Breast cancer metastasis to endometrium: Case report and up-date of literature

Introduction: Breast cancer is the leading neoplasia metastasizing to genital organs. Uterine metastases are seldom reported and those limited to endometrium account for 3.8% of patients with uterine spread. We reported on a woman with breast cancer metastasizing to endometrium and up-date of literature.

Presentation of case: In July 2022, a 59 years-old woman with breast cancer was referred to Gynecological consultation due to Positron Emission Tomography showing an enhanced signal to the endometrium. Throughout the four previous years, she underwent bilateral surgery due to metachronous lobular cancers and adjuvant therapies consisting of Letrozole, Exemestane, chemotherapy, and Tamoxifen. In May 2022, bony metastases were found and she shifted to Abemaciclib/Fulvestrant therapy. No gynecological complaints were recorded, and physical examination was uneventful while Transvaginal Ultrasound demonstrated an enhanced endometrial thickness as a unique abnormality. Hysteroscopy showed mucosal thickenings attributed to Tamoxifen-related cysts formation. The biopsy pathology reported stromal infiltration of neoplastic cells staining for Cytokeratins and GATA-3. Negative staining was reported for PAX-8 and CD-10. On these findings, a breast cancer metastasis was established. Four months later the patients died from metastatic brain progression.

Discussion: Endometrial metastasis from breast cancer is anecdotal. The case described supports that uterine spread is a late event, often concurrent with extragenital metastases and mostly associated with lobular histology. A hysteroscopic view can be misleading and a careful pathological study is needed for a differential diagnosis against endometrial primitiveness.

Conclusion: Endometrial abnormalities in breast cancer patients might be caused by metastasis. The management of these patients is challenging and must be tailored to the clinical background.

Introduction

Breast cancer is the leading cause of neoplastic-related death and its metastatic progression, mainly found in the lung, bone, liver, or brain, is associated with fatal outcomes [1]. Metastases to genital organs are seldom reported, showing a higher prevalence for ovarian seedings. Isolated uterine metastases from extragenital neoplasia are detected in about 4% of women with cancer spreading to the gynecological tract and breast cancer represents the primitiveness in more than 50% of cases. Among patients showing uterine metastases limited to the uterus, a prevalence of myometrial and endo-myometrial localizations was found in more than 95% of patients, whereas isolated metastases to the endometrium are estimated to occur only in 3.8% of them [2,3]. Uterine spread from breast cancer is often associated with concurrent multi-organ disease progression and early fatal prognosis although in some cases the uterus was found to be the unique localization of recurrence, allowing hysterectomy as an option to control the progression of disease [4-6]. Due to poorly understood biological pathways, lobular breast cancer shows a greater propensity for genital organ spread with respect to the commonest ductal histological type [7]. Abnormal Uterine Bleeding (AUB) is the leading symptom of endometrial pathology. In breast cancer patients, sharing the same genetic and environmental risk factors of endometrial cancer and mainly in those taking Tamoxifen, AUB needs a quick gynecological investigation based on physical examination, cervical cytology, and Transvaginal Ultrasonography (TVU), firstly to exclude a metachronous malignancy arising from the genital tract [8,9]. Hysteroscopy with targeted biopsy represents the reference diagnostics of endometrial pathologies, including endometrial cancer [10,11]. Herein, we describe the gynecological and pathological diagnostic workup carried out in an asymptomatic woman with lobular breast cancer showing an endometrial spread concurrent with bony metastases. Moreover, we reviewed the recent literature relevant to endometrial breast cancer metastases.

Case report

This report was conceptualized in line with the principles of the 1964 Declaration of Helsinki and its amendments. Given the retrospective and observational nature of a clinical case managed by procedures performed as part of routine care, Ethical approval was waived by the local Ethics Committee. The signed consent to publish sensible clinical data was obtained from the husband of the patient, after her death.

In May 2018, a 55 years-old menopausal woman (Gravida 3, Parous 2, 1 cesarean delivery) without concurrent morbidities, underwent a left breast lumpectomy with sentinel node sampling due to infiltrating breast cancer. Histology reported a grade 2 lobular carcinoma measuring 11 mm with metastasis detected in the sampled lymph node (pN1a). Histochemistry showed 95% expression of both estrogen and progesterone receptors, a ki-67 fraction of 13%, and an absence of c-Erb-B2 reactivity. Radiation therapy was delivered to the residual breast and an adjuvant hormone therapy with Letrozole was started. Before its beginning, gynecological examination and TVU showed normal findings, with an endometrial thickness measuring 3.5 mm. In June 2019, she underwent radical left axillary dissection following the diagnosis of axillary metastases, confirmed in 5 out of 30 removed lymph nodes. A 40% estrogen and 0% progesterone receptors expression, an 18% ki-67 fraction, and a weak positivity for c-Erb-B2 were found. A left supraclavicular radiotherapy was performed and the patient shifted to a therapy with Exemestane. In July 2021, a right metachronous grade 3 lobular breast cancer measuring 9 mm was diagnosed, leading to lumpectomy and sentinel node mapping. The biological profile showed 90% estrogen and 0% progesterone receptors expression, a ki-67 fraction of 25%, and an unexpressed c-Erb-B2. Four removed axillary lymph nodes were negative. Radiotherapy to the residual breast was administered and adjuvant chemotherapy based on 4 cycles of Epirubicin-Cyclophosphamide was started in August 2021, followed by Tamoxifen. In May 2022, we observed a rise in CEA (16 ng/ml), CA 15.3 (77 mUI/ml), and CA 125 (1168 mUI/ml). Computed Tomography showed sacral and lumbar bony metastases. In July 2022, a Positron Emission Tomography (PET) confirmed the lumbo-sacral vertebral body metastases as the only site of recurrence, reporting a weakly enhanced Standardized Uptake Value of 4.6 within the uterine cavity. Based on these findings, the patient stopped Tamoxifen and started Abemaciclib/Fulvestrant administration. A gynecological consultation found normal physical examination in a patient without uterine bleeding complaints. TVU showed a non-homogeneous endometrial thickening, measuring 12 mm on the longitudinal uterine scan with a well-defined endometrial-myometrial junction. No other uterine or ovarian abnormalities were found during ultrasound assessment and a diagnostic hysteroscopy was scheduled. In September 2022, the woman underwent an inpatient video-recorded hysteroscopic diagnostic procedure with a 5 mm operative hysteroscope, using saline as the distending medium. We found a normal lining of endocervical mucosa and a normally structured endometrial cavity. Slight focal and smooth mucosal thickenings sometime showing associated cyst-glands were observed in the background suggesting a sub-atrophic picture, referred to as Tamoxifen-induced stimulation. Neither atypical mucosal overgrowth, neo-angiogenetic vascular network, or necrotic features were found and no suspicion of neoplasia was reported. Using 5Fr mechanical instrumentation we fashioned and retrieved an endometrial biopsy to the posterior uterine wall, targeted to an uneventful mucosal thickening (Figure 1). Histologic assessment by Hematoxylin-Eosin (H&E) staining reported endometrial tissue harboring stromal infiltration by a carcinoma consistent with breast cancer primitiveness. Immunohistochemistry showed positivity for the Cytokeratin Pool (AE1/AE3) and GATA 3 and negative staining for PAX-8 and CD10. Estrogen and progesterone receptors were expressed 10% and 0% while a faint reactivity for c-Erb-B2 was found (Figure 2). Based on these results we confirmed a diagnosis of lobular breast cancer metastatic to endometrium. After the medical oncology joint meeting no gynecological measure was adopted following the diagnosis and the patient continued medical therapy. In November 2022, neurologic symptoms led to the diagnosis of leptomeningeal metastases and the patient died due to the progression of the disease in January 2023.

Figure 1: Hysteroscopic assessment. A: Hysteroscopic view of left cornual endometrial area. B: Hysteroscopic view of right cornual endometrial area. At hysteroscopic inspection we found an evenly shaped endometrial lining of uneventful sub-atrophic appearance showing scattered small mucosal thickenings sometimes suggesting subepithelial gland-cysts possibly related to Tamoxifen intake. Somewhere, an enhanced non atypical vascular network was found associated with mucosal thickenings. No suspicion for a neoplastic disease affecting endometrium was reported. C: The cutting mechanical biopsy targeted to an endometrial thickening arising from the posterior endometrial wall is in progress.

Figure 2: Pathologic assessment of endometrial biopsy. A: Hematoxylin & Eosin stain (magnification x 150). Nests of epithelioid neoplastic cells with solid growth pattern are found within the endometrial stroma. The cells show large and sometime peripherally-displaced nuclei remembering signet-ring features and display focal incohesive morphology. B: Pan-Cytokeratin AE1/AE3 stain (magnification x 150). A strong membrane positive staining of both normal endometrial gland cells and neoplastic cells infiltrating a stainless endometrial stroma was detected, suggesting an exquisite epithelial primitiveness of metastasis. C: GATA-3 stain (magnification x 150). A nuclear positivity limited to nests of neoplastic cells growing within endometrial stroma suggest a breast primitiveness. The clear incohesive morphology and “Indian-file”- like pattern of cell spread support a lobular histology.

Discussion

We described the case of an asymptomatic woman with metastatic breast cancer spreading to endometrium through a plausible hematogenous route, based on imaging findings suggesting neither ovarian nor myometrial involvement. Old pathological studies showed that extragenital cancers rarely spread to genital organs and that in only 4% of them, the uterus represents the unique localization, showing a higher prevalence of myometrial involvement and breast primitiveness [2,3,12]. Starting from the 1999 up-dating review of Piura (3) until June 2023, we performed a MEDLINE (accessed by PubMed) and Google Scholar literature search, using “uterine metastases”, “endometrial metastases” and “breast cancer uterine metastases” as Medical Subject Headings. The search was restricted to recovered full manuscripts in the English language and extended by the checking of Reference lists of identified studies, extracting reports escaped to electronic searches. Only patients with pathologically proven breast cancer spread to endometrium have been included. We identified 57 patients described mainly as case reports, while in eight case series, two patients were described together [6,13-19] (Table 1).

Establishing the true prevalence of breast cancer spreading to endometrium with the sparing of other genital organs is hampered by the clinical assessment of endometrial metastasis. This is often based on the performance of an endometrial biopsy possibly missing concurrent subclinical cervical, myometrial, and adnexal metastatic involvement, ruled out only by the pathological assessment of a Total Hysterectomy and Bilateral Salpingo-Oophorectomy specimen (TH-BSO). In the case presented, the significant rise of CA 125 before endometrial biopsy, leads to hypothesize a subclinical peritoneal surface involvement in metastatic spreading. We declined surgical therapy because of progressive bony disease in the absence of any gynecological symptoms. From the reviewed literature, 30 out of 57 patients (52.6%) with endometrial metastases underwent TH-BSO. Among these women, only 4 (13.3%) showed metastases limited to endometrium without any extragenital localization. In 3 of them, the metastasis was confined within a polyp. A 16-month mean Progression Free Survival (PFS) without evidence of disease was reported in 3 patients whereas follow-up data was unavailable in the fourth woman [20-23]. In the other 26 patients undergoing TH-BSO, concurrent combinations of genital metastases were found beside the endometrial spread. It included myometrium or leiomyomas in 6 patients [13,24-27], myometrium and uterine cervix in 4 [3,17,28,29], myometrium, cervix, and ovary in 8 [16,17,30-35], myometrium and ovary in 4 [7,18,36,37], myometrium and peritoneum in 2 [38,39] and ovary in 2 patients [4,15]. In this group of 26 women, the genital organs represented the only metastatic site in 15 out of 23 evaluable patients (65.2%). Follow-up data were available in 7 out of these 15 patients. Two of them died from disease progression 30 and 48 months later [17] whereas a mean PFS of 10.8 months, without evidence of disease was reported in the remaining 5 patients [3,4,16,24,28].

In women with breast cancer, regular gynecological surveillance is warranted, firstly due to genetic and environmental risk factors shared between breast and endometrial/ovarian malignancies. Moreover, the estrogen pathways activated by Tamoxifen on the endometrium and hypothalamic-pituitary axis either in postmenopausal or premenopausal women enhances the need for planned gynecological consultations [40,41]. However, AUB is the principal complaint needing a quick gynecological investigation. In the reviewed series the first symptom of endometrial metastasis was AUB in 46 out of 57 patients (80.7%). In 11 asymptomatic women, an endometrial biopsy was indicated because of an increased endometrial thickness detected by routine TVU in 8 patients [7,15,18,20,23,30,42,43], a bulky uterine mass in 2 patients [15,27] and an enhanced uterine PET-TC signal in one case [44]. AUB caused by metastatic spread to the endometrium was seldom reported as presenting symptom of unknown breast primitiveness [44-46]. Mostly, AUB due to uterine metastases is a late event of a known breast cancer history and it is often associated with other commonest distant localizations. In 10 out of the 57 patients reviewed, no information about the coexistence of extragenital metastases was provided whereas in 30 out of 47 cases evaluable (63.8%), uterine involvement was synchronous to one or more metastases in extragenital organs. Thirteen of these 30 patients underwent TH-BSO and for 6 of them follow-up data were available. A mean PFS of 17 months was found in 3 patients [15,32,36] whereas 3 patients died from progressive disease 5, 6, and 18 months following the diagnosis of uterine metastases [7,33,34].

Before the diagnosis of endometrial metastasis, our patient underwent Tamoxifen therapy lasting 8 months. From the examined literature, at the time of the diagnosis, 26 out of 57 patients were currently taking Tamoxifen and in 5 patients a previous administration of the drug was recorded [17,22,28,32,39]. Thus, 31 out of 57 patients with metastatic breast cancer to the endometrium (54.3%) experienced exposure to Tamoxifen. It is well known that Tamoxifen can promote endometrial proliferative disorders, including the growth of endometrial polyps (9). Genital breast cancer metastases limited to an endometrial polyp were found in 9 out of the 57 patients reviewed (15.7%), 7 of whom during Tamoxifen administration [14,18,20,21,47-49]. We can speculate that the angiogenetic properties of tamoxifen on the endometrium and the enhanced vascular network associated with polyp growth might lead to a favorable tissue milieu for cancer cell seeding [50,51]. Nevertheless, endometrial breast cancer spread was also reported in polyps unrelated to Tamoxifen intake [22,52] or in patients undergoing aromatase inhibitors therapy [19,30,31,53,54]. Obviously, based on the lack of prospective controlled trials we cannot conclude that Tamoxifen therapy or polyps associated with its intake might enhance the risk of breast cancer spread to endometrium.

In our patient we diagnosed a bilateral metachronous breast cancer of lobular histology refractory to endocrine, chemotherapy, and cyclin dependent-kinase inhibitor, showing an aggressive behavior leading to the quick development of bony, uterine, and brain metastases. Lobular breast cancer accounts for 10%-15% of breast malignancies and its clinical course is worse with respect to carcinomas showing ductal histology. The loss of E-Cadherin cell-membrane expression, a molecule of pivotal value in the mechanism of cell adhesion, is found in more than 90% of lobular cancer and its inactivation results in the inability of tumor cells to adhere to one another, accounting for the major risk of distant spread [55]. Accordingly, in the series evaluated breast cancer metastases were found to be of lobular and ductal type in 40 (70.1%) and 17 (29.8%) patients, respectively. Whether this finding relates to the major metastatic potential of lobular with respect to ductal tumors rather than a specific biological affinity to genital organs harbored by lobular histology remains to be established.

Hysteroscopy with endometrial biopsy is the current reference tool in investigating endometrial pathologies and in breast cancer people suffering from gynecological complaints, it is of utmost value to carry out concurrent endometrial malignancies. Hysteroscopic-view showing polypoid, papillary, or nodular mucosal overgrowth with cerebroid consistency, focal necrosis, and atypical vascular network are considered diagnostic cornerstones of endometrial carcinomas, although a confirmatory pathologic diagnosis obtained by targeted hysteroscopic biopsy or endometrial curettage is required [10,11,56]. In our patient, an uneventful hysteroscopic imaging, revealing small scattered mucosal thickenings ascribed to Tamoxifen intake resulted unsuspicious for malignancy. In the examined literature, the diagnosis of endometrial metastasis was obtained by blind biopsies in 39 patients, by a TH-BSO carried out without a previous endometrial biopsy in 3 cases, and by a hysteroscopic procedure of endometrial sampling in 15 women. Among these latter, no description was provided about the endoscopic imaging in 2 cases [3,14], uneventful common polyps were described in 8 patients [18,22,28,33,42,52,57], a polypoid endometrium in 3 cases [21,43,58] and a large friable polypoid mass in 1 case [36]. Similar to our findings, several small elevated endometrial nodules were described in 1 patient [47]. Therefore, breast cancer endometrial metastases seldom provide a hysteroscopic view suggesting an endometrial neoplasia [36]. We might assume that unlike common endometrial carcinoma, in which the neoplastic growth affects the gland epithelium leading to an early luminal projection of carcinomatous tissue, breast cancer cells, firstly infiltrating the endometrial stroma by hematogenous or lymphatic spread, can hamper or delay the reliability of hysteroscopic imaging.

The differential diagnosis between endometrial tumors and breast cancer metastasis to the endometrium is of pivotal value to address the appropriate management. Surgical staging represents the first choice in primary uterine neoplasms whereas it needs a careful and tailored assessment in breast cancer patients with uterine spread, often presenting synchronous extragenital metastatic sites more conveniently managed by systemic medical therapies. Besides the H&E, a panel of immunohistochemistry stains can reliably support the diagnosis of breast cancer metastatic localization. GCDFP-15 (Gross Cystic Disease Fluid Protein-15) and GATA-3 expression are known as sensitive biomarkers of mammary primitiveness whereas a negative staining for CD-10 and PAX-8 can exclude a neoplasia of mullerian origin. Moreover, tumor cells’ cytokeratin expression leads to exclude mesenchymal proliferative disorders [59]. In our patient H&E findings, immunohistochemistry positive staining for GATA-3 and cytokeratin pool, combined with no expression of PAX-8 and CD-10, and besides the clinical background, supported the diagnosis of endometrial breast cancer metastasis.

Conclusion

Although rarely described, endometrial metastasis from breast cancer must be known by the attending physicians as a possible cause either of AUB or of abnormal endometrial findings on imaging techniques. Isolated endometrial metastasis is an exceptional finding and such a diagnosis obtained by endometrial biopsy underscores a more extensive gynecologic involvement or extragenital metastases in more than 90% of patients. The differential diagnosis between breast cancer metastasis and endometrial cancer can be reliably supported by an immunohistochemistry study, providing data of utmost value to address the appropriate treatment. Based on clinical background, debulking pelvic surgery in breast cancer patients with metastases confined to the genital tract organs can be considered, firstly in order to stop bleeding symptoms and secondly to limit further disease progression theoretically arising from these metastatic implants.

We thank Caroline Calnan Sagrada, a native English speaker experienced in reviewing medical papers, for the support in English grammar and style revision of the manuscript. We thank the husband of the patient for the permission to publish the manuscript.

Author contributions

G. Garuti: Conceptualization, Writing-Review & Editing

P.F. Sagrada: Conceptualization, Formal Analysis

M. Mirra: Data curation, formal analysis, visualization

E. Marrazzo: Data curation, formal analysis, visualization

S. Migliaccio: Data curation, visualization, editing

I. Bonfanti: Formal analysis, visualization, data curation

M. Soligo: Supervision, visualization, validation

The first draft of the manuscript was written by Giancarlo Garuti. All authors and the patient’s husband have read and approved the submitted manuscript

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