Introduction
Breast cancer is the most common malignancy in women (1), negatively affecting women's health, and distant metastasis is the main factor affecting prognosis (2). The most common sites of distant breast cancer metastasis are the lung, liver, bone and brain. Luminal breast cancer is most likely to metastasize first to bone. Furthermore, among the breast cancer types, HR−/HER2+ tumors have the highest rates of liver metastasis, and HR+/HER2- tumors have the highest rates of lung metastasis. The brain has been previously reported to be a preferred site of metastasis in patients with triple-negative cancers (3). However, metastasis to the female reproductive system is less common, but when breast cancer does metastasize to the reproductive system, it is most commonly observed in the ovaries. The small size of the uterus, limited blood flow to the distal region, and abundant fibrous tissue within the uterus collectively create an environment that is not conducive to the spread of malignant tumors (4). Consequently, uterine metastatic cancer represents <10% of female reproductive system metastases (5). The metastatic patterns of lobular and ductal invasive breast cancer differ, although it is not explicitly known why this is the case. Invasive lobular carcinoma (ILC) metastasis usually involves the peritoneum, gastrointestinal tract and ovaries, whereas invasive ductal carcinoma (IDC) more commonly involves the lungs and pleura (6). The results of prior studies based on tumor registry data have demonstrated that ILC metastasizes to gynecologic organs in ~4.5% of cases, whereas IDC metastasizes to these organs in 0.8% of cases (7). Currently, the number of reported cases of breast cancer metastasis to the reproductive tract, both domestically and internationally, is limited. Therefore, additional data are needed to enhance our understanding of this phenomenon. In the present study, two cases of breast cancer combined with reproductive system metastasis and a synthesis of the clinical characteristics of this disease are presented on the basis of the previous literature. The characteristics of the patients are shown in Table I.
Discussion
In 2022, the incidence rates of breast cancer (23.8%) far exceeded those of other cancers in women, followed by lung cancer (9.4%). Breast cancer is the most common cancer in women and has a high mortality rate. The incidence and mortality of breast cancer are significantly influenced by demographic characteristics and geographical factors. White European and American women exhibit the highest incidence rates, ~130 per 100,000 individuals; however, women of African descent experience a higher mortality rate, which may be related to disparities in healthcare resources. By contrast, the incidence of breast cancer is relatively low among Asian women, although it has increased rapidly in recent years (Table II). The highest incidence rates were observed in France, Australia/New Zealand, North America and Northern Europe, where they are ~4-fold higher than those reported in South-Central Asia and Middle Africa (8). Among the pathological breast cancer subtypes, IDC accounts for >70% of cases, and ILC accounts for 5-15% of cases; however, the latter is the most common pathological type of metastatic breast cancer (9). In their study, Wang et al (10) analyzed 18,322 patients with metastatic breast cancer and reported that bone metastasis accounted for 39.8% of metastasis cases, followed by lung (10.94%), liver (7.34%) and brain metastasis (1.51%). Metastases of extragenital malignancies to the reproductive system are rare, most commonly in the digestive system (37.6%), followed by breast cancer, which often involves the ovaries (75.8%) and vagina (13.4%), followed by the endometrium (4.7%), cervix (3.3%) and salpinx (0.7%) (5,11). Since the cervix is composed mainly of fibrous muscle tissue with a limited blood supply and only incoming lymphatic drainage, metastasis to the cervix is extremely rare (12).
The timing of the occurrence of reproductive system metastasis in patients with breast cancer is inconsistent, and the precise mechanism of reproductive system metastasis remains unclear. At present, the literature on breast cancer metastasis to the reproductive system both domestically and internationally is composed primarily of case reports. The most frequently observed presentation of metastasis is vaginal bleeding (13). Additionally, the diagnosis of asymptomatic metastases among these patients is incidental, and asymptomatic metastasis is more likely to be overlooked than metastasis with abnormal vaginal bleeding symptoms. Despite the presence of uterine lesions, as evidenced on gynecological ultrasound or CT, there was no previous history of gynecological disease or current symptoms among these patients. Consequently, no further diagnosis was made. Metastatic uterine malignant tumors are frequently misdiagnosed as uterine fibroids or primary uterine malignant tumors on imaging, particularly following tamoxifen treatment. Endocrine medication is associated with a 5-30% incidence of increased endometrial thickness, a 26-60% incidence of endometrial polyps, and an endometrial cancer (EC) incidence of 0.8-8%, all of which are 2-7 times greater than those of the general population (14). Furthermore, international researchers have discovered that in individuals receiving endocrine therapy following breast cancer surgery, age is a risk factor for the development of EC. Premenopausal patients account for ~52% of endometrial disease cases, and EC is more common in patients older than 35 years (15). Patients are advised to receive routine examinations. Because the symptoms of endometrial alterations can be mistaken for those of other gynecological disorders, there is a chance of misdiagnosis even though the actual incidence of EC caused by endocrine therapy is low, at 0.1-0.2% (16). In such cases, a differential diagnosis of endocrine drug-induced primary EC is essential (17). Mazur et al (5) reported that ~42% of metastatic cervical tumors are incorrectly identified as primary cervical tumors. Nevertheless, importantly, some metastases are detected prior to or concurrently with the primary tumor (18,19). A pathological biopsy is typically the most rigorous criterion for differentiating a primary mass from a secondary mass that has metastasized beyond the reproductive tract. In cases of highly suspicious but difficult to differentiate findings on the basis of the imaging presentation, accurate immunohistochemistry is needed. It is therefore of particular importance to consider the contributions of pathology and immunology.
GATA3 is one of six members of the GATA family of transcription factors. It plays a specific role in regulating mammary gland morphogenesis and the differentiation of luminal epithelial cells in the breast (20,21). The expression rates of GATA-3 in IDC and ILC are 91 and 100%, respectively, whereas in EC, the expression rate is only 2%. Furthermore, GATA-3 is not expressed in cervical adenocarcinoma or ovarian mucinous carcinoma (22,23). In the present study, Patient 2 had GATA3 expression in the reproductive system tissues and a history of breast cancer. Therefore, in such cases, breast cancer metastasis to the reproductive system has to be strongly considered.
Treatment and prognosis
In patients with breast cancer metastasis to the reproductive tract, the disease prognosis is typically poor, and there is currently no uniform diagnosis or treatment plan. In some studies, it has been indicated that palliative hysterectomy and bilateral salpingo-oophorectomy were suggested as effective forms of castration therapy; however, the evidence supporting this is inconclusive with respect to survival outcomes. In other studies, systemic chemotherapy was suggested to be more efficacious when it is administered alone. Despite the generally poor prognosis among this group of patients, some patients achieve complete remission and remain disease-free for extended periods, with survival exceeding 20 years in some patients (24).
The present article presents two cases. In Patient 1, metastasis occurred in the uterine body and cervix, with abnormal vaginal bleeding as the initial symptoms. The patient was diagnosed at an early stage, with metastasis already present. In this patient, metastasis occurred when the primary tumor was in an early stage, almost at the same time as the primary tumor, and there was no metastasis to the lymph nodes or other sites, which is quite rare and has not been reported previously. The patient is currently undergoing regular follow-up, with no evidence of tumor recurrence or metastasis to other sites. In Patient 2, metastasis to the common ovary and uterus occurred, with no clinical symptoms. However, high echogenicity in the adnexa was observed on ultrasound. The disease was staged as an advanced stage malignancy, with an ILC component, and the pathological examination of the metastatic lesion indicated that it was primarily a metastasis of the ILC component. The GATA3 result was positive, whereas the PAX8 result was negative. Immunohistochemistry provided clear evidence that the tumor had originated in the breast, thus providing a means of distinguishing it from primary ovarian cancer. The patient underwent surgical intervention in conjunction with endocrine therapy, and the current status remained stable with regular follow-up.
In summary, although breast cancer metastasis to the reproductive system is rare, for patients with breast cancer, regular gynecological ultrasound should be performed during follow-up, even in the absence of clinical symptoms. Caution should be exercised in the event of the occurrence of metastatic tumors in the reproductive tract, particularly in patients with late-stage infiltrating lobular carcinoma and a history of similar drug treatments, such as tamoxifen. GATA-3 and other immunohistochemical markers are helpful in differentiating primary reproductive system tumors. At present, there is no consensus regarding the optimal treatment approach for these patients; the most important issue in clinical studies is the low number of patients because this type of metastasis is uncommon. It is considered that once more related cases are reported both domestically and internationally, a meta-analysis will be the next step, and on the basis of the findings of the meta-analysis, the best course of treatment can be chosen.