This disease is a frequent precursor to cases of endometrial carcinoma of
the uterus. Both diseases present with abnormal uterine bleeding. The treating
physician commonly performs a dilatation and curettage of the uterus yielding
abundant tissue showing the characteristic histology. Pathologists have refined
the diagnostic accuracy of this diagnosis stratifying endometrial hyperplasia
by both histology and risk of progression to carcinoma.
| DISEASE ASSOCIATIONS |
CHARACTERIZATION |
| ESTRADIOL |
|
Estradiol-induced hyperplasia in endometrial biopsies
from women on hormone replacement therapy.
Wright TC, Holinka CF, Ferenczy A, Gatsonis CA, Mutter GL,
Nicosia S, Richart RM.
|
Am J Surg Pathol 2002 Oct;26(10):1269-75
|
| TAMOXIFEN |
|
| 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. |
| PATHOGENESIS |
CHARACTERIZATION |
| APOPTOSIS |
|
| Dissociated Expression of Bcl-2 and Ki-67 in Endometrial
Lesions: Diagnostic and Histogenetic Implications
Björn Risberg, M.D., Ph.D.; Kerstin Karlsson, B.Sc.; Vera Abeler,
M.D., Ph.D.; Anders Lagrelius, M.D., Ph.D.; Ben Davidson, M.D., Ph.D.;
Mats G. Karlsson, M.D., Ph.D.
From the Department of Pathology, The Norwegian Radium Hospital
(B.R., V.A., B.D.), Oslo, Norway; the Gynecological Clinic, Huddinge
Hospital (A.L.), Karolinska Institute, Sweden; Astra-Zeneca Medical
Development (K.K.), Södertälje, Sweden; and the Department
of Pathology, Medical Center Hospital (M.G.K.), Örebro, Sweden.
|
Int J Gynecol Pathol 2002;21:155-160 Abstract quote
The objective of the present study was to analyze the expression of
the proliferation marker, Ki-67, and the anti-apoptotic protein, bcl-2,
in various endometrial lesions. Ki-67 and bcl-2 expressions were studied
in 194 specimens of endometrial hyperplasia, polyps, carcinomas, and
cyclic endometrium from a defined geographic area.
Results were statistically analyzed with respect to marker expression,
localization to the stromal or glandular component, and intraglandular
topography. The lowest glandular Ki-67 expression was seen in secretory
endometrium, in polyps, and in atypical hyperplasia. The Ki-67 score
was significantly higher and less heterogeneous in endometrial carcinomas
than in hyperplasia (p<0.001). Endometrial hyperplasia of all types
was characterized by a markedly heterogeneous glandular expression of
Ki-67. The glandular expression of bcl-2 was highest in proliferative
endometrium and polyps. Bcl-2 expression was significantly lower in
adenocarcinomas than in hyperplastic lesions (p=0.002). Ki-67 and bcl-2
expression showed a significant association in proliferative endometrium
(p=0.003). Endometrial polyps demonstrated a unique pattern of very
low expression of Ki-67 and high bcl-2 expression in both stroma and
glands.
Our findings indicate that an imbalance between proliferation and
apoptosis may be an important factor in the development of different
endometrial lesions, benign as well as malignant. The specific finding
of inter- and intraglandular Ki-67 heterogeneity may be valuable as
an adjunct to morphology in the differential diagnosis of endometrial
hyperplasia. |
| CHROMOSOMAL ALTERATIONS |
|
-
Distinct Molecular Alterations in Complex Endometrial Hyperplasia (CEH) With and Without Immature Squamous Metaplasia (Squamous Morules).
Brachtel EF, Sanchez-Estevez C, Moreno-Bueno G, Prat J, Palacios J, Oliva E.
From the *Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA; daggerLaboratory of Breast and Gynecological Cancer, Molecular Pathology, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; and double daggerDepartment of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. Supported in part by the Fondo de Investigaciones Sanitarias Grant No. FIS 02/0355.
|
-
| Am J Surg Pathol. 2005 Oct;29(10):1322-1329. Abstract quote |
|
Several molecular alterations, most commonly PTEN mutations but also K-ras mutations, microsatellite instability, and beta-catenin mutations have been detected in endometrioid endometrial carcinoma (EEC). Specifically, mutations in the beta-catenin gene are seen in 15% to 20% of EECs, whereas immunohistochemical expression of beta-catenin ranges from 13% to 44%, nuclear staining being concentrated in areas of immature squamous metaplasia (squamous morules). Complex endometrial hyperplasia with atypia (CEH-A) is a well-known precursor of EEC, which can also show immature squamous metaplasia.
In this study, we compared the immunohistochemical and molecular profiles of 13 CEH-A with and 11 CEH-A without squamous morules (SM) for mutations of beta-catenin, PTEN, K-ras, and microsatellite instability (MSI). In all cases of CEH-A with SM, beta-catenin immunostaining showed strong and diffuse nuclear expression in areas of SM and weak to moderate nuclear expression in the glandular component. Six different beta-catenin mutations were found in 7 of 13 cases (54%) (G34E, G34V, S33C, D32Y, S33F, D32A); however, no mutations of the PTEN or K-ras genes were identified. beta-Catenin immunostaining showed focal nuclear staining in only 2 cases of CEH-A without SM. Only 1 case had a beta-catenin mutation (S45A), which was associated with a K-ras mutation (G12D). Another 3 cases had both PTEN and K-ras mutations (C296Stop Ex 8 and G12V, 244del C Ex 7 and G12D, 251ins TGAT Ex 7 and G13D), and one had a PTEN mutation (G230E Ex 7) only. Of all 24 cases, only 1 case of CEH-A without SM showed MSI. In conclusion, marked differences in the molecular profiles regarding beta-catenin, PTEN, and K-ras mutations were observed between CEH-A with and without SM. beta-catenin mutations might represent a signaling pathway leading to a distinctive morphology in hyperplastic/neoplastic endometrium with SM. Other molecular events such as K-ras or PTEN mutations are likely to occur in CEH-A independently from beta-catenin. Furthermore, morphologic differences between CEH-A with SM and CEH-A without SM seem to correlate, at least to some extent, with the clinical course of the disease.
In our series, cases of CEH-A with SM and beta-catenin alterations appeared to have a less aggressive behavior when compared with CEH-A without SM and with K-ras and PTEN mutations.
|
| ESTROGEN STIMULATION |
|
|
Atypical endometrial hyperplasia shares genomic abnormalities with
endometrioid carcinoma by comparative genomic hybridization
Huseyin Baloglu, MD, Linda A. Cannizzaro, PhD, Joan Jones, MD, and
Leopold G. Koss, MD |
Hum Pathol 2001;32:615-622 Abstract quote
Endometrial hyperplasia is a common disorder that is now observed
with increasing frequency in women treated with hormonal replacement
therapy or with tamoxifen.
This study was undertaken to determine whether genomic features of
various forms of endometrial hyperplasias would allow their classification
as a benign, premalignant, or malignant abnormality.
Comparative genomic hybridization (CGH) was performed on endometrial
glands microdissected by laser capture microscope from 19 archival endometrial
samples, comprising 5 normal endometria, 1 polyp, 2 simple hyperplasias,
5 hyperplasias with nuclear abnormalities (atypical hyperplasias), and
4 low-grade and 2 high-grade endometrioid carcinomas, 1 with squamous
component (adenoacanthoma). Genomic DNA, extracted from the glands and
the squamous component in 1 case, was amplified by degenerate oligonucleotide—primed
polymerase chain reaction (DOP-PCR) and compared with sex-matched DNA
by CGH. No genomic imbalances were observed in the normal samples, the
polyp, or the simple hyperplasias. However, in atypical hyperplasia,
regardless of the level of cytologic atypia, genomic abnormalities were
observed that also occurred in endometrioid carcinomas. Chromosomes
1, 8, and 10 were most often affected. The results are compared with
molecular genetic abnormalities recently reported in these lesions.
This study strongly suggests that atypical endometrial hyperplasias
are closely related to endometrioid carcinoma and should be considered
precancerous lesions, contrary to simple hyperplasia, which is a benign
disorder. The squamous component of one of the high-grade carcinomas
showed genetic abnormalities similar to those of endometrioid carcinoma
and therefore does not represent squamous metaplasia but is an integral
part of the malignant process. |
| MISMATCH REPAIR GENES |
|
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. |
LABORATORY/
RADIOLOGIC |
CHARACTERIZATION |
| HYSTEROSCOPY |
|
|
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).
|
| ULTRASOUND |
|
|
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.
|
| HISTOLOGICAL TYPES |
CHARACTERIZATION |
| General |
Each category is further divided by the presence or absence of cytologic
atypia
Atypia is defined as stratified cells with loss of polarity and increased
nuclear:cytoplasmic ratio |
-
Diagnosing Endometrial Hyperplasia: Why is it so Difficult to Agree?
-
Departments of *Pathology †Obstetrics and Gynecology ‡Epidemiology, University of Washington Medical Center §Public Health Sciences Division, Fred Hutchinson Cancer Research Center ∥Group Health Center for Health Studies, Seattle, WA.
|
-
Am J Surg Pathol. 2008 May;32(5):691-698.
Abstract quote
Current World Health Organization classification of endometrial hyperplasia is problematic because of poor diagnostic reproducibility.
We sought to determine factors that cause diagnostic disagreement in a review of 2601 endometrial specimens. Blinded random specimens of normal endometrium, hyperplasias, and carcinoma were reviewed by 2 pathologists, with review by a third pathologist in cases with disagreement.
All cases of endometrial hyperplasia or carcinoma were scored for degree of glandular crowding, architectural complexity, and cytologic atypia. Sample adequacy, hyperplasia volume, presence of metaplasia, or endometrial polyp were also scored. The overall kappa for agreement was 0.71, with a lower kappa of 0.36 when cases called "no hyperplasia" were excluded. The percent specific agreement was 90.3% for no hyperplasia, 31.1% for simple hyperplasia, 51.1% for complex hyperplasia, 49.8% for atypical hyperplasia, and 57.5% for adenocarcinoma. Cases categorized as "low volume hyperplasia" had more diagnostic disagreement than "high volume," (62% vs. 39%, P=0.003). Similarly, cases called "scant" had more diagnostic disagreement than "not scant" (65% vs. 57%, P=0.013).
The histologic feature associated with the most diagnostic disagreement was cytologic atypia (P<0.0001). Architectural crowding, architectural complexity, or the presence of a polyp were all associated with diagnostic disagreement (P<0.0001).
High diagnostic disagreement in endometrial hyperplasia is related to both sample adequacy and interpretation of histologic features present. Although obtaining additional tissue may increase diagnostic reproducibility, differences in interpretation of key histologic features like cytologic atypia remain major factors contributing to diagnostic disagreement.
|
|
Prospective Multicenter Evaluation of the Morphometric D-Score for
Prediction of the Outcome of Endometrial Hyperplasias
Jan P. A. Baak, M.D., Ph.D.; Anne Ørbo, M.D., Ph.D.; Paul J. van
Diest, M.D., Ph.D.; Mehdi Jiwa, M.D., Ph.D.; Peter de Bruin, M.D., Ph.D.;
Marc Broeckaert, B.Sc.; Wim Snijders, M.D.; P. Jan Boodt, M.D., Ph.D.;
Guus Fons, M.D.; Curt Burger, M.D., Ph.D.; Renee H. M. Verheijen, M.D.,
Ph.D.; Paul W. H. Houben, M.D., Ph.D.; H. Sien The, M.D., Ph.D.; Peter
Kenemans, M.D., Ph.D.
From the Departments of Pathology (J.P.A.B., P.J.v.D., M.B.) and
Gynecology (C.B., R.H.M.V., P.K.), Free University Medical Center, Amsterdam;
the Departments of Pathology (J.P.A.B., M.J., P.d.B.) and Gynecology
(W.S., P.J.B., G.F.), Medical Center Alkmaar, Alkmaar; the Department
of Gynecology (P.W.H.H., H.S.T.), Gemini Hospital, Den Helder, The Netherlands;
and the Department of Pathology (A.O.), Institute of Medical Biology,
University of Tromsø, 9037 Tromsø, Norway |
Am J Surg Pathol 2001;25:930-935 Abstract quote
Prospective multicenter evaluation of the WHO classification and the
morphometric D-score to predict endometrial hyperplasia cancer progression.
In 132 endometrial hyperplasias WHO classification was performed by
two experienced gynecologic pathologists. The D-score was assessed blindly
by technicians in a routine diagnostic setting. Development of endometrial
carcinoma during a 1–10-year follow-up was used as the end point. Eleven
of 132 patients (8%), 10 of 61 (16%) atypical hyperplasias, and 1 of
71 (1%) nonatypical hyperplasias developed cancer. Twenty-six curettings
had a D-score 0 (``unfavorable'' or endometrial intraepithelial neoplasia)
of which 10 (38%) developed cancer. None of the 86 cases with a D-score
>1 (``favorable'') and one of the 20 (5%) cases with 0 < D-score 1 (``uncertain'')
developed cancer. Sensitivity of the D-score was 100%, specificity 82%,
the positive and negative predictive values were 38% and 100%, respectively.
These values are similar to those in three prior retrospective D-score
studies but higher than the WHO values (which are 91%, 58%, 16%, and
99%, respectively).
The D-score in endometrial hyperplasias is a more sensitive and specific
marker for cancer prediction than the WHO classification, can be assessed
in a routine clinical setting on standard hematoxylin and eosin sections
(15–30 minutes per case), and is highly reproducible and cost-effective
(U.S. $50 per case). |
|
Accuracy of outpatient endometrial biopsy in the diagnosis of endometrial
hyperplasia.
Clark TJ, Mann CH, Shah N, Khan KS, Song F, Gupta JK.
Academic Department of Obstetrics & Gynaecology, Birmingham
Women's Hospital, Birmingham B15 2TG, U.K
|
Acta Obstet Gynecol Scand 2001 Sep;80(9):784-93 Abstract
quote
BACKGROUND: To determine the accuracy of outpatient endometrial biopsy
in diagnosing endometrial hyperplasia in women with abnormal uterine
bleeding. DESIGN: Systematic quantitative review of published medical
literature.
DATA SOURCES: Relevant papers were identified through electronic scanning
of MEDLINE (1980-1999) and EMBASE (1980-1999), manual searching of bibliography
of known primary and review articles and contact with manufacturers.
REVIEW METHODS: Studies were selected if accuracy of outpatient endometrial
biopsy, in women with abnormal pre or postmenopausal uterine bleeding,
was estimated compared to a reference standard, which was endometrial
histology obtained by tissue sampling under anesthesia. Quality assessment
and data extraction were performed in duplicate. Diagnostic accuracy
was determined by pooled likelihood ratios (LR) for positive and negative
test results for endometrial hyperplasia.
RESULTS: There were 881 subjects in 8 diagnostic evaluations reported
in 6 primary studies. Postmenopausal women represented 25% of the participants
studied. There were 43 patients in whom outpatient sampling was inadequate.
A positive test result on outpatient biopsy diagnosed endometrial hyperplasia
with a pooled LR of 12.0 (95% CI 7.8-18.6) while a negative test result
had a pooled LR of 0.2 (95% CI 0.1-0.3). With a positive test result,
the posttest probability of endometrial hyperplasia was 57.7% (95% CI
41.1%-72.7%) while it was 2.2% (95% CI 0.9%-4.1%) with a negative test.
CONCLUSION: Outpatient endometrial biopsy has modest accuracy in diagnosing
endometrial hyperplasia. Therefore, additional endometrial assessment
should be undertaken, especially if symptoms persist or intrauterine
structural abnormalities are suspected. |
| Simple |
Increase in the glandular and stromal components with slight
architectural abnormalities |
| Complex |
Crowded glands with little intervening stroma
Back to back glands and papillary intraluminal infoldings |
|
Simple and Complex Hyperplastic Papillary Proliferations of the
Endometrium A Clinicopathologic Study of Nine Cases of Apparently Localized
Papillary Lesions With Fibrovascular Stromal Cores and Epithelial Metaplasia
Michael B. Lehman, M.D. ; William R. Hart, M.D.
From the Department of Anatomic Pathology, Division of Pathology
and Laboratory Medicine, Cleveland Clinic Foundation, Cleveland, Ohio,
U.S.A. |
Am J Surg Pathol 2001;25:1347-1354 Abstract quote
The clinicopathologic features of nine cases of papillary proliferation
of the endometrium devoid of malignant nuclear features were studied.
The patients ranged in age from 33 to 71 years (median 57 years). All
were postmenopausal, except the youngest. The most common symptom was
postmenopausal bleeding. Two patients were receiving hormonal replacement
therapy and two were taking megestrol acetate. Two lesions were incidental
findings in a hysterectomy specimen. Seven were diagnosed in endometrial
biopsy or curettage specimens. In six cases (67%) the lesion involved
an endometrial polyp.
In all cases the papillae had fibrovascular stromal cores and variable
degrees of branching. Two architectural patterns were found.
A simple papillary pattern with involvement of only a few glands and
little epithelial proliferation occurred in five cases, including three
that were entirely intracystic.
A complex papillary pattern with more extensive involvement of endometrial
glands, a greater degree of branching of the papillae, and cellular
tufting occurred in four cases. One or more metaplastic epithelial changes
occurred in all cases, including endocervical-type mucinous metaplasia
in nine cases (90%), eosinophilic cell change in eight (89%), ciliated
cell change in seven (70%), focal squamous metaplasia in two cases (22%),
and hobnail cell change in two (22%). Mitotic figures were found in
three cases. In four lesions (44%), all with a complex papillary pattern,
the proliferating cells had mild nuclear atypia. Three of these patients
underwent hysterectomy within 5 months. Simple nonpapillary hyperplasia
and two endometrial polyps were found in one patient, complex nonpapillary
hyperplasia in one, and atrophic endometrium in the other. Two patients
had additional endometrial samplings within 4 months that contained
small residual simple papillary lesions. One of these had another biopsy
at 16 months that showed only atrophy. One patient had no subsequent
diagnostic or therapeutic procedures. One patient was a recent case.
Of the three patients with intact uteri and appreciable follow-up, all
were alive and well at 14, 96, and 102 months, respectively.
We conclude that these papillary proliferations are a form of hyperplasia
that is closely associated with endometrial epithelial metaplasia. Polypectomy
and/or curettage may be effective in removing them because they often
are localized lesions. Although all of our patients had an uneventful
outcome, the number of cases is small. Our findings question the validity
of diagnosing endometrial lesions as well-differentiated carcinoma solely
because of a complex papillary architectural pattern. |
| SPECIAL STAINS/IMMUNOHISTOCHEMISTRY |
CHARACTERIZATION |
| TENASCIN |
|
| 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.
|
| PROGNOSIS AND TREATMENT |
CHARACTERIZATION |
| Prognostic Factors |
Cytologic atypia is one of the most important histological predictors
of progression to carcinoma
|
|
Without cytologic atypia
|
<2% progress to carcinoma |
|
With cytologic atypia
|
23% progress to carcinoma |
| p53 |
|
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.
|
| TREATMENT |
|
|
Progestin treatment of atypical hyperplasia and well-differentiated
carcinoma of the endometrium in women under age 40.
Randall TC, Kurman RJ.
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore,
Maryland, USA.
|
Obstet Gynecol 1997 Sep;90(3):434-40 Abstract quote
OBJECTIVE: To determine the efficacy of conservative management of
atypical hyperplasia and well-differentiated carcinoma of the endometrium
in women under age 40.
METHODS: Pathology records were searched to identify women under age
40 diagnosed with atypical hyperplasia or well-differentiated carcinoma
of the endometrium between January 1990 and January 1996. All available
biopsy, curettage, and hysterectomy specimens were reviewed. Follow-up
was obtained from the patients' gynecologists.
RESULTS: Sixty-seven records were identified. Atypical hyperplasia
was found in 32 patients and well-differentiated carcinoma in 35 patients.
Seven patients were excluded from analysis; four declined all treatment
and follow-up, and three received no further treatment or tissue sampling
from their physicians. Among 27 remaining patients with atypical hyperplasia,
eight underwent hysterectomy, two were treated with ovulation induction,
and 17 were treated with progestins, of whom 16 had regression of their
lesions, and one had a persistent lesion. Among 33 women with well-differentiated
carcinoma, 19 underwent hysterectomy, one was treated with bromocriptine,
one was treated with oral contraceptives, and 12 were treated with progestins,
of whom nine had regression of their lesions and three had persistent
lesions. The median length of treatment required for a regression was
9 months. At a mean follow-up of 40 months, all patients were alive
and well without evidence of progressive disease. Twenty-five women
attempted to become pregnant, and five delivered healthy, full-term
infants.
CONCLUSION: Treatment of atypical hyperplasia and well-differentiated
carcinoma of the endometrium with progestins appears to be a safe alternative
to hysterectomy in women under age 40.
|
|
Atypical endometrial hyperplasia treatment with progestogens and
gonadotropin-releasing hormone analogues: long-term follow-up.
Perez-Medina T, Bajo J, Folgueira G, Haya J, Ortega P.
Department of Obstetrics and Gynecology, Department of Pathology,
Getafe University Hospital, Getafe, Madrid, Spain.
|
Gynecol Oncol 1999 May;73(2):299-304 Abstract quote
OBJECTIVE: The aim of this study was to assess the long-term effect
of gonadotropin-releasing hormone analogues (GnRH-a) in combination
with high-dose progestogens in the treatment of atypical endometrial
hyperplasia in selected surgical high-risk patients and in women desiring
reproductive potential. We hypothesized that this therapy is effective
for most couples.
METHODS: In the Department of Gynecology of a university hospital,
a conservative treatment was offered to a series of 22 patients with
atypical endometrial hyperplasia who had a surgical or anesthetic risk
history or wished to preserve their fertility potential. After informed
consent, they were treated with 500 mg norethisterone acetate weekly
for 3 months and 3.75 mg Triptorelin depot every month for 6 months.
Three patients failed to complete the study, so the group finally consisted
of 19 subjects. They were prospectively followed for 5 years by hysteroscopy
and multiple selected biopsies every 6 months.
RESULTS: At a 5-year follow-up, regression was noted in 16 patients
(84.2%), persistence in 1 (5.1%), recurrence in 1 (5.1%), and progression
in 1 (5.1%).
CONCLUSION: Consistent with our hypothesis, combined treatment with
progestogens and GnRH-a is an effective alternative in selected patients
with atypical endometrial hyperplasia.
|
