How should endometrial carcinoma be diagnosed, staged, and treated, including surgical, adjuvant, fertility‑preserving, and second‑line options?

Endometrial Carcinoma: Diagnosis, Staging, and Treatment

Diagnosis

Obtain endometrial tissue through office-based Pipelle biopsy or dilation and curettage (D&C) to establish histological diagnosis 1. Both methods are acceptable initial approaches, though D&C may provide more representative sampling when Pipelle yields inadequate tissue 1, 2.

Preoperative Workup

• Clinical and gynecological examination to assess uterine size and cervical involvement 1
• Transvaginal ultrasound to evaluate endometrial thickness and myometrial invasion 1
• Pelvic MRI with contrast enhancement is the most accurate imaging modality for assessing myometrial invasion depth and cervical stromal involvement 1, 3
• Complete blood count, liver and renal function profiles 1
• Additional imaging (chest/abdominal CT or FDG-PET-CT) should be considered in high-risk patients (Grade 3, non-endometrioid histology, deep myometrial invasion) to detect extrapelvic disease 1

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Staging

Endometrial carcinoma uses the FIGO 2009 surgical staging system 3:

Stage	Definition
IA	No invasion or invasion <50% of myometrium [3]
IB	Invasion ≥50% of myometrium [3]
II	Cervical stromal invasion [3]
IIIA	Serosal/adnexal involvement or positive peritoneal cytology [3]
IIIB	Vaginal involvement [3]
IIIC	Pelvic or para-aortic lymph node metastasis [3]
IVA	Bladder/bowel mucosal invasion [3]
IVB	Distant metastases [3]

Histological Grading (Endometrioid Type)

• Grade 1: ≤5% solid (non-squamous, non-morular) growth 3
• Grade 2: 5–50% solid growth 3
• Grade 3: >50% solid growth 3
• Notable nuclear atypia upgrades the tumor by one grade regardless of architecture 3

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Surgical Treatment

Standard surgery consists of total hysterectomy with bilateral salpingo-oophorectomy 1, 4. This is the cornerstone of treatment for all stages.

Surgical Approach

• Minimally invasive surgery (laparoscopic or robotic) is preferred over laparotomy, providing equivalent oncologic outcomes with shorter hospital stays and fewer complications 1, 4
• Robotic approach is particularly beneficial in obese women 1
• Peritoneal washings and thorough abdominal exploration should be performed at the start of surgery 1

Lymph Node Assessment

Lymph node evaluation strategy depends on risk factors 1:

• Omit lymphadenectomy in endometrioid FIGO IA Grade 1-2 disease (lymph node metastasis risk <5%) 1
• Perform lymph node evaluation in non-endometrioid histology, FIGO IB, or Grade 3 disease 1
• Sentinel lymph node biopsy with indocyanine green is emerging as the preferred alternative to systematic lymphadenectomy, with high sensitivity for detecting nodal metastases 1
• Systematic pelvic lymphadenectomy does not improve survival in early-stage disease based on randomized trials 1

Special Considerations

• Omentectomy should be performed for carcinosarcoma and serous-type endometrial cancer 1, 5
• Ovarian preservation may be considered in premenopausal patients with FIGO stage IA Grade 1 endometrioid cancer, but is contraindicated in Lynch syndrome or germline BRCA mutation carriers 1

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Risk Stratification and Adjuvant Therapy

Approximately 75% of patients present with Stage I disease, which is subdivided into three risk categories 1, 3:

Low-Risk Disease

Stage IA Grade 1-2 endometrioid histology 1, 3

• No adjuvant therapy required 1, 3
• Five-year disease-free survival 93–96% with surgery alone 4

Intermediate-Risk Disease

Stage IB Grade 1-2 or Stage IA Grade 3 endometrioid histology 1, 3

• Adjuvant pelvic radiotherapy significantly reduces pelvic/vaginal recurrence but does not improve overall survival 1, 3
• Recommend pelvic and/or vaginal brachytherapy in patients ≥60 years with deeply invasive Grade 1-2 or Grade 3 tumors where locoregional relapse risk exceeds 15% 1, 3

High-Risk Disease

Stage IB Grade 3 endometrioid, or any stage with serous, clear-cell, or carcinosarcoma histology 1, 3

• Combined pelvic radiotherapy plus platinum-based chemotherapy (carboplatin/paclitaxel) improves overall survival and progression-free survival compared to radiotherapy alone 1, 3, 5
• Cisplatin and doxorubicin combination significantly improves progression-free survival and overall survival in optimally debulked Stage III-IV disease 1, 5

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Advanced and Recurrent Disease

Stage III-IV Disease

• Maximal surgical cytoreduction to no residual macroscopic disease should be attempted in patients with good performance status 5, 6
• Carboplatin/paclitaxel doublet is first-line chemotherapy 5, 6
• Combined chemoradiation reduces risk of relapse or death by 36% 5

Recurrent Disease

• Carboplatin/paclitaxel for platinum-sensitive recurrence 6, 7
• Pembrolizumab plus lenvatinib is FDA-approved for endometrial cancer (all histotypes) after progression on chemotherapy 6
• Single-agent pembrolizumab for MSI-high tumors 6
• Progestational agents (medroxyprogesterone acetate 200 mg daily) are active in steroid-receptor positive Grade 1-2 tumors 1

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Fertility-Preserving Options

For highly selected young women with Grade 1 endometrioid adenocarcinoma confined to the endometrium who desire fertility 4:

• Confirm diagnosis with D&C (superior to Pipelle) by specialist gynaecopathologist 4
• Pelvic MRI to exclude myometrial invasion and adnexal involvement 4
• Medroxyprogesterone acetate 400-600 mg/day or megestrol acetate 160-320 mg/day 4
• Durable complete response occurs in ~48% of conservatively treated cases 4
• Close surveillance with repeat endometrial sampling every 3-6 months is mandatory 4

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Special Histological Subtypes

Carcinosarcoma

Carcinosarcoma is a high-grade endometrial carcinoma with sarcomatous trans-differentiation 6:

• Complete surgical staging including omentectomy and retroperitoneal lymph node dissection 5
• Combined chemotherapy and radiotherapy for all stages, even early disease 5, 6
• Carboplatin/paclitaxel is first-line chemotherapy 5, 6

Serous and Clear-Cell Carcinoma

Automatically classified as high-risk irrespective of stage or grade 3:

• Omentectomy at initial surgery 1
• Platinum-based chemotherapy plus radiotherapy 3

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Follow-Up

• History, physical, and gynecological examination every 3-4 months for the first 3 years 4
• Extend to every 6 months during years 4-5 4
• Annual examinations thereafter 4
• Focus on early detection of vaginal or pelvic relapses, which may be amenable to curative treatment 4

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Key Pitfalls to Avoid

• Up to 25% of preoperative endometrial sampling diagnoses change after final pathology—do not rely solely on preoperative grade for treatment planning 3
• Frozen-section assessment is unreliable for intraoperative risk stratification—base lymphadenectomy decisions on preoperative risk assessment 3
• Systematic lymphadenectomy does not improve survival in low-risk disease—avoid overtreatment 1
• Pipelle biopsy has limited capacity to identify endometrial polyps—consider D&C if clinical suspicion is high despite negative Pipelle 2