Endometrial Cancer

Overview

Endometrial carcinoma is an epithelial malignancy of the uterine corpus mucosa, usually an adenocarcinoma. Endometrial carcinoma is the most common female genital tract malignancy. Postmenopausal bleeding always needs to be investigated because it can indicate malignant disorders and premalignant conditions, such as endometrial hyperplasia. The most common etiology of postmenopausal bleeding is atrophic endometritis or vaginitis.

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Epidemiology

• Most common lower gyaenocological cancer
• Most common in postmenopausal women

Atiology & Risk Factors

Aetiology

• Endometrial hyperplasia
• Unopposed endogenous/exogenous oestrogen
• Familial cancer syndromes (family history, Lynch syndrome, Cowden’s syndrome)

Risk Factors

Endometrial malignancy typically developed from unopposed oestrogen. Progesterone stabilises the endometrium.

Increased risk of endometrial cancer	Protective Factors
Early Menarche	Parity (high progesterone in pregnancy)
Post-menopausal women	Combined Oral Contraceptive Pill
Obestiy, Hypertension, Diabetes
Endometrial hyperplasia
Tamoxifen use
Unopposed endogenous/exogenous oestrogen
Family history of endometrial cancer
Family history of ovarian and breast cancer
Lynch syndrome
Radiotherapy

Pathophysiology

Epithelial tumours (endometrial carcinoma) is the most common type of endometrial carcinoma, found in up to 90%.

Clinical Manifestation

Abnormal uterine bleeding in postmenopausal women is the cardinal symptom of endometrial cancer. Occasionally, women with no abnormal uterine bleeding present with abnormal findings on cervical cytology. The clinical presentations of the following age group need prompt evaluation to rule out endometrial cancer

• Postmenopausal women – Any bleeding
• Premenopausal (>45yo) – Abnormal uterine bleeding including intermenstrual bleeding , frequent, heavy or prolonged bleeds.
• Younger than 45yo – Persistent abnormal uterine bleeding with risk factors or failed management of the bleeding

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Clinical Examination

• Uterine mass
• Fixed uterus or adnexal mass indicating extra-uterine disease

Diagnosis & Investigations

• Pelvic Ultrasound (sonography) is first line
• Transvaginal ultrasound
• Endometrial sampling (biopsy)
• Hysteroscopy and D&C if biopsy is not possible
• Pap smear – Primarily used to screen for cervical dysplasia. It is not a screening test for endometrial cancer

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Endometrial carcinoma is a histologic diagnosis made based upon the results of evaluation of an endometrial biopsy, curettage sample, or hysterectomy specimen.

Staging

International Federation of Gynecology and Obstetrics (FIGO) staging of uterine cancer (2009)
Stage	Description
I	Tumour invades cervical stroma, but does not extend beyond the uterus
II	Tumour invades cervical stroma, but does not extend beyond the uterus
III	Local and regional spread of the tumour
IV	Tumour invades the bladder and/or bowel mucosa and/or distant metastases

Treatment

Management Endometrial cancer is treated by surgery, radiotherapy, chemotherapy, or, commonly, a combination of these therapies, with the goal of maximising the chance of cure, with minimal morbidity.

Surgery (First-line)

• Total hysterectomy + bilateral salpingo-oophorectomy
• Sentinel lymph node biopsy for staging when indicated

Adjuvant Treatment (Risk-dependent)

• Vaginal brachytherapy.
• Carboplatin + paclitaxel ± radiotherapy

Advanced Disease (Stage III–IV)

• Cytoreductive surgery if feasible.
• Chemotherapy: Carboplatin + paclitaxel.
• Immunotherapy: Pembrolizumab or dostarlimab combined with chemotherapy in eligible patients.

Recurrent or Metastatic Disease

• dMMR/MSI-H: PD-1 inhibitors (pembrolizumab or dostarlimab).
• pMMR/MSS: Pembrolizumab + lenvatinib after platinum chemotherapy in eligible patients.
• Hormonal therapy: Progestins for selected low-grade, ER/PR-positive cancers.
• Palliative radiotherapy for symptom control

Term	Meaning	Clinical significance
dMMR	Deficient mismatch repair	Defective DNA repair; often responds well to immunotherapy
pMMR	Proficient mismatch repair	Functional DNA repair; generally less responsive to immunotherapy alone
MSI-H	Microsatellite instability–high	High levels of DNA replication errors; often associated with dMMR
MSS	Microsatellite stable	Minimal microsatellite instability; usually associated with pMMR

Molecular Classification

• POLE-mutated: Excellent prognosis; may allow treatment de-escalation.
• MMRd/MSI-H: Responsive to immunotherapy.
• p53-abnormal: High-risk; often requires intensive treatment.
• NSMP: Treatment guided by stage, grade and other risk factors.

Complications & Prognosis

Complications

• Bladder instability following surgery
• Radiotherapy induced vaginal stenosis/atrophy
• Radiotherapy induced bowel or bladder distulae
• Sexual dysfunction following treatment
• Metastatic disease
• Lymphoedema
• Chemotherapy associated toxicity

Prognosis 

The 5-year survival rate for all types and grades of endometrial adenocarcinoma, following treatment, is:

• 75% to 95% for stage I
• 70% for stage II
• 50% to 60% for stage III
• 5% to 15% for stage IV

References

1. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15(1):10-17. doi:10.1016/0090-8258(83)90111-7.
2. Clarke MA, Long BJ, Del Mar Morillo A, Arbyn M, Bakkum-Gamez JN, Wentzensen N. Association of endometrial cancer risk with postmenopausal bleeding in women: a systematic review and meta-analysis. JAMA Intern Med. 2018;178(9):1210-1222. doi:10.1001/jamainternmed.2018.2820.
3. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 734: The role of transvaginal ultrasonography in evaluating the endometrium of women with postmenopausal bleeding. Obstet Gynecol. 2018;131(5):e124-e129.
4. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. doi:10.1038/nature12113.
5. Creasman W. Revised FIGO staging for carcinoma of the endometrium. Int J Gynaecol Obstet. 2009;105(2):109. doi:10.1016/j.ijgo.2009.02.010.
6. Berek JS, Matias-Guiu X, Creutzberg C, Fotopoulou C, Gaffney D, Kehoe S, et al. FIGO staging of endometrial cancer: 2023. Int J Gynaecol Obstet. 2023;162(2):383-394. doi:10.1002/ijgo.14923.
7. Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Marnitz S, et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int J Gynecol Cancer. 2021;31(1):12-39. doi:10.1136/ijgc-2020-002230.