Introduction
Breast cancer (BC), after lung cancer, is the second leading cause of cancer mortality among women. According to the American Cancer Society, approximately 1.3 million women worldwide are diagnosed with BC annually, and > 465,000 women die of this disease [1]. Most of them are estrogen receptor-αpositive (ERα+) and require an adjuvant hormonal therapy. Tamoxifen (TAM) is available as a first-line adjuvant treatment for pre- and postmenopausal BC patients. Long-term administration of TAM may bring about several changes in the endocervix and endometrium, including carcinomas. Regardless of the drug intake, BC patients have an enhanced risk of endometrial proliferative disorders, including endometrial hyperplasi, as indicated by the high prevalence of this pathology detected in BC patients undergoing endometrial assessment prior to the initiation of TAM administration [2].
Purpose
The aim of the study was to query publications on the early, most accurate diagnosis of pathological changes in the endometrium which occur during and after TAM therapy for BC, in order to analyze the most important risk factors and outline clear rules for dealing with TAM-treated patients.
Perspective
There is no evidence that patients receiving adjuvant TAM could benefit from a screening program based on the ultrasound examination alone. Asymptomatic BC patients on adjuvant TAM-treatment should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report any abnormal vaginal bleeding promptly.
Methods and search strategy
MEDLINE (http://www.ncbi.nlm.nih.gov/pubmed), EMBASE (http://www.embase.com) and Scopus (http://www.scopus.com) databases were searched using the following MeSH terms in titles and abstracts: (“tamoxifen endometrial hyperplasia” OR “tamoxifen endometrial pathology” OR “endometrial pathology tamoxifen”). No language restriction was used in the literature search. The search was limited to studies in humans.
Discussion
Postoperative adjuvant systemic therapy prolongs survival in selected women with BC and reduces the odds of death by 25% per year. Several studies have shown that TAM can significantly reduce the risk of recurrence and the risk of contralateral BC. Continuing TAM therapy in patients with ER-positive BC for 10 years is associated with lower recurrence and mortality rates than the treatment lasting 5 years [1, 2].
Tamoxifen and the risk of endometrial proliferative disorders
Tamoxifen is associated with various adverse effects, including hot flashes, vaginal discharge, menstrual irregularities, sexual dysfunction, thromboembolic complications, endometrial hyperplasia and cancer, which can reduce patients’ adherence to adjuvant endocrine treatment [3]. Biochemically, depending on any individual organ, circulating levels of endogenous estrogen and the dose, TAM can show complex hormonal actions. On the one hand, it blocks estrogen stimulation in breast tissue, on the other hand, it has an ER-agonist activity in the endometrium that is able to stimulate proliferation and, in some cases, to increase the risk of uterine pathologies. Notably, regardless of the drug intake, BC patients have an enhanced risk of endometrial proliferative disorders, including endometrial hyperplasia, as indicated by the high prevalence of this pathology detected in BC patients undergoing endometrial assessment prior to the initiation of TAM administration [3]. Long-term administration of TAM may bring about several changes in the endocervix and endometrium: atrophy, polyposis, proliferation, vascular changes, endometrial hyperplasia, and carcinomas [2].
It is impossible to predict which postmenopausal BC patients may develop endometrial pathologies during TAM treatment, as no statistically significant differences of various clinical features tested among patients with or without endometrial pathologies were found. Some clinical features, however, may be associated with an increased risk of the occurrence of endometrial pathologies following postmenopausal TAM treatment. It has been proven that TAM therapy for > 48 consecutive months was associated with an increased frequency of endometrial lesions, especially endometrial polyps [4]. But other authors have found that there is no increased risk of developing endometrial pathologies following an additional 18 months of continuous TAM therapy; moreover, there is no aggravation of already existing endometrial pathologies [4].
The most serious adverse effect attributed to the use of TAM is an increased risk of endometrial cancer (EC). The risk of EC is not associated with a daily dosage of TAM, but with the time of duration and accumulative usage [3].
In spite of the long history of TAM use in BC patients, an adequate endometrial observation strategy is still controversial. In Poland, for instance, there is no standard follow-up protocol for the assessment and management of patients with BC treated with TAM. Considering the large number of women taking adjuvant TAM, and the potentially negative impact of invasive examinations on compliance with the treatment, a potential program of endometrial surveillance in asymptomatic patients should be based on simple and acceptable procedures with a cost/benefit ratio. There is little doubt that any patient taking TAM and reporting abnormal vaginal bleeding should be promptly evaluated to exclude the presence of an endometrial malignancy [5].
Endometrial polyps during tamoxifen therapy
Endometrial polyps represent the most common endometrial pathology associated with postmenopausal TAM exposure, with the rate of 8–36%. Although most polyps are benign, they may contain premalignant or malignant lesions in up to 23.8% of cases. The literature lists various risk factors for the development of malignancy in polyps, such as advanced age, menopausal status, and abnormal uterine bleeding [4, 6].
Endometrial polyps removed from TAM-treated patients are more translucent, edematous and are distinguished microscopically from typical polyps by their higher fibrotic content, with less stromal cellularity. Inactive and cystic glands in the polyps are often found to be associated with hyperplastic glands and occasionally with atypical hyperplastic and neoplastic changes, which points toward a possible neoplastic potential of an endometrial polyp which may represent a step in endometrial carcinogenesis. Some authors consider „nonfunctional” endometrial polyps to represent endometrial involution or atrophy, while others see any polypous growth as an estrogen-related hyperplastic growth. Mucinous metaplasia also occurs more frequently, usually in association with larger polyps and longer duration of TAM therapy. Endometrial polyps may also be composed of a mixture of simple endometrial hyperplasia, complex endometrial hyperplasia (with or without atypia) and a small focus of endometrial carcinoma. The polyps are often multiple and of varying sizes. They are larger in postmenopausal TAM-treated patients (median size: 2.9 cm; range: 0.3–11.0 cm), than those observed in healthy, postmenopausal women on hormone replacement therapy (median size: 1.05 cm; range: 0.3–2.0 cm) or in healthy, postmenopausal, untreated controls (median size: 1.35 cm; range: 0.2–3.6 cm) [4, 7].
Endometrial polyps were found to be significantly more common among postmenopausal BC TAM-treated patients with vaginal bleeding as compared to asymptomatic patients. Cohen identified some risk factors for endometrial polyps in postmenopausal BC TAM-treated patients: older age at menopause, longer duration of breast disease, heavier body weight and thicker endometrium, measured by TVUS, compared with similar patients without endometrial polyps. What is more, it has been found that previous use of hormone replacement therapy and additional years of TAM treatment [4] may significantly increase the risk of developing recurrent endometrial polyps in such patients. It is worth noting that all the recurrent polyps were benign [4].
Interestingly, the presence of abnormal vaginal bleeding did not differ between patients with endometrial polyp and normal endometrium, which is in contrast to other studies reporting that endometrial polyps were more common among TAM-treated BC patients with vaginal bleeding compared with asymptomatic patients [7–9].
Based on TVUS measurements, TAM is known to trigger endometrial thickening. Gerber et al. [10] reported a significant increase in the mean endometrial thickness after 3 years of this drug administration.
Yela et al. [6] analyzed the group of patients who took TAM for 2 to 3 years. Despite the fact that studies have shown that the use of TAM for 2 consecutive years increases the incidence of endometrial polyps, and also that the incidence of endometrial cancer increases as the drug use is prolonged (5 years), in the analyzed samples more cases of cancer have been found when the endometrial thickness in ultrasonography exceeded 12.5 mm [6]. Conversely, according to Gerber, ultrasonography offered a high false-positive rate, even with a cutoff value of 10 mm for endometrial thickness and repeated scans [10].
Risk factors for carcinogenesis during tamoxifen therapy
In a retrospective analysis of 821 biopsies, Jeon et al. [11] also analyzed the factors associated with endometrial pathologies in TAM-treated women with BC. This study revealed that parity, presence of bleeding, endometrial thickness on ultrasonography increased the risk of endometrial pathologies in TAM users. Upon comparing women with and without pathology, parity was significantly lower (1.1 ±1.0 vs. 1.9 ±0.8, p = 0.014) and endometrial thickness was significantly higher (19.7 ±9.0 vs. 9.9 ±5.2 mm, p < 0.001) in women with pathology. In addition, the presence of bleeding symptoms was more common in the pathology group (50.0 vs 29.3%, p < 0.001). However, age, body mass index, menopausal status, and duration of TAM use did not differ with reference to the presence of pathology. Comparing the characteristics between women with endometrial polyps and normal endometrium, significant differences were found in parity (1.5 ±0.9 vs. 1.9 ±0.8, p < 0.001), duration of TAM use (903.8 ±531.9 vs. 764.3 ±544.4 days, p = 0.003) and endometrial thickness (12.8 ±5.9 vs. 9.9 ±5.2 mm, p < 0.001), but not in age, BMI, menopausal status, and the presence of uterine bleeding.
In the Jeon et al. study, the mean duration of TAM use in women with normal endometrium was 764 days. Other studies demonstrated that the risk of endometrial cancer increased significantly after 2 years of TAM treatment. Long-term TAM users have a worse prognosis of endometrial cancers, as indicated by less favourable histology and higher stage of cancer [11–13].
Lee et al. [2] in their study assessed 284 premenopausal BC women treated with adjuvant TAM who had undergone ultrasonography and endometrial biopsy with or without hysteroscopy. Most asymptomatic patients treated with TAM were subject to yearly ultrasonography examinations. If a patient had abnormal bleeding, with or without endometrial thickening, hysteroscopic evaluation was performed. Endometrial biopsy was performed if endometrial thickness was greater than 10 mm or if a new or enlarging polypoid lesion was observed, even in the absence of symptoms.
The most common abnormal histology were endometrial polyps (n = 114, 40.1% of biopsies), while endometrial hyperplasia was present in 7 patients (2.5%), and endometrial cancer was observed in 5 patients (1.8%). Atypia was present in all biopsies exhibiting complex endometrial hyperplasia.
Lee et al. [2] have further found that the presence of abnormal uterine bleeding was the most important factor associated with the presence of endometrial pathology (hyperplasia or cancer) and that abnormal uterine bleeding, treatment with chemotherapy, and increased endometrial thickness on ultrasonography were risk factors associated with endometrial cancer in premenopausal women with BC treated with TAM.
Surprisingly, some authors suggest that most TAM-treated patients had no pathologic endometrial changes. Endometrial polyps, hyperplasia, and metaplasia, consistent with an estrogen-agonist effect of TAM, were found in roughly one-third of all patients [7].
According to Ryu et al.’s [14] study from 2022 there is a clear indication that physicians should consider the risk of endometrial cancer and other uterine malignancies in women using TAM, regardless of menopausal status. They conducted a population-based, retrospective, longitudinal cohort study using a nationwide cohort data set with long-term follow-up. Among 78,320 female participants with a mean (SD) age of 42.1 (6.1) years, 34,637 (44.2%) were categorized into the TAM group and 43,683 (55.8%) were categorized into the control group.
The study found that premenopausal women with BC who received TAM had significantly increased risks of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. Tamoxifen use was associated with an approximately 4-fold higher risk of developing endometrial cancer, even after controlling for several confounding factors, including age, BMI, diabetes, hypertension, dyslipidemia, PCOS, and GnRH agonist treatment. This study also found a higher risk of benign disease in women taking TAM before menopause than in previous clinical trials. The authors also confirmed an increased risk of uterine cancers other than endometrial cancer, such as sarcoma, in women taking TAM before menopause [14].
Ghanavati et al. [15] presented a meta-analysis with the most up-to-date data on the association between TAM exposure and endometrial cancer, emphasizing participants’ age, TAM dose, cumulative TAM dose, and duration of TAM use. Twenty-six studies met the inclusion criteria and were included in the pooled analysis. The analysis showed a significant increase in endometrial cancer risk in patients with breast cancer who used tamoxifen, and this relation remained significant regardless of the studies being conducted in different continents and with different study designs.
The main conclusions were that an increasing cumulative amount of TAM and higher dose of TAM independently increased the risk of EC, with higher risk in patients taking 20 mg per day. Furthermore, the risk of EC depended on the duration of TAM use, with longer duration of TAM use being associated with a higher risk of EC [15].
The authors also cited the ATLAS and ATTom studies, which showed that longer duration of TAM use increased the risk in women taking TAM for 10 years compared with 5 years of TAM, with a cumulative risk of 1.5–3.2% for extended therapy [16, 17].
The study further reported that the risk of EC was higher in women aged 55–69 years compared to those 45 years or younger. The higher risk in postmenopausal women is associated with a higher body mass index, which is more common in older women, a common risk factor in the general population, regardless of TAM use. In addition, there is a higher incidence of endometrial proliferative disorders in postmenopausal women [15].
Table 1 illustrates the most frequently reported risk factors of the presence of endometrial pathologies during TAM therapy.
Table 1
The most frequent risk factors of endometrial pathology, according to the literature
| Author | Cumulative TAM dose | Duration of TAM | Vaginal bleeding | Menopausal status | BMI | Thicker endometrium measured by ultrasonography | Parity |
|---|---|---|---|---|---|---|---|
| Cohen et al.[4] | + | + | + | NA | NA | + | NA |
| Hann et al. [28] | NA | + | – | NA | NA | + | NA |
| Bertelli et al.[5] | NA | NA | + | + | – | + | – |
| Jean et al.[11] | NA | - | + | – | – | + | + |
| Yela et al.[6] | NA | NA | + | + | – | – | + |
| Ghanavati et al.[15] | + | + | NA | + | NA | NA | NA |
| Lee et al.[2] | NA | – | + | – | – | + | – |
Diagnostic methods
The main tool to assess the potential risk of uterine pathology is the clinical examination and transvaginal ultrasound [4]. Ultrasonography is the most commonly used tool for gynecological surveillance in TAM users.
The utility, however, of TVUS for screening of TAM-induced endometrial proliferation is debatable. Owing to increased iatrogenic morbidity and high false-positive rates of TVUS, Gerber et al. [10] expressed uncertainty regarding the utility of endometrial screening using TVUS in women treated with TAM. Since TAM stimulates subendometrial glandular hypertrophy, endometrial thickness may increase in the absence of pathologies. In addition, no clear-cut value for detecting endometrial pathology or ensuring safety has been established yet. Even with a cut-off value of 10 mm, diagnostic efficacy was not improved in previous studies [10, 18]. Moreover, several endometrial pathologies, such as polyps, atrophy, or hyperplasia, may present with similar ultrasonographic features [19].
According to the guidelines of the American College of Obstetricians and Gynecologists, premenopausal patients with a history of TAM use have an uncertain increased risk of endometrial cancer and do not require any further monitoring beyond routine gynecologic examinations. These guidelines are based on outdated evidence, as they do not take into account newer studies which demonstrate a correlation between TAM and endometrial cancer risk.
However, resection of endometrial polyps diagnosed by ultrasonography in postmenopausal TAM-treated BC patients is recommended because of the relatively high risk of malignancy in these women. Malignant transformation was reported in 3.0–10.7% of endometrial polyps recovered from postmenopausal BC TAM-treated patients. Despite the severity of this endometrial entity, only about 50.0% of the patients complained of vaginal bleeding. No correlation was found between malignant polyps and polyp size and treatment duration. It was impossible to predict which polyps would contain malignant tissue, as none of the various clinical features, including duration of TAM treatment and mean endometrial thickness (as detected by transvaginal ultrasonography), compared between patients with malignant endometrial polyps and those with benign endometrial polyps were found to be significantly different. Although the potential for malignant transformation is lower in premenopausal patients than in postmenopausal BC patients, it is suggested that the removal of endometrial polyps ought to be considered in premenopausal TAM-treated BC patients, both symptomatic and asymptomatic. This may be important for patients with a relatively thick endometrium (e.g. ≥ 12 mm) and abnormal uterine bleeding, as these factors further increase the probability of endometrial cancer; it is important to remember, however, that nearly 50% of these malignant endometrial polyps were diagnosed in gynecologically asymptomatic patients [2, 4].
In the study of Bertelli et al. [5], 43% of the asymptomatic patients had an indication for biopsy due to an increase in the threshold for abnormal endometrial thickness in postmenopause from 5 to 8 mm. Such paradoxical sonographic finding of thickened, heterogeneous endometrium, often with irregular sonolucencies, in patients who have normally atrophic endometrium on biopsy has been interpreted to be actually subendometrial in origin. Although TAM duration was associated with an increase in the risk of proliferation, no epithelial hyperplasia was observed on biopsy. TAM-induced hyperproliferation, in fact, appeared to be mediated by the stromal component of the material obtained by endometrial biopsy.
Bertelli et al. [5] recommend saline infusion sonography in all postmenopausal TAM-treated patients where transvaginal ultrasonography revealed thick endometrium, as it has been suggested to be the best diagnostic method for identification of endometrial polyps in these patients.
Indications for hysteroscopy and endometrial biopsy
It is important to identify ultrasonographic findings that represent robust indications for hysteroscopy and endometrial biopsy in order to avoid unnecessary second-level diagnostic procedures.
Indications for hysteroscopy included ultrasonographic suspicion of endometrial/myometrial changes, such as endometrial polyps, submucous myoma, or suspected endometrial malignancy, thickening of the endometrium and abnormal vaginal bleeding.
Most of the authors agree that operative hysteroscopy should be used for the removal of endometrial polyps, since blind endometrial biopsy may yield no tissue, especially in the presence of large endometrial polyps. Moreover, it is imperative to extract these polyps entirely [2, 4, 5].
Following a literature search, we have found that other authors report the use of hysteroscopy also in asymptomatic women on TAM therapy, where they presented with endometrial thickness. There is no consensus regarding which endometrial thickness cut-off should be used for recommending endometrial biopsy in asymptomatic postmenopausal women. Certain authors report the criterion of endometrial thickness > 5 mm at TVUS [5]. Vitale et al. [20] provide updated data for the gynecologist who performs endometrial biopsy in gynecologic clinical practice according to an international committee of gynecology experts. The authors claim that women with sonographic endometrial thickness > 4 mm using tamoxifen should undergo hysteroscopic biopsy [20].
Several trials have reported that for women presenting with postmenopausal bleeding, the use of transvaginal US is not indicated as a screening tool in evaluating women who have a history as TAM use, due to poor diagnostic accuracy. Instead, hysteroscopy and endometrial biopsy are considered the most reliable diagnostic methods [20, 21].
Following the clinical indications, hysteroscopy remains an accurate second-level procedure for the diagnosis of endometrial abnormalities, especially for the identification of endometrial polyps and normal endometrium. Screening programs for TAM users have largely proven to be ineffective because the cost-to-efficacy ratio is unfavorable. Patients with a personal history of BC who report vaginal bleeding need a second-level procedure for endometrial evaluation, regardless of endometrial thickness, to identify small cancers not otherwise identifiable at TVUS [22].
Controversy exists regarding the most optimal method of screening. The value of TVUS in assessing endometrial thickness and endometrial characteristics has improved with technological development; however, it has yet to achieve sufficient sensitivity and specificity in patients with abnormal endometrial thickness [3, 23].
Although dilation and curettage (D&C) was long considered the gold standard, hysteroscopic evaluation with direct lesion biopsy has now proven superior to all other approaches [22, 24]. In high-risk populations for endometrial cancer, such as patients undergoing TAM therapy, it is recommended that biopsy and hysteroscopic evaluation should be used in combination. Although it is assumed that hysteroscopic examination in high-risk cancer patients may increase the risk of dissemination of malignant cells into the peritoneal cavity, in a recent meta-analysis, no evidence was found to support an association between hysteroscopic examination and peritoneal cytology. Conversely, in the study performed by Korkmazer et al. [25], 18.6% (n = 11) of endometrial pathologies were missed in the D&C. This highlights the difficulty of obtaining accurate histological data in D&C and this method alone would not provide sufficient information, especially in high-risk women. At this point, hysteroscopic evaluation and directed biopsy stand out in endometrial assessment among TAM users. Sensitivity and specificity of hysteroscopy are especially high for large lesions of the endometrium, but it is not effective in certain cases, like, for instance, hyperplasia [25]. Wider studies on this issue recommend that hysteroscopic evaluation must be supported with biopsy [22]. Also in this study, there was an underlying pathology in 45.8% of the patients so that histopathologic specimen could not be obtained during curettage. Thus, in current clinical practice, D&C has largely been replaced by hysteroscopy with targeted endometrial biopsy [12]. As TAM treatment is considered as one of the additional risk factors of EC, as is Lynch syndrome, obesity, advanced age, nulliparity and the use of exogenous hormones, in each of these cases, hysteroscopy is an important tool for diagnosis making. The greatest advantage of hysteroscopic endometrial biopsy is the fact that it is performed under direct visualization, allowing selective biopsy of targeted areas of the endometrium [26].
Furthermore, a statistically significant association has been demonstrated between EC hysteroscopically spread throughout the whole uterine cavity and sentinel node mapping uptake at the common iliac lymph nodes [27].
Conclusions
The results of an ultrasound investigation of the endometrium in asymptomatic BC patients receiving TAM should be interpreted with caution. An overdiagnosis of endometrial abnormalities, and the consequent unnecessary invasive diagnostic procedures could discourage some patients from continuing the adjuvant treatment with TAM, putting them at increased risk of recurrent BC. There is no evidence that patients receiving adjuvant TAM therapy could benefit from a screening program based on the ultrasound examination alone. Asymptomatic BC patients on adjuvant TAM-treatment should not be submitted routinely to ultrasound examination or biopsy, but encouraged to report any abnormal vaginal bleeding promptly. It is necessary to develop guidelines for diagnostic procedures for intra-uterine lesions in BC patients treated with TAM.
