Metastatic Breast Cancer to the Cervix and Endometrium Mimicking a Primary Gynecologic Malignancy

Abstract

The most common sites of breast cancer metastasis include the bone, lung, liver, and brain. Metastasis to the uterine cervix and endometrium is uncommon and can mimic primary gynecologic malignancies, leading to substantial diagnostic challenges. The authors have reported a 56-year-old postmenopausal woman with metastatic invasive mammary carcinoma of the left breast, including biopsy-confirmed liver metastasis, who presented after a syncopal event following an episode of heavy vaginal bleeding. Following her presentation, she underwent cervical and endometrial biopsies. Cervical biopsy revealed scattered discohesive tumor cells positive for GATA3, mammoglobin, TRPS1, AE1/3, and CAM5.2 and negative for PAX8, which were consistent with metastatic breast carcinoma. Endometrial biopsy showed cohesive nests of atypical carcinoma with diffuse p16, p63, and CK5/6 positivity and negative staining for mammoglobin, TRPS1, SOX10, and PAX8, initially raising concern for a human papillomavirus–associated squamous cell carcinoma. Following multidisciplinary evaluation, it was established that these features represented metastatic breast human papillomavirus–associated squamous cell carcinoma to the endometrium rather than a new primary gynecologic malignancy. This case highlighted the importance of considering metastatic disease in patients with breast cancer presenting with abnormal uterine bleeding and demonstrated the value of multidisciplinary evaluation in determining an accurate diagnosis.

Introduction

Breast cancer is the most common type of cancer among women worldwide and remains a leading cause of cancer-related mortality. ¹ When breast cancer metastasizes, it most frequently spreads to the bone, lung, liver, and brain. ² Involvement of the female genital tract is uncommon, with endometrial metastasis being extremely rare and cervical metastasis occurring in approximately 0.8% to 1.7% of cases. ³

When cervical or endometrial metastases do occur, patients most commonly present with abnormal vaginal bleeding, abnormal vaginal discharge, and lower abdominal or pelvic pain. ^3–5 The rarity of metastatic involvement of the cervix is likely related to its relatively small size, dense fibrous connective tissue stroma, and limited vascular supply with predominantly lymphatic drainage, which may reduce susceptibility to metastatic spread. ³ A review by Perez-Montiel et al reported that lobular carcinoma was the most frequent histologic subtype associated with cervical metastasis, followed by ductal carcinoma. ⁴ Metastasis to the endometrium most commonly occurs secondary to ovarian metastases through retrograde lymphatic spread. ⁶ By contrast, isolated endometrial metastasis are rare and likely occur through hematogenous spread. ^6,7

The authors have presented the case of a 56-year-old woman with metastatic invasive ductal carcinoma of the breast who developed abnormal uterine bleeding and was found to have cervical and endometrial involvement, initially concerning for a secondary primary gynecologic malignancy. This case highlighted the diagnostic challenges associated with metastatic breast carcinoma involving the female genital tract.

Case Patient Presentation

A 56-year-old postmenopausal woman with a history of invasive ductal carcinoma of the left breast with mixed ductal and lobular features (estrogen/progesterone [ER/PR] positive, HER2 negative) and known metastatic disease, including biopsy-confirmed liver metastases with triple-negative receptor status, presented to the emergency department following a syncopal episode in the setting of new, heavy vaginal bleeding of 1-day duration, which occurred approximately 1 year after her initial cancer diagnosis. She reported soaking 7 adult diapers with clots reportedly up to golf ball–sized. She denied preceding abdominal pain, pelvic pain, vaginal discharge, or other gynecologic symptoms. She reported that her last documented Papanicolaou smear was more than 10 years earlier; outside records were unavailable, and prior human papillomavirus (HPV) status was unknown.

Clinical History

Approximately 1 year prior to presentation, she was hospitalized and found to have widespread metastatic disease on imaging. Initial staging computed tomography (CT) imaging demonstrated suspected breast cancer with mild bilateral axillary adenopathy, bilateral pulmonary, hepatic, and diffuse skeletal metastases, peritoneal/omental metastases with ascites, and minimal mediastinal and inguinal adenopathy. Subsequent diagnostic mammography and left breast ultrasonography demonstrated a 4.9 x 4.2 cm spiculated left breast mass with associated left axillary lymphadenopathy.

A liver biopsy performed at that time demonstrated poorly differentiated metastatic carcinoma. Immunohistochemical staining was positive for CK7 and GATA3 and negative for CK20, TTF-1, GCDFP, ER, PR, and HER2/neu, which were findings most consistent with metastatic breast carcinoma with triple-negative features. Ki-67 proliferation index was approximately 80%. Immunohistochemical analysis performed at NeoGenomics Laboratories demonstrated programmed death-ligand expression with a tumor proportion score of 5%. Concurrent molecular profiling identified pathogenic alterations in PIK3CA and AKT1. BRCA testing was negative.

Subsequent core needle biopsy of the left breast demonstrated high-grade poorly differentiated invasive mammary carcinoma with mixed ductal and lobular features that was ER-positive, PR-positive, and HER2-negative. She was then started on systemic therapy with pembrolizumab and nab-paclitaxel based on programmed death-ligand expression, along with tamoxifen for hormone receptor-positive disease. Tamoxifen was selected over anastrozole due to the patient’s preference to avoid arthralgia-related adverse effects. Zoledronic acid was also initiated for management of diffuse skeletal metastases.

Follow-up CT imaging performed approximately 3 months after initiation of treatment demonstrated a mixed treatment response, with interval decrease in size of the primary breast lesion but progression of metastatic disease involving the lungs, liver, and peritoneum. This discordant response suggested differential treatment sensitivity between the hormone receptor-positive breast lesion and the triple-negative metastatic disease. Given overall disease progression, pembrolizumab and nab-paclitaxel were discontinued, and treatment was transitioned to sacituzumab govitecan. Tamoxifen was continued given interval reduction in the size of the primary breast mass.

Subsequent magnetic resonance imaging of the brain revealed metastatic involvement of the medial rectus muscle and optic chiasm, prompting evaluation by ocular oncology and ophthalmology. During treatment with sacituzumab govitecan, she experienced substantial diarrhea and fatigue, which led to a 20% dose reduction in her therapy. Despite these adverse effects, her ascites burden improved with sacituzumab govitecan therapy, as evidenced by a decreased frequency of therapeutic paracenteses.

Gynecology Evaluation and Pathologic Review

Her new-onset heavy vaginal bleeding initially raised concern for a possible new primary gynecologic malignancy. Given her ongoing tamoxifen therapy, there was also concern for tamoxifen-induced endometrial hyperplasia. CT imaging obtained during this presentation demonstrated heterogeneous appearance of the uterus and cervix (Figure) and heterogeneous right adnexal mass with moderate left renal hydronephrosis, with otherwise stable pulmonary, hepatic, and skeletal metastases.

Figure:

Axial computed tomography abdomen/pelvis with intravenous contrast demonstrating heterogenous pelvic masses involving the uterine and adnexal regions with extension into the cul-de-sac and possible rectal invasion.

Differential Diagnosis

Several diagnoses were considered during the evaluation of this patient’s abnormal uterine bleeding, including primary cervical squamous cell carcinoma, primary endometrial carcinoma, tamoxifen-induced endometrial hyperplasia, and metastatic breast carcinoma involving the cervix and endometrium. To further evaluate the source of her bleeding and establish a diagnosis, cervical and endometrial biopsies were obtained. Cervical biopsy demonstrated scattered discohesive tumor cells within a necrotic background that stained positive for AE1/AE3, CAM5.2, GATA3, mammoglobin, and TRPS1 and negative for PAX8, which were findings consistent with metastatic breast carcinoma.

By contrast, the endometrial biopsy revealed cohesive nests of poorly differentiated carcinoma with greater cytologic atypia and pleomorphism within extensive necrotic and inflammatory debris. Immunohistochemical staining showed patchy weak GATA3 positivity with strong diffuse staining for p63, CK5/6, and p16, while mammoglobin, TRPS1, SOX10, and PAX8 were negative. HPV in situ hybridization demonstrated only rare possible nuclear signals and was not definitively diagnostic. These findings initially raised concern for HPV-associated squamous cell carcinoma.

Clinical Reasoning/Determining an Approach

Given the differing morphologic and immunohistochemical patterns between the cervical and endometrial specimens, the possibility of 2 separate malignant processes was initially considered. However, following multidisciplinary review involving pathology, gynecologic oncology, and medical oncology, the overall immunohistochemical profile, clinical history, and pattern of metastatic disease were ultimately interpreted as most consistent with metastatic breast carcinoma involving both the cervix and endometrium rather than a synchronous primary gynecologic malignancy.

Treatment Pathway and Outcomes

The patient was discharged with close outpatient follow-up with oncology. Hysterectomy was not pursued, given that her vaginal bleeding became clinically controlled, in addition to her not being a surgery candidate due to advanced disease; she was continued on systemic therapy for metastatic disease. Despite ongoing treatment, her disease continued to progress. She was later transitioned to hospice care and died during a later hospitalization.

Discussion

Metastasis of breast cancer to the uterine cervix and endometrium is exceedingly rare, with only limited reports in the literature. ^7,8 Such occurrences can closely mimic primary gynecologic malignancies both clinically and histologically, leading to diagnostic challenges. ^7,8 Establishing the correct diagnosis in these scenarios is critical in order to determine appropriate management.

The rarity of cervical and endometrial metastases from breast cancer likely contributed to the initial diagnostic uncertainty in this case. Metastatic involvement of the cervix is particularly uncommon due to its dense fibrous stroma and relatively limited vascular supply, while isolated endometrial metastases are thought to occur primarily through hematogenous dissemination rather than retrograde lymphatic spread. ³

In this case, new-onset abnormal uterine bleeding raised concern for both a primary gynecologic malignancy and tamoxifen-induced endometrial hyperplasia. The endometrial biopsy revealed an immunophenotypic profile overlapping with metastatic breast carcinoma and HPV-associated squamous cell carcinoma, creating substantial diagnostic uncertainty. Final diagnosis required multidisciplinary clinicopathologic correlation, which supported metastatic breast carcinoma involving the endometrium rather than a synchronous primary gynecologic malignancy.

The p16-positive endometrial lesion created a diagnostic challenge. Although p16 is classically associated with HPV-driven squamous neoplasms, studies have revealed that it can also be expressed in invasive breast cancer, particularly in high-grade and basal-like phenotypes. ^9–11 Some studies report a weak association, while others note that p16 may carry a substantial role in the development of aggressive and invasive breast cancer. ³ For example, a study examined 20 cases of basal-like breast carcinoma, loosely defined as lacking ER, PR, and HER2 overexpression, and found that 80% were p16-positive, compared to 50.8% in cases that were not basal-like breast carcinoma. ¹² In this case, diffuse p16 positivity together with strong p63 and CK5/6 expression initially raised concern for an HPV-associated squamous cell carcinoma. However, the absence of definitive HPV in situ hybridization findings, patchy GATA3 positivity, the patient’s known history of metastatic breast cancer, and multidisciplinary clinicopathologic review ultimately supported metastatic breast carcinoma as the most likely diagnosis. These findings demonstrated how overlapping immunohistochemical features between breast carcinoma and squamous neoplasms may create substantial diagnostic ambiguity when evaluating gynecologic tract lesions. ¹¹

Cervical and endometrial metastasis of breast cancer is uncommon, with most patients lacking specific clinical symptoms that allow for early detection. This case underscored the importance of maintaining a broad differential diagnosis in patients with a history of breast cancer who present with abnormal uterine bleeding, including metastatic disease to the female genital tract. Although rare, recognition of this phenomenon is critical, because it may impact staging, prognosis, and management decisions. Multidisciplinary evaluation between pathology, oncology, and gynecology remains essential in distinguishing metastatic disease from primary gynecologic malignancies in diagnostically challenging cases.

Key Learning Takeaways

1. Metastatic breast cancer should remain in the differential diagnosis in patients with a history of breast cancer who present with abnormal uterine bleeding.

2. The expression of p16 is not specific for HPV-associated malignancies and can be observed in certain breast cancers.

3. Multidisciplinary evaluation is essential to accurately diagnose and distinguish metastatic disease from a second primary malignancy.

Relevancy Statement.

This case report demonstrated a team-based approach to patient care by integrating gynecologic, pathologic, and oncologic expertise to resolve a diagnostically challenging endometrial lesion and ensure accurate identification of metastatic breast carcinoma.