparing Type 1 (endometrioid) and Type 2 (papillary serous carcinoma) tumors. The mitotic index, MIB-1, and p53 immunostaining in 39 tumors from patients with low-grade Stage Ia or Ib endometrioid adenocarcinoma; as well as 23 tumors from patients with Stage I papillary serous carcinoma. In low-grade endometrioid adenocarcinoma, mitotic and MIB-1 indices were statistically significant independent prognostic indicators (P =.004 and P =.018, respectively), and both were strongly correlated with p53 expression (P =.01 and P =.006, respectively). The mean mitotic index was 5 mitoses/10 high-power fields, and mean MIB-1 index was 27.5%. There was no significant correlation between mitotic or MIB-1 indices and patient outcome or p53 expression in papillary serous carcinoma. The mean mitotic index was 31 mitoses/10 high-power fields, and mean MIB-1 index was 30.5% in these tumors. p53 expression and proliferative indices are strongly correlated in low-grade endometrioid adenocarcinoma. MIB-1 and mitotic indices are independent prognostic indicators in these tumors.

Papillary serous carcinoma of endometrium is rapidly proliferative in tumors even at an early stage, and quantification of proliferative activity in these tumors does not allow prediction of patient outcome.


Prognostic Relevance of hMLH1, hMSH2, and BAX Protein Expression in Endometrial Carcinoma

Gloria Peiró, M.D., Joachim Diebold, M.D., Doris Mayr, M.D., Gustavo B. Baretton, M.D., Rainer Kimmig, M.D., Michael Schmidt, M.D. and Udo Löhrs, M.D.

Institute of Pathology (GPJD, DM, GBB, UL), Department of Gynecology and Obstetrics (RK), and Tumor Registry (MS), Ludwig-Maximilians University Munich, München, Germany

Mod Pathol 2001;14:777-783 Abstract quote

Endometrial carcinoma is the most common gynecologic malignancy in perimenopausal and postmenopausal women. A role of mismatch repair genes, like hMLH1 and hMSH2 in their pathogenesis, has been suggested. Loss of their function leads to the accumulation of replication errors (mutator phenotype), which are responsible for further mutations in genes with microsatellite sequences in their coding region, such as Bax.

We analyzed the expression of hMLH1, hMSH2, and Bax genes in 89 formalin-fixed paraffin-embedded endometrial carcinomas. The immunostains were scored with regard to percentage of positive tumor cells (0%, <10%, 10 to 50%, >50%), and relative staining intensity (1+, 2+, 3+). The staining results were correlated with clinicopathologic features and survival.

Loss of hMSH2 expression (0% positive cells) was observed in 1.1% (1/89) of the tumors; loss of hMLH1 was seen in 12.4% (11/89) of the cases, particularly in endometrioid tumors with mucinous differentation (5/11; 45%; P = .03). No significant association was found between the immunoscores and grade, stage criteria of the International Federation of Obstetrics and Gynecology (FIGO), or age of the patients. Among 11 tumors with loss of Bax expression (12.4%), 4 had also loss of hMLH1 (4/11; 36.4%; P = .017). In multivariate analysis (Cox model), significantly longer survival was found for patients with tumors in FIGO Stage I–II (P < .0001), endometrioid type (P = .001), low grade (P = .001), and absence of hMLH1 expression (P = .027).

Our results suggest that loss of function of hMLH1 and Bax occur in a subgroup of endometrial carcinoma. In addition to the classical prognostic factors, absence of hMLH1 expression is associated with better outcome of patients.

Microsatellite instability, loss of heterozygosity, and loss of hMLH1 and hMSH2 protein expression in endometrial carcinoma.

Peiro G, Diebold J, Lohse P, Ruebsamen H, Lohse P, Baretton GB, Lohrs U.

Institute of Pathology and the Department of Clinical Chemistry, Grosshadern Hospital Ludwig-Maximilian University of Munich, Munich, Germany.


Hum Pathol 2002 Mar;33(3):347-54 Abstract quote

Microsatellite instability (MSI) due to replication errors occurs frequently in hereditary tumors. Association with functional inactivation of the mismatch repair (MMR) genes and lack of protein expression has been described. In endometrial carcinoma (EC), the prevalence and clinical significance of these phenomena are not well known.

Therefore, DNA samples from 89 EC and 5 metachronous tumors were analyzed with polymerase chain reaction, using 5 microsatellite markers and a DNA sequencer for amplicon detection. The results were correlated with immunohistochemistry of hMLH1 and hMSH2. MSI at >/=2 loci (MSI-H) was detected in 10/89 EC (11%); 1 of 10 showed loss of both hMLH1 and hMSH2, and 5 of 10 showed loss of hMLH1 (P < 0.0001). MSI-H was observed frequently in tumors with mucinous differentiation (P = 0.048), >10% of solid-cribriform pattern (P = 0.037), International Federation of Obstetrics and Gynecology (FIGO) stage III to IV (4 of 13; P = 0.016), and necrosis >5% (P = 0.07). Loss of heterozygosity (LOH) in >/=1 loci was found in 17 of 156 (11%). Survival (Kaplan-Meier) was longer for patients with endometrioid tumors with predominant glandular pattern, <5% necrosis, low FIGO stage and grade, superficial myometrial infiltration, no lymph-vascular invasion (LVI), and loss of hMLH1 expression (all P </= 0.04). Cox analysis showed independent value for stage, grade, histologic type and pattern, LVI, and hMLH1 expression (all P < 0.05).

Age, MSI status, LOH, peritumoral inflammatory reaction, hMSH2, and development of metachronous tumors did not influence survival. In conclusion, MSI phenotype was observed in a small subset of mainly advanced-stage EC, frequently showing mucinous differentiation, areas of solid-cribriform pattern, and necrosis. It is often associated with loss of hMLH1 expression, which may be a prognostic marker, but only rarely with defects of hMSH2.


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.

Upstaging based solely on positive peritoneal washing does not affect outcome in endometrial cancer.

Fadare O, Mariappan MR, Hileeto D, Wang S, McAlpine JN, Rimm DL.

1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Mod Pathol. 2005:18:673-680 Abstract quote  

Surgical staging of endometrial carcinoma includes the collection of peritoneal washings in the abdomen and pelvis. A positive finding upstages patients to International Federation of Gynecology and Obstetrics stage IIIA. However, the prognostic significance of such an upstaging, and thus the justification for the routine performance of this procedure, is unclear.

This 5-year retrospective study was conducted to determine the frequency and prognostic significance of upstaging of endometrial carcinoma based solely on positive washings. The cohort for the study was collected by review of pathology reports of all washings that were performed prior to hysterectomies for suspected endometrial carcinomas over a 5-year period (01/1995-12/1999). Cases with positive cytology were selected if there was no grossly apparent intraperitoneal disease, no histologic evidence of extra-uterine tumor and the cases would otherwise have been considered stage I or II (case group). An age-matched control group was selected of stage I and II patients with the same histologic subtypes and negative washings (n=19). Of 220 endometrial carcinomas, peritoneal washing cytology was abnormal in 19 (8.6%) and was solely responsible for upstaging only 10 patients (4.5% of all cases, eight-endometrioid, one-serous, one-mixed; nine stage IA or IB and one stage IIB). Adjuvant therapy was administered in 90% of the case group and 74% of the control group. After a median follow-up of 51 months (case group) and 63 months (control group), we found only a single patient with progression of disease (recurrence, metastases or death) in the control group.

It is concluded that abnormal cytology without other evidence of extrauterine disease leads to upstaging of a minority of endometrial carcinoma patients (4.5%), but does not appear to affect their overall outcome. Although this is a small single site study, it raises questions about the value of this procedure in patients with endometrial cancer.

Role of DNA ploidy analysis in endometrial adenocarcinoma

Darshana N. Jhala, MD
Barbara F. Atkinson, MD
Gulnar R. Balsara, MD
Enrique Hernandez, MD
Nirag C. Jhala, MD

Ann Diagn Pathol 2001;5:267-273 Abstract quote

Endometrial adenocarcinoma is the leading cause of malignancy of the female genital tract. Prognosis of this tumor, which has implications on patient management, is determined by evaluation of the stage of disease, architectural grade, nuclear grade, myometrial invasion, and peritoneal cytology. These parameters have inherent subjectivity and, therefore, the search for an objective reliable parameter to determine prognosis is required. DNA ploidy is under investigation as an objective and reproducible prognostic parameter.

This study will evaluate the role of DNA ploidy and its relationship to the traditional parameters as predictors of prognosis in patients with endometrial carcinoma. Fifty-eight patients were evaluated by two observers for architectural grade according to the International Federation of Gynecology and Obstetrics classification, nuclear grade, and depth of myometrial invasion. DNA ploidy was evaluated using flow cytometer (FACscan, Becton Dickinson, San Jose, CA). Histologic parameters were than compared with DNA ploidy. Survival data were obtained from the tumor registry. Results of patient survival were compared with histologic parameters and DNA ploidy. Higher nuclear grade and aneuploidy correlated with poor survival rate (P < .05). Higher nuclear grade correlated with aneuploidy. The survival of patients with architectural grade 2 (moderately differentiated) endometrial adenocarcinoma is poorer if the tumor is aneuploid as compared with diploid as determined by flow cytometry.

In conclusion, aneuploidy and nuclear grade correlates with poor patient survival. The poorer survival rates with aneuploid architectural grade 2 endometrial adenocarcinoma may have an impact on clinical management.


High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus

Gabriele Bonatz, MD, Sven O. Frahm, MD, Wolfram Klapper, MD, Andreas Helfenstein, MD , Klaus Heidorn, PhD, Walter Jonat, MD, Guido Krupp, PhD, Reza Parwaresch, MD, and Pierre Rudolph, MD

Hum Pathol 2001;32:605-614. Abstract quote

Telomerase activity, a mechanism granting cellular immortality, has been detected in most cancer entities, but its association with clinical, histopathologic, and prognostic parameters is not fully understood.

We investigated whether quantitative telomerase levels are correlated to established prognostic factors, telomere lengths, cell cycle kinetics, and the clinical course in endometrioid adenocarcinoma of the uterus (EC).

A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telomerase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immunohistochemically on paraffin sections using monoclonal antibodies to 2 distinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the expression of which is restricted to the cell cycle phases S, G2, and M. The ratio of the 2 immunolabeling indices defines the rate of transition through the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P = .01) and FIGO grade (P = .003) but not with myometrial invasion. They were weakly associated with the overall proliferative activity (Ki-67, r = .48) but significantly with the repp86 index (r = .64) and even more strongly with the repp86:Ki-67 ratio (r = .77). There was no correlation with mean telomere length. In the group of tumors with high telomerase activity, 5 patients had relapses and 2 died of the disease within a median follow-up period of 29 months. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion, and Ki-67 indices, telomerase activity emerged as the only independent predictor of disease progression (P = .0002).

It is concluded that beyond a link to proliferation, high telomerase activity reflects a deregulation of the cell cycle associated with an increased rate of cells entering S phase and a higher degree of malignancy. Therefore, quantitative analysis of telomerase activity may be useful for identifying EC patients at high risk for recurrence.


Thymidine phosphorylase expression in tumor-infiltrating macrophages may be correlated with poor prognosis in uterine endometrial cancer.

Tanaka Y, Kobayashi H, Suzuki M, Kanayama N, Suzuki M, Terao T.

Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan, and Department of Obstetrics and Gynecology, Jichi University School of Medicine, Tochigi, Japan

Hum Pathol 2002 Nov;33(11):1105-13 Abstract quote

Expression of thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, in several types of malignant tumors has been associated with angiogenesis and an unfavorable prognosis.

We performed a retrospective study on the immunohistochemical expression of TP in patients with uterine endometrial cancer to investigate correlations between the expression of TP and the clinicopathologic features and the prognosis. The immunohistochemical staining for TP, CD68 (macrophage/monocyte-specific antibody), and von Willebrand factor was performed in surgically resected specimens from 101 patients with operable endometrial cancer. A semiquantitative grading system was used to examine the staining pattern for TP. Positive staining for both cancer cell and tumor stromal cell TP was noted in 41% of the cases. Most of tumor stromal cells expressing TP were shown to coexpress CD68. High angiogenesis was also associated with TP overexpression in either cancer cells or tumor stromal cells.

When stromal macrophages/fibroblasts exhibited high TP expression, independent of whether cancer cells showed the positive TP expression, a significant decrease in disease-free survival and overall survival was observed, which was found to be an independent prognostic factor. Stromal macrophage/fibroblast TP expression remained significant on multivariate analysis.

We conclude that (1) TP is present in both cancer cells and stromal macrophages/fibroblasts, (2) high angiogenesis correlated with TP overexpression, (3) TP produced by neighboring tumor-infiltrating macrophages may play a part in the regulation of the local invasion and distant metastatic behavior, and (4) TP overexpression in stromal macrophages/fibroblasts may be associated with a poor prognosis.

5 Year Survival

Stage I 90%
Stage II 30-50%
Stage III-IV <20%

Overall 78%


Regional lymph nodes
Peritoneum and omentum

TREATMENT Surgery alone or in combination with radiation therapy

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.

Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports.

Rose PG, Brandewie EV, Abdul-Karim FW.

The Division of Gynecologic Oncology, Department of Reproductive Biology and The Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio.

Int J Gynecol Cancer 1999 Sep;9(5):362-364 Abstract quote

Tamoxifen's agonist effect on the endometrium has been associated with an increased incidence of endometrial carcinoma. It has been suggested that this agonist effect may be averted by the concomitant use of a progestational agent.

We report two patients with breast cancer receiving tamoxifen who developed endometrial carcinoma and atypical endometrial hyperplasia, respectively. In one patient, this occurred despite the use of concomitant megestrol acetate. In the other patient, tamoxifen-associated endometrial hyperplasia persisted and progressed despite cessation of tamoxifen and initiation of megestrol acetate therapy.

These cases may have implications for strategies to avert tamoxifen induced endometrial neoplasia.

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Uterus and cervix

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