Endometrial cancer

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Endometrial cancer commonly presents early because a small intrauterine tumour bleeds. Endometrioid carcinoma is the dominant histology and often follows unopposed oestrogen and atypical hyperplasia. Serous, clear-cell, carcinosarcoma and some high-grade endometrioid tumours behave more aggressively and may disseminate with limited myometrial disease. Obesity and metabolic disease affect both cancer risk and operative or thrombotic safety.

Postmenopausal bleeding assessment begins with examination and transvaginal ultrasound. A thin regular endometrium makes carcinoma unlikely after a single episode, but recurrent bleeding can arise from a focal polyp or small cancer invisible to blind biopsy. Office Pipelle sampling is useful for diffuse disease; hysteroscopy sees and samples focal lesions. Inadequate or discordant tissue is not a negative result.

Surgical pathology and molecular class determine treatment. Minimally invasive hysterectomy and bilateral salpingo-oophorectomy is standard for most uterine-confined disease. Sentinel-node mapping can stage lymphatics with less morbidity in selected patients; extensive nodal dissection is not automatic. Vaginal brachytherapy controls cuff recurrence, external-beam radiation treats broader pelvic risk and chemotherapy addresses systemic relapse risk. Molecular information can de-escalate some POLE-mutated tumours or support immune treatment in mismatch-repair-deficient recurrence.

Conservative fertility treatment requires an unusually favourable cancer and a patient able to undergo repeated invasive surveillance. Oral or intrauterine progestogen can induce regression, but occult myometrial or ovarian disease and later relapse remain possible. Advanced disease management is individualised around symptoms, receptor and molecular findings, prior radiation and systemic treatment, with early palliative and metabolic support.

Key points

Postmenopausal bleeding is the key early presentation. Most cases are not cancer, but every episode needs timely assessment and a cervical smear is not an endometrial test.
First-line evaluation commonly combines speculum and bimanual examination with transvaginal ultrasound; an endometrial thickness of 4 mm or less lowers risk but does not end investigation of persistent bleeding.
The diagnostic reference standard is representative endometrial histology from outpatient biopsy or hysteroscopy-directed sampling; focal lesions and repeated bleeding favour hysteroscopy.
Do not reassure from an insufficient sample when ultrasound, symptoms or risk remains concerning; repeat with hysteroscopic visualisation under suitable analgesia or anaesthesia.
Pathology should report histological type and grade, myometrial and lymphovascular invasion after surgery and molecular markers including mismatch repair, p53 and POLE where required for risk classification.
MRI pelvis is preferred for local myometrial and cervical staging when it changes surgery; CT chest, abdomen and pelvis assesses nodes and distant spread in higher-risk disease.
First-line curative treatment for most operable disease is total hysterectomy with bilateral salpingo-oophorectomy, generally minimally invasive, with sentinel or nodal assessment selected by risk.
Low-risk stage I endometrioid cancer may need surgery alone; vaginal brachytherapy, external-beam radiotherapy and chemotherapy are added according to stage, histology, molecular group and recurrence risk.
Fertility-sparing progestogen treatment is exceptional: grade 1 endometrioid cancer must be confined to endometrium, pathology reviewed, MRI reassuring and serial hysteroscopic biopsies mandatory.
Offer definitive hysterectomy after childbearing or if conservative treatment fails, progresses or cannot be monitored reliably.
Recurrent and advanced treatment uses surgery or radiotherapy for selected sites and carboplatin–paclitaxel, immune or hormone-based systemic therapy according to molecular biology, pace and prior treatment.
Universal tumour mismatch-repair assessment identifies an immune-treatment biomarker and a Lynch-screening pathway; abnormal tumour testing is not automatically a germline diagnosis.
Address surgical menopause, fertility, obesity, diabetes, thrombosis, bone, sexual function and lymphoedema as part of cancer treatment.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Unopposed oestrogen exposure

Obesity, anovulatory polycystic ovarian syndrome, nulliparity, late menopause and oestrogen-only therapy stimulate endometrium without adequate progesterone opposition.

Metabolic and treatment factors

Older age, diabetes, hypertension and tamoxifen exposure are associated with increased risk, while combined oral contraception and parity are protective.

Inherited mismatch-repair deficiency

Lynch syndrome causes earlier endometrial cancer through germline mismatch-repair failure and creates colorectal, ovarian and other organ risks for relatives.

Sporadic molecular evolution

POLE proofreading defects, mismatch-repair loss, TP53 abnormalities and other endometrioid pathways produce distinct prognostic groups beyond traditional type I and type II labels.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Hyperplasia can progress to invasion
Prolonged oestrogenic proliferation produces atypical hyperplasia or endometrial intraepithelial neoplasia that may coexist with or evolve into endometrioid carcinoma.
2
Myometrial invasion opens lymphatics
Increasing depth and lymphovascular-space invasion raises pelvic and para-aortic nodal and distant spread, shaping surgery and adjuvant treatment.
3
Histologies behave differently
Low-grade endometrioid tumours are often hormone sensitive, while serous, clear-cell, carcinosarcoma and p53-abnormal disease disseminate earlier.
4
Molecular class refines prognosis
POLE-mutated tumours often have excellent outcomes despite high grade, mismatch-repair-deficient cancers are immunogenic, and p53-abnormal cancers carry higher recurrence risk.
5
Local growth causes bleeding
Friable neoplastic glands and surface ulceration shed unpredictably, making postmenopausal bleeding an early symptom before a palpable pelvic mass develops.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Postmenopausal bleeding

Any spontaneous vaginal blood after menopause is the cardinal presentation and requires endometrial and lower-genital-tract assessment.

Premenopausal abnormal bleeding

Persistent intermenstrual, irregular or heavy bleeding with obesity, anovulation, tamoxifen or Lynch risk can indicate hyperplasia or cancer.

Advanced pelvic disease

Pelvic pain, enlarged uterus, hydronephrosis, leg oedema, discharge or bowel and bladder symptoms suggest extrauterine extension.

Metastatic pattern

Ascites, supraclavicular node, cough, pleural fluid, bone pain or neurological symptoms may reveal high-risk disseminated disease.

Pyometra or haemorrhageRed flag

Fever, uterine tenderness, purulent discharge or haemodynamic bleeding requires urgent infection and haemostasis management.

Lynch pattern

Young endometrial cancer or family colorectal, ovarian, upper urinary or other Lynch tumours supports genetics completion after tumour screening.

Red flags requiring action

Any postmenopausal bleeding requires prompt endometrial assessment even when the volume is small, anticoagulation is present or cervical screening is normal.
Persistent or recurrent bleeding despite a thin endometrium or benign blind sample needs hysteroscopic reassessment for a focal lesion.
Heavy bleeding with syncope, tachycardia, chest pain or severe anaemia requires same-day stabilisation and source control.
Purulent discharge, fever and a distended fluid-filled uterus suggests pyometra with possible cervical obstruction and sepsis.
Hydronephrosis, leg swelling, pelvic pain, ascites or supraclavicular nodes suggests locally advanced or metastatic disease.
A young patient with endometrial cancer or a Lynch-associated family pattern requires tumour mismatch-repair testing and genetics completion.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line transvaginal ultrasoundFirst stepFirst line
Why
Measure endometrial thickness and morphology and identify focal lesions, fibroids, adnexal disease and pelvic fluid.
Interpretation and limitations
A 4 mm or thinner regular lining lowers risk after a first postmenopausal bleed, but persistent bleeding, irregularity or an unreadable cavity requires tissue assessment.
02
Preferred outpatient endometrial biopsyPreferred
Why
Obtain tissue efficiently for diffuse hyperplasia and carcinoma in a patient able to tolerate office sampling.
Interpretation and limitations
Adequacy matters; scant tissue may be expected with a thin lining but is discordant with thickening, focal abnormality or recurrent bleeding.
03
Reference hysteroscopy-directed sampling
Why
Visualise the cavity and biopsy or remove a focal polyp, abnormal area or lesion missed by blind sampling.
Interpretation and limitations
Use when ultrasound is focal, biopsy is insufficient or symptoms recur; negative histology must still explain the visual and imaging target.
04
MRI pelvis for local staging
Why
Estimate myometrial depth, cervical stromal involvement and extrauterine anatomy when preoperative risk or fertility treatment depends on it.
Interpretation and limitations
Final stage remains surgical-pathological when operated; MRI cannot reliably exclude microscopic invasion in a fertility pathway.
05
CT chest abdomen and pelvis
Why
Assess nodal, peritoneal, lung, liver and other distant disease in higher-risk, advanced or recurrent cancer.
Interpretation and limitations
Small nodal metastases can be normal sized and inflammatory nodes can enlarge; histology and risk guide surgical nodal assessment.
06
Molecular and inherited-risk testing
Why
Classify POLE, mismatch-repair, p53 and no-specific-molecular-profile groups and identify possible Lynch syndrome.
Interpretation and limitations
Use validated tumour testing with MLH1 methylation and germline reflex steps; integrate molecular class with stage and histology rather than replacing anatomy.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Endometrial or vaginal atrophy

Thin fragile postmenopausal epithelium is a common cause of bleeding, but malignancy must be excluded before symptoms are attributed to atrophy.

Polyp and submucosal fibroid

Focal benign lesions cause intermittent bleeding and may be missed by blind sampling; saline sonography or hysteroscopy visualises and targets them.

Cervical or vaginal disease

Cervical cancer, ectropion, polyps, infection and vulvovaginal lesions require speculum examination alongside endometrial investigation rather than a sequential delay.

Endometrial hyperplasia

Non-atypical and atypical hyperplasia produce abnormal bleeding and have different progression risk, surveillance and progestogen or hysterectomy pathways.

Non-gynaecological bleeding

Haematuria, rectal bleeding and trauma can be mistaken for vaginal blood; direct examination and urinalysis or rectal assessment establish the source.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Postmenopausal bleedingImage and obtain representative tissueFirst stepA patient reports any vaginal bleeding after menopause.

1Confirm the bleeding source with speculum and pelvic examination, assess haemodynamic state and arrange transvaginal ultrasound through the urgent pathway.
2Obtain outpatient biopsy for a thickened or suspicious lining and use hysteroscopy-directed sampling for a focal lesion, insufficient biopsy or recurrent bleeding despite a thin lining.
3Communicate histology and close the loop on inadequate or discordant results, returning confirmed cancer to the specialist gynaecological oncology MDT.

02Operable cancerStage surgically with risk-adapted nodesHistology confirms endometrial cancer and imaging shows potentially resectable disease.

1Review histology, grade, MRI, comorbidity and molecular tests and prepare thrombosis, anaesthetic, fertility and menopause plans.
2Perform minimally invasive total hysterectomy and bilateral salpingo-oophorectomy when feasible, adding sentinel mapping or nodal assessment according to risk and centre protocol.
3Use final stage, type, grade, lymphovascular invasion, nodes and molecular class to choose observation, vaginal brachytherapy, pelvic radiotherapy and chemotherapy.

03Fertility sparingUse progestogen only in a tightly selected pathwayA patient strongly wishes to preserve fertility and has apparent grade 1 endometrioid cancer confined to endometrium.

1Obtain expert pathology review, MRI pelvis, ovarian assessment and counselling about occult disease, response, relapse, infertility and the standard hysterectomy option.
2Use levonorgestrel intrauterine and or oral progestogen within a specialist protocol and repeat hysteroscopic biopsy at short defined intervals until complete response or failure.
3DefinitiveAttempt pregnancy promptly after complete response with fertility support and perform definitive hysterectomy after childbearing or for persistence, progression or recurrence.

04Advanced or recurrentMatch local and systemic treatment to biologyExtrauterine unresectable, metastatic or recurrent endometrial cancer is confirmed.

1Biopsy recurrence when feasible and reassess histology, ER or PR, mismatch repair, p53, HER2 in relevant serous disease, symptoms and prior radiation.
2Use surgery or focused radiotherapy for selected isolated relapse and choose platinum–taxane, immune, endocrine or targeted systemic treatment within the current molecular and funding indication.
3Review response and organ toxicity early and integrate bleeding, pain, bowel, urinary, lymphatic, metabolic and palliative care throughout treatment.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Provides adjuvant or first-line systemic treatment for high-risk, advanced and recurrent endometrial cancer and forms a backbone for selected immune combinations.

Carboplatin and paclitaxel

A common 21-day systemic regimen gives carboplatin AUC 5 to 6 and paclitaxel 175 mg/m² intravenously on day 1 for six cycles, adjusted to setting, renal function, marrow, neuropathy and response.

Monitor hypersensitivity, neutropenic sepsis, thrombocytopenia, neuropathy, alopecia, renal function and thrombosis and use the current protocol for growth-factor and dose modification.

Delivers high local progestogen to selected grade 1 endometrioid cancer confined to endometrium while fertility is temporarily preserved.

Levonorgestrel intrauterine system

Insert a 52 mg levonorgestrel-releasing intrauterine system within a specialist fertility-sparing protocol, sometimes combined with oral progestogen, and replace only according to product life and surveillance plan.

It is not standard treatment for invasive or high-grade disease; require expert pathology, MRI, serial hysteroscopic biopsy and a predefined hysterectomy trigger for non-response, progression or completed childbearing.

Adds PD-1 blockade for eligible primary advanced or recurrent endometrial cancer, with benefit particularly relevant to mismatch-repair-deficient biology.

Dostarlimab in eligible systemic treatment

Use the licensed intravenous schedule within the current NICE-funded indication, commonly 500 mg every 3 weeks for six doses with carboplatin–paclitaxel followed by 1,000 mg every 6 weeks as maintenance to the protocol stop point.

Monitor for immune lung, bowel, liver, endocrine, renal, cardiac, skin and neurological toxicity and assess infection, progression, autoimmunity and transplant context before immunosuppression or rechallenge.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Anaemia and haemorrhage

Chronic or episodic uterine blood loss causes iron deficiency, fatigue, cardiovascular strain and occasionally acute transfusion and haemostatic intervention.

Pelvic organ invasion

Cervical, parametrial, bladder, ureteric or bowel extension causes pain, hydronephrosis, fistula, infection and loss of pelvic function.

Nodal and distant recurrence

Pelvic or para-aortic nodes, peritoneum, lung, liver, bone and brain can be involved, particularly in high-grade and p53-abnormal disease.

Treatment morbidity

Surgery, nodal assessment, radiotherapy, chemotherapy and endocrine treatment can cause lymphoedema, menopause, neuropathy, bowel, bladder, sexual and marrow toxicity.

Synchronous and inherited cancer

Lynch syndrome and shared risk can produce synchronous ovarian or later colorectal and other cancers requiring coordinated surveillance and family care.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

After surgery, monitor bleeding, infection, VTE, bladder and bowel function, wound, menopausal symptoms and lower-limb lymphoedema.
During adjuvant treatment, review blood counts, renal and liver function, neuropathy, bowel and bladder radiation effects, fatigue and vaginal symptoms at each cycle or weekly visit.
Fertility-sparing care requires serial hysteroscopy and histology at protocol intervals; ultrasound or symptom improvement alone cannot establish complete response.
After curative treatment, use symptom-directed clinical follow-up with rapid access for bleeding, pelvic pain, leg swelling, cough, bone or neurological symptoms.
For immune treatment, check endocrine and organ symptoms and blood tests during and after therapy because delayed toxicity can arise after the final dose.
Complete Lynch reflex testing, genetics referral and colorectal and family surveillance rather than recording tumour MMR loss without action.
Address weight, diabetes, blood pressure, thrombosis, bone, sexuality and psychological recovery without implying that metabolic risk makes the cancer the patient’s fault.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

A smear does not test endometrium

Cervical screening samples the cervix and cannot reassure a patient with postmenopausal bleeding about the uterine cavity.

Thin endometrium has an exception

A reassuring thickness lowers risk after one episode, but recurrent bleeding can reflect a focal cancer and returns to hysteroscopy.

Insufficient is not always benign

Scant tissue fits an atrophic thin lining but is unsafe when imaging is thick, irregular or focal or symptoms persist.

Molecular class changes traditional risk

POLE and p53 findings can move prognosis away from what grade and histology alone would predict, but stage still matters.

Conservative treatment postpones standard surgery

Progestogen can create a fertility window but does not erase recurrence risk, making repeated biopsy and later hysterectomy essential.

MMR loss needs a reflex pathway

Tumour deficiency may be sporadic through MLH1 methylation or inherited through Lynch; only the complete reflex sequence distinguishes them.

11Common pitfallsFrequent interpretation and management errors.

01
Reassuring postmenopausal bleeding because the volume is small, anticoagulation is present or cervical screening is normal.
02
Accepting an insufficient blind sample despite a thick or irregular endometrium.
03
Failing to investigate recurrent bleeding after an initially thin endometrium.
04
Choosing adjuvant treatment from stage alone without histology, lymphovascular and molecular risk.
05
Offering fertility-sparing progestogen for high-grade, non-endometrioid or myoinvasive disease.
06
Monitoring conservative treatment with ultrasound only rather than serial histology.
07
Performing extensive nodal dissection routinely when sentinel staging can answer the selected question with less morbidity.
08
Recording mismatch-repair loss without MLH1 methylation, genetics and family follow-through.
09
Ignoring obesity, diabetes and thrombotic optimisation or discussing them in a stigmatising way.