Endometrial Histopathology in 700 Patients Treated with Tamoxifen for Breast Cancer

doi:10.1006/gyno.2000.5859

Gynecologic Oncology

Volume 78, Issue 2, August 2000, Pages 181-186

https://doi.org/10.1006/gyno.2000.5859 Get rights and content

Abstract

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.

References (34)

P Neven et al.
Longitudinal hysteroscopy follow up during tamoxifen treatment
Lancet
(1998)
SM Ismail
Endometrial changes during tamoxifen treatment. Comment on
Lancet
(1998)
SG Silverberg
New aspects of endometrial carcinoma
Clin Obstet Gynecol
(1984)
LM Ramondetta et al.
Endometrial cancer in polyps associated with tamoxifen use
Am J Obstet Gynecol
(1999)
RR Barakat et al.
Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histological features
Gynecol Oncol
(1994)
JJ Folk et al.
Secretory endometrial adenocarcinoma in a patient on tamoxifen for breast cancer: a report of a case
Gynecol Oncol
(1995)
MM Gottardis et al.
Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse
Cancer Res
(1988)
S Ismail
Pathology of endometrium treated with tamoxifen
J Clin Pathol
(1994)
Y Daniel et al.
The effects of tamoxifen treatment on the endometrium
Fertil Steril
(1996)
JR Lorret De Mola
Endometrial changes with chronic tamoxifen use
Curr Opin Obstet Gynecol
(1997)

MM Kennedy et al.

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

Int J Gynecol Pathol

(1999)

S Ozsener et al.

Endometrial pathology of 104 postmenopausal breast cancer patients treated with tamoxifen

Eur J Gynaecol Oncol

(1998)

RE Scully et al.

International Classification and Histologic Typing of Female Genital Tract Tumors

(1994)

B Uziely et al.

The effect of tamoxifen on the endometrium

Breast Cancer Res Treat

(1993)

I Cohen et al.

Time-dependent effect of tamoxifen therapy on endometrial pathology in asymptomatic postmenopausal breast cancer patients

Int J Gynecol Pathol

(1996)

I Cohen et al.

Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients

J Clin Pathol

(1999)

Cited by (153)

4,4′-(9-Fluorenylidene)dianiline (BAFL) is antiestrogenic and has adverse effects on female development in CD-1 mice
2022, Ecotoxicology and Environmental Safety
Many phenolic compounds have been found to have endocrine disrupting activities, but their arylamine analogs, the phenolic hydroxyl groups substituted by aniline amino groups, have rarely been reported. 4,4′-(9-Fluorenylidene)dianiline (BAFL) is an arylamine analog of fluorene-9-bisphenol (BHPF) and BHPF has been reported to be a strong antiestrogen which could cause endometrial atrophy, ovarian damage and adverse pregnancy outcomes in animals. BAFL has been widely used as material to synthetize polymers, such as polyimides, polyamide, and polyamine, for various uses since the 1970s. Here, we assessed the antiestrogenicity of BAFL using a variety of methods and looked into its impacts on the development of females in CD-1 mice. With the aid of a yeast estrogen screen assay, we found BAFL possessed obviously antiestrogenic activity (IC₅₀ = 8.15 × 10⁻⁶ M), which close to that of tamoxifen and BHPF. Using a 10-d mouse uterotrophic assay, we found that BAFL obviously decreased uterine weight in a dose-dependent way. Histological analyses of mouse uteri revealed that BAFL induced marked endometrial atrophy and inhibited the uterine development. Immunohistochemical analyses showed that Sprr2d, an estrogen-responsive gene encoding protein, was mainly expressed in endometrial epithelial cells and BAFL decreased the areas and levels of Sprr2d staining in mouse uteri. It was clear from uterine transcriptome investigations that BAFL significantly downregulated the expressions of multiple genes responding to estrogen. Molecular docking showed that BAFL could effectively occupy the antagonist-binding pocket of hERα, and one of the amino groups of BAFL formed hydrogen bonds with the side chains of Arg394 and Glu353 in the receptor. These results indicated that BAFL exhibited clearly antiestrogenic characteristics and could interfere with normal female development in mice, which should be avoided using in commodities that come into direct contact with humans. Moreover, this study indicated that the arylamine analogs of phenolic endocrine disrupting chemicals might also have endocrine disrupting activities.
Antiestrogenic property of 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene (BPEF) and its effects on female development in CD-1 mice
2022, Ecotoxicology and Environmental Safety
Identifying chemicals with endocrine disrupting properties linked to disease outcomes is a key concern, as stated in the WHO-UNEP 2012 report on endocrine-disrupting chemicals. The chemical 9,9-bis[4-(2-hydroxyethoxy)phenyl]fluorene (BPEF) is widely and increasingly applied in synthesizing fluorene-based cardo polymers with superior optical, thermal and mechanical properties for various uses. However, little toxicological information is available regarding its safety. Here, we studied the endocrine disrupting property of BPEF by multiple toxicological tools and investigated its effects on female development in adolescent mice. Using the yeast two-hybrid bioassay, BPEF showed strong antiestrogenicity which was similar to that of tamoxifen, an effective antiestrogenic drug. In adolescent CD-1 mice, BPEF significantly decreased the uterine weight at relatively low doses and induced marked endometrial atrophy. Immunohistochemical staining and transcriptome analyses of the mice uteri revealed that BPEF could repressed the expressions of estrogen-responsive genes. Molecular simulation indicated that BPEF could be docked into the antagonist pocket of human estrogen receptor α, and the formation of hydrogen bonds and hydrophobic interactions between BPEF and the active site of receptor maintained their strong binding. All of the data demonstrated that BPEF possessed strong antiestrogenic property and might disrupt female development, suggesting it should be avoided in making products that might directly expose to people, particularly immature women.
Searching for an ideal SERM: Mining tamoxifen structure–activity relationships
2021, Bioorganic and Medicinal Chemistry Letters
The repurposing of old drugs for new treatments has recently garnered increased attention in the face of new diseases and declining productivity of the pharmaceutial industry. This report draws attention to potential opportunities hiding in plain sight within the SAR of off-patent drugs. Herein we explore the untapped potential of Selective Estrogen Receptor Modulators (SERMs). SERMs are a class of molecules that have been highly influential in the treatment of estrogen receptor-positive breast cancers. However, the most commonly prescribed SERM, tamoxifen, has been found to increase the risk of endometrial cancer. Another SERM, raloxifene, does not increase incidence of endometrial cancer, but has been abandoned as a breast cancer treatment. We report the design, synthesis, and evaluation of an unexplored tamoxifen substitution pattern which mimics the geometry of raloxifene to confer its favorable pharmacodynamics. This substitution pattern was found to maintain excellent binding affinity to estrogen receptor-α.
The significance of recurrence in endometrial polyps: a clinicopathologic analysis
2020, Human Pathology
A subset of endometrial polyps recurs after resection. The clinicopathologic significance of the phenomenon is evaluated herein. Consecutive cases of recurrent polyps (index polyp removed by hysteroscopy-directed polypectomy or by curettage; at least one more polyp diagnosed ≤12 months after) were compared with an age-matched control group of nonrecurrent polyps regarding 15 clinicopathologic features. A total of 107 (5.6%) of the 1908 polyps diagnosed in a sampling specimen during the study period was a recurrence, and 102 (6.9%) of the 1478 patients who were diagnosed with an endometrial polyp in a sampling specimen had at least 1 recurrence. Eighty-six percent of patients with any recurrences had only one recurrence, with a mean duration between the index polyp and the first recurrence of 4.36 months. On univariate analyses, the recurrent polyps were, compared with controls, significantly larger, had a higher stromal mitotic index, and more frequently displayed prominent thick-walled vessels in most fragments of the polyp. However, on Cox regression multivariate analyses, no single clinicopathologic feature was significantly associated with a recurrence. No malignancies were diagnosed during the follow-up of the study and control group patients at median follow-up durations of 23 and 34 months, respectively. In conclusion, the recurrence of an endometrial polyp is relatively uncommon (5.6% of polyps) and does not portend an increased risk of malignancy. We could not identify any clinicopathologic features that conclusively predict a recurrence.
Nonneoplastic Lesions of the Endometrium
2020, Gynecologic Pathology, Second Edition
This chapter describes the most common benign changes of the endometrium encountered in pathology practice. We present an overview of the histologic appearance of the normal (physiologic) endometrium in reproductive, inactive and gestational states. This is followed by a discussion of the changes seen under exogenous hormonal therapy, as well as the most important anatomic and functional alterations of the endometrium. The chapter concludes with the topic of endometrial metaplasia, and the criteria used for the distinction between benign and pre-malignant / malignant in the setting of endometrial metaplastic change.
Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor
2018, Gynecologic Oncology

View all citing articles on Scopus

View full text

Regular ArticleEndometrial Histopathology in 700 Patients Treated with Tamoxifen for Breast Cancer

Abstract

Lancet

Lancet

Clin Obstet Gynecol

Am J Obstet Gynecol

Gynecol Oncol

Gynecol Oncol

Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse

Cancer Res

Pathology of endometrium treated with tamoxifen

J Clin Pathol

The effects of tamoxifen treatment on the endometrium

Fertil Steril

Endometrial changes with chronic tamoxifen use

Curr Opin Obstet Gynecol

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

Int J Gynecol Pathol

Endometrial pathology of 104 postmenopausal breast cancer patients treated with tamoxifen

Eur J Gynaecol Oncol

International Classification and Histologic Typing of Female Genital Tract Tumors

The effect of tamoxifen on the endometrium

Breast Cancer Res Treat

Time-dependent effect of tamoxifen therapy on endometrial pathology in asymptomatic postmenopausal breast cancer patients

Int J Gynecol Pathol

Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients

J Clin Pathol

Regular Article
Endometrial Histopathology in 700 Patients Treated with Tamoxifen for Breast Cancer