Obstetrics and Gynaecology chapters
Endometrial hyperplasia and endometrial cancer
Why unopposed oestrogen leads to endometrial hyperplasia and cancer, how postmenopausal bleeding is investigated, and how endometrial cancer is staged and treated, with uterine sarcomas in brief.
- Endometrial cancer is driven mainly by unopposed oestrogen: obesity, nulliparity, late menopause, PCOS, tamoxifen, oestrogen-only HRT and Lynch syndrome raise the risk; atypical hyperplasia is the precursor.
- It presents early with postmenopausal bleeding; a transvaginal scan showing endometrium under 4 mm makes cancer very unlikely, otherwise biopsy and/or hysteroscopy.
- Staging is surgical (FIGO); standard treatment is total hysterectomy with bilateral salpingo-oophorectomy, with radiotherapy or chemotherapy for high-risk disease; most present at stage I and do well.
On this page
Overview
Endometrial cancer arises from the lining of the uterine body. It is the commonest gynaecological cancer in high-income countries, and it is rising with obesity and an ageing population. The mean age at diagnosis is about 62 years, but about 15% occur before the menopause.
The good news: it usually bleeds early, so most women present with stage I disease that is cured by surgery.
Classification
| Feature | Type 1 | Type 2 |
|---|---|---|
| Histology | Endometrioid adenocarcinoma, low grade | Serous, clear cell, carcinosarcoma; high grade |
| Driver | Oestrogen-dependent | Not oestrogen-related |
| Background | Endometrial hyperplasia | Atrophic endometrium |
| Typical patient | Younger postmenopausal, obese | Older, thin |
| Behaviour | Slow; good prognosis | Aggressive; p53 abnormal; poor prognosis |
| Share | Most cases | Minority |
A newer molecular classification sorts tumours into four groups: POLE-mutant (excellent outcome), mismatch repair (MMR)-deficient (intermediate; screen for Lynch syndrome), no specific profile (mostly hormone receptor-positive endometrioid; good) and p53-abnormal (worst; may benefit most from chemotherapy).
Risk factors
Most risk factors mean more oestrogen without progesterone to oppose it.
| Raise risk | Lower risk |
|---|---|
| Obesity (fat converts androgens to oestrogen; anovulation) | Combined oral contraceptive pill |
| Type 2 diabetes (insulin and IGF stimulate the endometrium) | Progestogen contraception (injectable, implant) |
| Nulliparity, infertility | Intrauterine devices (copper IUD and LNG-IUS) |
| Late menopause (over 52) | Pregnancy and parity |
| PCOS (anovulation, unopposed oestrogen) | Healthy weight, exercise |
| Oestrogen-only HRT in a woman with a uterus | Hysterectomy |
| Tamoxifen (anti-oestrogen in breast, stimulant in endometrium) | |
| Oestrogen-secreting ovarian tumours: granulosa cell tumour, thecoma | |
| Lynch syndrome; family history of bowel or endometrial cancer |
"Fat, Fertile-less, Late, and Tamoxifen-treated": obesity, nulliparity, late menopause and tamoxifen.
The combined pill protects against endometrial cancer, but oestrogen-only HRT increases it. Any woman with a uterus on HRT needs a progestogen as well.
Lynch syndrome (hereditary non-polyposis colorectal cancer)
- Autosomal dominant defect in a mismatch repair gene: MLH1, MSH2, MSH6, PMS2.
- Lifetime endometrial cancer risk 40-60%; about 3% of endometrial cancers are due to Lynch.
- Also colorectal, ovarian and urothelial cancers. Endometrial cancer in Lynch syndrome tends to occur at a younger age.
- Prevention: hysterectomy once the family is complete; aspirin reduces cancer risk; colonoscopic surveillance.
Endometrial hyperplasia
- Overgrowth of endometrial glands relative to stroma, caused by unopposed oestrogen (obesity, PCOS, anovulation, oestrogen-only HRT, oestrogen-secreting tumours).
- Usually presents with abnormal bleeding: heavy or irregular periods, or postmenopausal bleeding.
- Classified with or without atypia. Atypia is the key predictor of cancer.
| Type | Cancer risk | Management |
|---|---|---|
| Hyperplasia without atypia | Low | Remove the cause (weight loss, stop unopposed oestrogen); progestogen (for example the LNG-IUS); repeat biopsy |
| Atypical hyperplasia | Premalignant: 25-50% progress; often coexists with cancer | Total hysterectomy with BSO; high-dose progestogen (oral or LNG-IUS) only if fertility is wanted or she is unfit, with close biopsy follow-up (relapse is common) |
Atypical hyperplasia is treated like early cancer (hysterectomy) because a coexisting cancer is often already present.
Clinical features
- Postmenopausal bleeding (PMB): the classic symptom. About 5-10% of women with PMB have a gynaecological cancer, so PMB is always a red flag.
- Before the menopause: heavy, irregular or intermenstrual bleeding, particularly in an obese woman or one with PCOS.
- Blood-stained watery discharge; pyometra in elderly women (stenosed cervix).
- Late disease: pelvic pain, bladder or bowel symptoms, breathlessness.
- Occasionally found as abnormal glandular cells on cervical cytology.
- Examination is often normal; there may be blood from the os or a bulky uterus.
Other causes of PMB: vaginal atrophy (a common benign cause), endometrial polyp, HRT bleeding, cervical cancer, vulval and vaginal lesions, oestrogen-secreting ovarian tumour.
Investigation of postmenopausal bleeding
- Examination: inspect vulva, vagina and cervix with a speculum (excludes lower tract causes); bimanual for uterine size and masses.
- Transvaginal ultrasound (TVUSS): measure endometrial thickness.
- Under 4 mm: cancer very unlikely; no further investigation needed (unless bleeding recurs).
- 4 mm or more: go on to endometrial biopsy and/or hysteroscopy.
- Endometrial biopsy: outpatient Pipelle sampler.
- Hysteroscopy: outpatient where possible; allows directed biopsy of focal lesions; general anaesthesia (with dilatation and curettage) if outpatient sampling fails or the cervix is stenosed.
Endometrial biopsy and/or hysteroscopy is the gold standard for diagnosis; MRI defines the extent (depth of myometrial invasion, cervical involvement, nodes). Cervical cytology is not a test for endometrial cancer.
A thick endometrium on scan is not a diagnosis. Tissue is needed. Equally, a normal pelvic examination does not exclude endometrial cancer.
Staging work-up
- MRI pelvis: myometrial invasion and cervical stroma.
- CT chest, abdomen and pelvis for high-grade tumours.
- Tumour typing with p53 and MMR immunohistochemistry; MMR-deficient tumours trigger genetic counselling for Lynch syndrome.
FIGO staging (surgical-pathological)
| Stage | Extent | 5-year survival |
|---|---|---|
| IA | Confined to uterus, less than 50% myometrial invasion | 92% (stage I) |
| IB | 50% or more of the myometrium invaded | |
| II | Cervical stroma invaded | 74% |
| IIIA | Uterine serosa | 48% (stage III) |
| IIIB | Vagina and/or parametrium | |
| IIIC | Pelvic and/or para-aortic lymph nodes | |
| IV | Bladder and/or bowel mucosa, or distant metastases | 15% |
- Overall 5-year survival about 76%; most present in stage I.
- Poor prognostic factors: older age, grade 3, non-endometrioid type, p53-abnormal, deep myometrial invasion, lymphovascular space invasion, nodal and distant spread.
"Endometrial: I = Inside the uterus, II = Into the cervix, III = Into the pelvis or nodes, IV = Invades bladder, bowel or beyond".
Endometrial (and ovarian) cancer is staged surgically; cervical cancer is staged clinically.
Management
Surgery (mainstay)
- Total hysterectomy with bilateral salpingo-oophorectomy (TH + BSO), ideally laparoscopic (same cure, quicker recovery, fewer complications than open surgery).
- Lymph node assessment (pelvic and para-aortic dissection or sentinel node biopsy) for high-risk tumours: it gives staging information but node dissection itself does not improve survival.
- Low-grade stage IA disease can be treated at a local hospital; high-grade or stage IB onwards in a cancer centre.
- In selected premenopausal women with low-grade early disease, the ovaries may be conserved without harming survival.
- Many patients are obese with diabetes, hypertension and heart disease, so fitness for anaesthesia must be assessed.
Adjuvant treatment
- Vaginal vault brachytherapy for intermediate-risk disease (reduces local recurrence).
- External beam pelvic radiotherapy + brachytherapy for locally advanced (stage III) disease.
- Chemotherapy for high-risk tumours, especially p53-abnormal.
- Radiotherapy lowers the chance of the cancer coming back in the pelvis, yet women do not live longer because of it.
Hormonal treatment
- High-dose progestogen (oral or LNG-IUS) for women unfit for surgery or wanting to keep fertility with atypical hyperplasia or low-grade stage IA cancer. Responses occur, but relapse is common.
Advanced and recurrent disease
- Combinations of surgery, radiotherapy, chemotherapy and hormones; immune checkpoint inhibitors for MMR-deficient tumours. Outcomes are poor.
Uterine sarcomas (brief)
- About 5% of uterine cancers.
- Leiomyosarcoma: from myometrium; rapidly enlarging, painful, soft uterus, often after the menopause; rarely from a fibroid (most arise on their own); MRI may show necrosis; blood-borne spread to lungs and brain; surgery is the main treatment.
- Endometrial stromal sarcoma: perimenopausal, irregular bleeding, soft enlarged uterus; mostly low grade.
- Carcinosarcoma (malignant mixed Müllerian tumour): now grouped with high-grade (type 2) endometrial cancers; may follow pelvic radiotherapy.
- Embryonal rhabdomyosarcoma (sarcoma botryoides): in young girls, a grape-like mass from the cervix or vagina.
Expect: unopposed oestrogen as the common mechanism (obesity, nulliparity, late menopause, PCOS, tamoxifen, oestrogen-only HRT, granulosa cell tumour and thecoma); the combined pill and IUDs as protective; Lynch syndrome; atypia as the key feature of hyperplasia and hysterectomy for atypical hyperplasia; postmenopausal bleeding as the presenting symptom, TVUSS with a 4 mm cut-off, Pipelle biopsy and hysteroscopy; endometrioid as the commonest type and serous as the aggressive type; surgical FIGO staging (IA under half, IB half or more of the myometrium, II cervix, IIIC nodes); TH + BSO as the standard operation; adjuvant radiotherapy; leiomyosarcoma arising de novo.
Quick revision
- Unopposed oestrogen drives type 1 (endometrioid) cancer and hyperplasia.
- Risk: obesity, diabetes, nulliparity, late menopause, PCOS, tamoxifen, oestrogen-only HRT, granulosa/theca tumours, Lynch.
- Protection: combined pill, progestogens, IUDs, pregnancy.
- Atypical hyperplasia: 25-50% progress; hysterectomy.
- PMB: TVUSS; under 4 mm reassuring; otherwise biopsy and/or hysteroscopy.
- Staging is surgical; IA under 50% myometrium, IB 50% or more, II cervical stroma, IIIC nodes.
- Treatment: TH + BSO (laparoscopic); radiotherapy or chemotherapy for high risk.
- 5-year survival: stage I 92%, overall 76%.
Written by The House Job from standard references (Gynaecology by Ten Teachers).
FAQ
Why does obesity cause endometrial cancer?
Fat tissue converts androgens into oestrogen and obesity causes anovulation, so the endometrium is stimulated by oestrogen without the protective effect of progesterone.
If the endometrium is 3 mm on scan in a woman with one episode of postmenopausal bleeding, is a biopsy needed?
Usually not; an endometrium under 4 mm makes cancer very unlikely, but she should be investigated further if the bleeding comes back.
Can a young woman with endometrial cancer keep her fertility?
Only with atypical hyperplasia or low-grade stage IA disease, using high-dose progestogen under close biopsy follow-up, and she should know that relapse is common.
Why is a woman with endometrial cancer at 40 tested for Lynch syndrome?
Young onset and mismatch repair-deficient tumours suggest Lynch syndrome, and diagnosing it allows bowel surveillance and cancer prevention for her and her relatives.