Management of Endometrial Carcinoma and Uterine Sarcoma

Systemic and Biomarker-Directed Therapy

The landscape of systemic therapy for endometrial carcinoma has been revolutionized by molecular analysis. Treatment is no longer "one size fits all" but is instead tailored to the tumor's molecular signature, including MSI/MMR status, TMB-H (Tumor Mutational Burden High), HER2 expression, and gene fusions like NTRK or RET.

Advanced and Recurrent Disease

For stage III–IV tumors, preferred regimens often involve platinum-based chemotherapy, such as carboplatin/paclitaxel, frequently combined with immunotherapy. For example, in $dMMR$ (deficient Mismatch Repair) tumors, carboplatin/paclitaxel plus pembrolizumab is a key consideration.

When disease recurs, the choice of first-line therapy depends heavily on the biomarker profile:

• pMMR (mismatch repair proficient) tumors: A category 1 recommendation for certain settings is the combination of lenvatinib + pembrolizumab.
• HER2-positive tumors: For uterine serous carcinoma or carcinosarcoma that expresses HER2, trastuzumab or fam-trastuzumab deruxtecan-nxki may be utilized.
• TMB-H tumors: Immunotherapy with ipilimumab + nivolumab is a targeted option.
• RET gene fusion-positive: Targeted therapy with selpercatinib is indicated.

Hormonal Therapy

Hormonal interventions serve two primary roles:

1. Fertility Preservation: For patients with uterine-limited, low-grade endometrioid disease desiring to preserve fertility, continuous progestin-based therapy (e.g., levonorgestrel IUD) is preferred.
2. Recurrent/Metastatic Disease: In ER-positive tumors, agents such as megestrol acetate, tamoxifen, letrozole/palbociclib, or abemaciclib/fulvestrant may be used.

Uterine Sarcoma Management

Uterine sarcomas are mesenchymal tumors that require aggressive management based on their histological subtype.

Low-Grade vs. High-Grade Sarcomas

The management strategy is bifurcated by the aggressiveness of the histology:

• Low-Grade Endometrial Stromal Sarcoma (ESS) and Adenosarcoma: The primary treatment is surgical resection (TH with en bloc resection $\pm$ BSO). For advanced stages (II–IV), additional therapy may include systemic endocrine therapy or palliative External Beam Radiation Therapy (EBRT).
• High-Grade ESS, Leiomyosarcoma (LMS), and Undifferentiated Uterine Sarcoma (UUS): These are significantly more aggressive. While stage I may sometimes be managed with observation if completely resected, stages II–IV typically require systemic therapy and/or EBRT.

Relapsed Disease and Local Control

For patients with relapsed sarcoma, management includes surgical exploration, local ablative therapies, or systemic therapy. If a recurrence is radiologically isolated in the pelvis, surgical resection—potentially combined with Internal Radiation Therapy (IORT)—is a viable consideration.

CRITICAL SAFETY ALERT: In any case where a malignant mesenchymal sarcoma is suspected, morcellation must be avoided to prevent the fragmentation and widespread dissemination of tumor cells.

Summary of Molecular Targets in Sarcoma

Just as in carcinoma, uterine sarcomas benefit from molecular profiling to identify rare but actionable targets.

By integrating surgical precision with molecularly-guided systemic agents, clinicians can provide increasingly personalized care for patients facing these complex uterine malignancies.