Endometrial cancer is the most common gynecological cancer in the United States, with an estimated 66,200 new cases diagnosed by 2023 (1). The 5-year relative survival rate is 94.9% for localized uterine cancer and decreases significantly to 69.8% and 18.4% in regional and distant stages, respectively (1). Approximately 6%–10% of early-stage endometrial cancers (2) and 27% of advanced-stage endometrial cancers develop distant metastasis over time (3, 4). The most common sites of distant metastasis include the pelvic and para-aortic lymph nodes, vagina, peritoneum, and lungs (5). High-risk histologies, such as serous carcinoma and carcinosarcoma, can spread hematogenously to the parenchyma of the liver, spleen, supraclavicular lymph nodes, and even the brain (6). Axillary lymph node metastasis presenting as the first site of recurrence, whether isolated or non-isolated, is uncommon and has not been widely reported. We present four cases of recurrent endometrial cancer that developed axillary lymph node metastasis after completing adjuvant treatment and provide an in-depth discussion of their distinctive clinical behavior and the various treatment strategies employed.

Axillary lymph node metastasis is uncommon in any type of gynecologic cancer and has not been well reviewed. In our series of four cases, three cases developed isolated axillary lymph node metastasis as the first site of recurrence. In one case, it was the harbinger of a second large-volume disease recurrence. Of the three patients with isolated axillary lymph node metastasis, two had long-term survival after aggressive locoregional treatment, including surgery and radiation. As of November 2023, three of the four patients were alive, under surveillance, or received systemic therapy. Their overall survival ranged from 24 months to 128 months after the initial diagnosis.

The majority of extrauterine spread in endometrial cancer involves the retroperitoneal lymph nodes. In a retrospective study from Italy on high-risk early-stage patients with endometrial cancer, the observed occurrence was 3.3% in both pelvic and para-aortic lymph nodes in those who underwent lymphadenectomy (7). In the evaluation of uncommon lymph node recurrence other than the above sites, an earlier single institutional study of 22 patients with endometrial cancer documented the first recurrence sites to be the inguinal, supraclavicular, and axillary lymph nodes (8). There were two cases of axillary lymph node metastasis: one had simultaneous supracervical lymph node metastasis, and the other had isolated axillary lymph node involvement. The latter patient had a history of stage III endometrial cancer at diagnosis and was treated with surgical excision and high-dose radiotherapy (≥5,000 cGy).

The metastatic route of gynecologic cancers to the axillary lymph node is postulated by two routes: (1) transthoracic lymphatic drainage or the transdiaphragmatic route, and (2) the posterior route (9). In the transdiaphragmatic route, such as in the presence of ascites and peritoneal carcinomatosis, tumor cells cross the diaphragm and invade the superior diaphragmatic lymph node. The tumor cells then drain toward the prepericardial and parasternal lymph nodes and continue directly to the internal jugular and subclavian veins or the subclavian lymph trunk and thoracic duct. The posterior route gathers all lymphatic pathways from the deep lymphatic vessels inferior to the diaphragm (iliac, para-aortic, and mesenteric) and superficial lymphatic vessels inferior to the level of the umbilicus. This lymphatic drainage unification forms the cisterna chyli and thoracic duct, which travels in the posterior mediastinum and drains into the junction of the left subclavian and internal jugular veins. Notably, drainage from the left subclavian and internal jugular veins to the axillary lymph nodes presumably follows the reverse route. In addition, isolated axillary lymph node recurrence also represents a “skipping” metastasis along the way. In a small series in which PET/CT was used to evaluate advanced-stage epithelial ovarian cancer, a significant number of patients had supradiaphragmatic lymph node metastasis (9).

When reviewing the routes of axillary lymph node metastasis, each case showed a unique pattern. Case #3 had widespread peritoneal carcinomatosis and retroperitoneal lymph node involvement, which likely contributed to right axillary lymph node metastasis through both the transdiaphragmatic and posterior routes. Case #1 had positive pelvic cytology and pelvic lymph node involvement, and both characteristics could potentially lead to disease spread via the transdiaphragmatic and posterior lymphatic drainage routes. However, in cases #2 and #4, neither the transdiaphragmatic nor the posterior route could explain the cause of the right axillary lymph node metastasis. There were no malignant cells in the pelvic washing or peritoneal carcinomatosis. Although case #2 was incompletely staged, the fact that she did not develop disease in the pelvic or para-aortic lymph nodes indicates that the posterior route of lymphatic drainage was not a contributing factor to axillary lymph node metastasis.

All four patients received adjuvant chemotherapy after their initial diagnosis because of aggressive histology. Patients in cases #1 and #2 received sequential chemotherapy and pelvic radiation based on multiple phase II study results available at that time (10, 11). Currently, systemic therapy is considered the foundation of adjuvant therapy in patients with extrauterine diseases. Two prospective randomized control studies (RCT) demonstrated the effectiveness of concurrent chemoradiation with cisplatin and external-beam radiation followed by carboplatin and paclitaxel in treating advanced-stage endometrial cancer (3, 12). For high-risk uterine cancer with disease limited to the uterus, we applied the treatment strategy endorsed by the GOG 249 study, which demonstrated the similar efficacy of either pelvic radiation or vaginal brachytherapy followed by carboplatin and paclitaxel (13) This treatment was used in case #4. Notably, concurrent chemoradiation with cisplatin and external-beam radiation followed by carboplatin and paclitaxel can be a reasonable option as well (3, 12) Patients in cases #1 and #3 also received pembrolizumab and lenvatinib at the time of disease progression and benefited from prolonged disease control (14, 15). This real-world evidence supports the efficacy of this regimen in both slow-growing, low-volume disease as well as rapidly progressing, high-volume disease of carcinosarcoma. With the newest evidence demonstrating survival benefits in treating advanced stage endometrial cancer, including carcinosarcoma, with immunotherapy in addition to front-line chemotherapy (16, 17), we expect to see a change in the treatment paradigm that may further impact the recurrence pattern.

All four patients had aggressive histology (serous carcinoma and carcinosarcoma) and either stage I or stage III disease at presentation. IHC and NGS testing showed no definite differences in predicting axillary recurrence ( Table 1 ). However, isolated axillary lymph node metastasis, as presented in cases #1 and #2, appears to predict a disease characteristic of truly isolated oligometastasis and a more indolent course. Neither case #1 nor case #2 ever had axillary recurrence after receiving aggressive locoregional treatment for axillary lymph node metastasis with curative intent. These included axillary LND, radiation followed by systemic chemotherapy, and concurrent chemoradiation. Most importantly, neither case #1 nor case #2 developed widespread distant metastasis. The clinical progression pattern observed in cases #1 and #2 suggests that aggressive locoregional treatment could improve disease control in isolated axillary lymph node metastasis. Our observation is consistent with a previous study by Foote et al. that in their series of 22 patients with isolated peripheral lymph node recurrence, six patients remained free of disease at a median follow-up of 27 months. This observation and hypothesis were the basis for the recommendation of the treatment plan for case #4.

Of note, in cases #1 and #2, adjuvant radiation was applied to the axilla to ensure sterilization of cancer cells in all the potential tumor-involved lymph nodes, and no further axillary recurrence developed. A new method for intraoperative lymph node assessment was developed using optical coherence tomography (18). Lymph node dissection can become more accurate with the advancement of this technology,.

In conclusion, axillary lymph node metastasis as the first site of recurrence is uncommon and is more often seen in endometrial cancer with high-risk histologies. There was no direct association between isolated axillary lymph node metastasis and disease stage at diagnosis. This recurrence pattern may not be due to a disseminated recurrence or metastasis. We recommend aggressive loco-regional treatment in addition to systemic treatment to maximize the chance of long-term disease control.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Maimonides Medical Center Institutional Review Board. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with national legislation and institutional requirements. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

YAC: Writing – original draft, Writing – review & editing. MO: Writing – original draft. YX: Writing – original draft, Writing – review & editing.