Uterine Neoplasms

Background:

• Risk factors:

  • Obesity

  • Chronic anovulation/ prolonged unopposed estrogen exposure

    • PCOS/chronic anovulation

    • Estrogen-only menopausal hormone therapy

    • Estrogen-producing tumors

  • Obesity

  • Nulliparity/ infertility

  • Early menarche/ late menopause → greater lifetime estrogen exposure

  • Increasing age/ postmenopausal status

  • Tamoxifen

  • Endometrial hyperplasia

• Combined OCP, progestin exposure and multiparity decrease risk of endometrial cancer

• High association with Lynch syndrome

• Subgroups:

  • Epithelial malignancies (endometrial carcinoma, ~95%)

  • Mesenchymal malignancies (uterine sarcomas, 3–5%)

• Atypical endometrial hyperplasia (AEH):

  • Premalignant lesion with risk of progression to and coexistence with endometrial carcinoma.

  • Definitive treatment: Total hysterectomy

    • Postmenopausal patient

    • If fertility preservation is not desired

  • Conservative management: progestin therapy

    • Requires close endometrial surveillance with repeat sampling.

      • If persistent disease despite adequate therapy → reassess management and consider definitive surgery.

      • If complete response → consider maintenance progestin if ongoing risk factors are present.

Endometrial Carcinoma

Classification:

• Traditional dualistic model:

  • Type I/endometrioid (~80%):

    • Associated with increased estrogen exposure

    • Better prognosis than type 2

  • Type II/ non-endometrioid (~20%):

    • Hormone-independent

    • Higher risk histologies (Serous, clear cell)

    • Includes: Serous carcinoma (TP53-mutated), clear-cell carcinoma, carcinosarcoma

• New molecular classification:

  • POLE-mutated

    • Excellent prognosis, near-zero recurrence

  • dMMR/MSI-H

  • NSMP

  • p53-aberrant

    • Worst prognosis

    • Greatest absolute benefit of adding chemotherapy to radiotherapy

Treatment:

• Total hysterectomy + BSO with surgical staging

  • Ovarian preservation may be considered in premenopausal patients with stage IA G1 endometrioid disease without high-risk molecular features.

• Adjuvant therapy:

  • Stage I:

    • Options range from observation (IA, G1–2) to vaginal brachytherapy (VBT) to External-Beam Radiation Therapy (EBRT) ± systemic therapy (IB G3)

  • Stage II:

    • EBRT (preferred) ± VBT ± systemic therapy

  • Stage III–IV:

    • Systemic therapy and immunotherapy become central:

      • Carbo/paclitaxel

      • Carbo/paclitaxel + pembrolizumab (NRG-GY018)

        • Except for carcinosarcoma

      • Carbo/paclitaxel + dostarlimab (RUBY)

      • Carbo/paclitaxel + durvalumab

        • dMMR only

      • Carbo/paclitaxel + durvalumab/Olaparib maintenance in pMMR (DUO-E)

      • Carbo/paclitaxel + trastuzumab

        • For HER2-positive serous carcinoma or carcinosarcoma

  • Recurrent/progressive disease

    • Pembrolizumab + lenvatinib (Keynote 775)

      • pMMR tumors

    • Pembrolizumab

      • MSI-H/dMMR

      • TMB-High

    • Dostarlimab

      • MSI-H/dMMR

    • Fam-trastuzumab deruxtecan (Enhertu)

      • HER2 positive (IHC 3+ or 2+)

    • Larotrectinib, Entrectinib, Repotrectinib

      • NTRK fusion positive

• Hormonal/endocrine therapy:

  • Consider for low-grade endometrioid carcinoma, particularly ER/PR-positive, indolent/asymptomatic disease.

  • Options include:

    • Progestins (megestrol acetate)

    • Megestrol acetate/tamoxifen (alternating)

    • Aromatase inhibitors

    • Fulvestrant

    • Everolimus + letrozole

  
  

Uterine Sarcoma

Subtypes:

• Leiomyosarcoma

  • Most common

  • High metastatic potential

  • Avoid morcellation

• Endometrial Sarcoma

  • Low-grade endometrial stromal sarcoma (LG-ESS)

    • JAZF1::SUZ12 rearrangement

    • Strongly ER/PR-positive

    • Indolent

    • 5-yr OS ~90–100% early stage

    • late recurrences common (36–56%) even in early stage

    • Treatment:

      • Total hysterectomy ± BSO + Endocrine therapy

      • Chemotherapy has essentially no role

      • Tamoxifen is contraindicated

  • High-grade endometrial stromal sarcoma (HG-ESS)

    • YWHAE::NUTM2 fusion or BCOR alterations

    • ER/PR often negative in high-grade component

    • Diffuse cyclin D1

    • Aggressive (median OS ~11–24 months)

• Undifferentiated Uterine Sarcoma (UUS)

  • High-grade/ poor prognosis

  • Pleomorphic

  • Lacks any resemblance to endometrial stroma

  • Lacks smooth-muscle differentiation

  • Lacks the specific defining fusions of LG-ESS and HG-ESS

• Adenosarcoma

  • Rare

  • Biphasic uterine malignancy:

    • Benign/atypical epithelial glands + Malignant stromal component

  • Risk stratification:

    • Adenosarcoma WITHOUT sarcomatous overgrowth: More indolent

    • Adenosarcoma WITH sarcomatous overgrowth: More aggressive

Treatment:

• Primary treatment:

  • Total hysterectomy ± BSO

• Adjuvant therapy (except for LG-ESS):

  • Stage I:

    • Observation

  • Stage II/III

    • Observation if completely resected with negative margins

    • Consider systemic therapy and/or EBRT

  • Stage IV:

    • Systemic therapy and/or EBRT

      • Doxorubicin

      • Docetaxel/gemcitabine

      • Doxorubicin/trabectedin

      • Doxorubicin/ifosfamide

      • Doxorubicin/dacarbazine

      • Larotrectinib, Entrectinib, Repotrectinib

        • If NTRK fusion positive

      • Crizotinib, Ceritinib, Brigatinib, Lorlatinib, Alectinib (IMT with ALK translocation)

      • Selpercatinib

        • If RET Fusion positive

Gestational Trophoblastic Diseases

Hydatidiform Mole

• Complete mole

• Partial mole

Gestational Trophoblastic Neoplasia (GTN)

• Subtypes:

  • Invasive mole

  • Choriocarcinoma

  • Placental-site trophoblastic tumor (PSTT)

  • Epithelioid trophoblastic tumor (ETT)

• Staging:

  • Prognostic scoring index: low risk <7, high risk ≥7

• Treatment:

  • If low risk:

    • Can use dactinomycin or MTX

      • Can change from one to the other if good response but follows by hCG plateau or re-escalation of hCG (<1000)

    • Consider hysterectomy or salpingectomy

  • If high risk:

    • EMA/CO

      • Etoposide, MTX, Actinomycin D/ Cyclophosphamide, vincristine (Oncovin)

      • Can also use if poor response to initial therapy OR good response but rapid rise in hCG >1000

    • Consider hysterectomy or salpingectomy

      • For chemotherapy-resistant disease

    • EMA/EP

      • Etoposide, Methotrexate, Actinomycin D/ Etoposide, Cisplatin

      • If poor response to EMA/CO

    • If incomplete response to treatment with EMA/EP or EP/EMA:

      • Platinum-based regimens + Bleomycin, Ifosfamide or Paclitaxel