Endometrial Cancer and Uterine Sarcoma: Molecular Classification and Treatment

Uterine Sarcomas: Classification and Genetics

Uterine sarcomas are mesenchymal tumors that require distinct management compared to epithelial carcinomas. These include uterine leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS).

Endometrial Stromal Sarcoma (ESS)

ESS is categorized by its grade and specific genetic drivers. Molecular analysis has identified several key fusions and mutations that define these tumors:

• Low-grade ESS: Often associated with the JAZF1 and JJAZ1 gene fusion.
• High-grade ESS: These may be characterized by YWHAE-FAM22 or C3H7B-BCOR fusions.

Other Sarcomas

Other notable malignancies include uterine carcinosarcoma, which is treated as a high-grade endometrial cancer, and undifferentiated uterine sarcoma.

Staging and Surgical Principles

The FIGO staging system remains the standard for surgical and pathologic staging of uterine neoplasms. Several critical factors influence the stage and subsequent treatment plan:

• Myometrial Invasion: The depth of invasion is a primary criterion for staging.
• Lymphovascular Space Invasion (LVSI): Substantial LVSI is defined as $\ge 5$ vessels in at least one hematoxylin and eosin (H&E) slide.
• Lymph Node (LN) Involvement: Assessing pelvic and para-aortic nodes is vital for determining if adjuvant therapy is required.

To minimize surgical morbidity, sentinel lymph node (SLN) mapping is the preferred alternative to full lymphadenectomy for patients with disease that appears confined to the uterus.

Treatment Modalities

Primary Treatment

The cornerstone of primary treatment is surgical, typically involving a total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO). In specific cases, such as premenopausal patients with early-stage (Stage IA, Grade 1) endometrioid cancer and no family history of Lynch syndrome, ovarian preservation may be considered.

Adjuvant and Systemic Therapy

Adjuvant therapy, including radiotherapy (RT) or systemic therapy, is determined by risk factors like high-grade histology or nodal involvement.

For advanced or recurrent endometrial carcinoma, systemic therapy options include:

• Chemotherapy: The combination of carboplatin and paclitaxel is a standard regimen.
• Immunotherapy: For patients with MSI-H/dMMR tumors, agents like pembrolizumab are used. In some cases, combinations such as lenvatinib plus pembrolizumab are considered.
• Targeted Therapy: For patients with NTRK gene fusion-positive or RET fusion-positive solid tumors, specific inhibitors like selpercatinib (for RET) may be utilized.

Hormonal Therapy

Hormonal interventions are used in specific clinical contexts:

1. Recurrent/Metastatic ER-positive disease: Regimens may include aromatase inhibitors (e.g., letrozole) combined with CDK4/6 inhibitors (e.g., palbociclib) or abemaciclib/fulvestrant.
2. Fertility Preservation: For patients desiring uterine preservation, continuous progestin-based therapy (such as a Levonorgestrel IUD) is preferred.
3. Low-grade ESS: Aromatase inhibitors are a preferred option for low-grade ESS or adenosarcoma without prior salpingectomy.

Clinical Note: When managing patients receiving platinum-based chemotherapy like carboplatin, clinicians must be vigilant for hypersensitivity reactions. If a patient develops a reaction, specific desensitization protocols may be required.

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References NCCN Guidelines® Uterine Neoplasms Version 3.2026 — June 16, 2026.