Assess and manage endometrial hyperplasia and endometrial cancer

In one line

Endometrial cancer is the commonest gynaecological malignancy of the developed world and now the second commonest in South Africa, driven by obesity-related unopposed oestrogen; the consultant-level shift is that it is no longer one disease staged by anatomy alone but four molecular entities (POLEmut, MMRd, NSMP, p53abn) that the FIGO 2023 system folds into stage and that increasingly dictate adjuvant and systemic therapy.

This chapter assumes the histopathology groundwork — Type I vs Type II, EIN/atypical hyperplasia, grading — covered at endometrial carcinoma basics. It develops the consultant-level layer: molecular triage, fertility preservation and the contested new staging, and the defence of a risk-stratified plan.

Why this matters in South Africa

Endometrial cancer is the second commonest gynaecological cancer in South Africa and a rising one, because the two great drivers — obesity and falling parity — are both increasing across the epidemiological transition. The disease therefore behaves differently here in three ways. First, the mortality is ethnically skewed: black South African women die of endometrial cancer disproportionately, presenting later and with a higher share of aggressive non-endometrioid (p53abn) histology — the inverse of the indolent, oestrogen-driven Type I picture that dominates high-income series. Second, access to molecular testing is the binding constraint: MMR and p53 immunohistochemistry are deliverable through NHLS, but POLE sequencing is concentrated in a handful of academic centres, so the elegant four-way classification that European guidelines assume is, for most SA units, a two- or three-marker reality. Third, the systemic agents that have rewritten advanced disease — checkpoint inhibitors — are largely unavailable in the public sector, which inverts the value proposition: the highest-yield, deliverable intervention is not the immunotherapy itself but the cheap MMR-IHC that identifies who would benefit and who has Lynch syndrome. The defensible approach is to adopt the molecular biology fully while triaging testing and treatment to what the patient in front of you can actually access.

Pathophysiology — the four molecular entities and why they change management

This assumes the Type I / Type II and EIN groundwork in endometrial carcinoma basics; the advanced layer is the molecular taxonomy that has displaced the dualistic model. The Cancer Genome Atlas (Kandoth/TCGA, Nature 2013, n=373) resolved endometrial cancer into four genomic groups with distinct biology, prognosis and distinct therapeutic vulnerabilities. The ProMisE classifier (Talhouk) then made this clinically deliverable by replacing whole-exome sequencing with two cheap immunohistochemistry stains plus one targeted sequence, applicable even to a diagnostic Pipelle.

• POLEmut (ultramutated, ~7% of cases). A pathogenic mutation in the exonuclease (proofreading) domain of DNA polymerase ε abolishes proofreading, producing an astronomical somatic mutation burden. The mechanistic consequence is paradoxical: despite frequently presenting as high-grade tumours with LVSI, the colossal neoantigen load provokes a brisk anti-tumour immune response, and outcomes are excellent — near-universal recurrence-free survival in early stage. The clinical corollary is de-escalation: a uterus-confined POLEmut tumour is a candidate to omit adjuvant therapy entirely. Diagnosis requires sequencing the eleven established pathogenic hotspots; surrogate IHC does not exist, which is exactly why POLE is the SA access bottleneck.
• MMRd (mismatch-repair-deficient / MSI-high, ~28%). Loss of one of the mismatch-repair proteins (MLH1, PMS2, MSH2, MSH6) — usually sporadic via MLH1 promoter hypermethylation, but in a minority germline (Lynch syndrome) — yields a hypermutated, microsatellite-unstable genome. The high mutational and neoantigen burden makes these tumours the prime responders to PD-1 blockade. Two mechanism→action links follow: every MMRd tumour mandates a Lynch work-up (MLH1-methylation/BRAF reflex testing to separate sporadic from germline), and MMRd status is the single best predictor of immunotherapy benefit in advanced disease. Prognosis is intermediate.
• NSMP (no specific molecular profile / copy-number-low, ~39%). The largest group — POLE-wildtype, MMR-proficient, p53-wildtype. This is the classic oestrogen-driven, low-grade endometrioid, PTEN/PIK3CA/CTNNB1-mutated, ER/PR-positive Type I tumour. Prognosis is generally favourable but heterogeneous: CTNNB1 (β-catenin) mutation and L1CAM expression identify an NSMP subset that recurs like higher-risk disease, and oestrogen-receptor positivity is what makes this the group where endocrine therapy and fertility-sparing progestins work. Management here is driven by the classical histopathological risk factors (grade, depth of invasion, LVSI) because no dominant molecular driver overrides them.
• p53abn (copy-number-high / serous-like, ~26%). Aberrant p53 IHC reflects TP53 mutation, extensive copy-number instability and an aggressive phenotype that captures uterine serous carcinoma, clear-cell carcinoma, carcinosarcoma and ~25% of high-grade endometrioid tumours. These behave as high-grade disease regardless of apparent stage — they metastasise early, recur distantly, and are the histology behind most endometrial-cancer deaths. The mechanistic link to action is decisive: p53abn is the molecular class that derives the survival benefit from adjuvant chemotherapy (PORTEC-3), so its identification upstages, fully stages and chemotherapy-directs the patient.

An ordering rule governs conflicting markers (which occurs in ~3–5% — "multiple-classifier" tumours): POLEmut beats MMRd beats p53abn. A tumour that is both POLEmut and p53-aberrant is classified and treated as POLEmut (excellent prognosis, candidate for de-escalation); the p53 abnormality is a passenger, not the driver. Getting this hierarchy wrong over-treats a curable patient.

Assessment

• The cardinal symptom is postmenopausal bleeding (PMB): ~10% of PMB is endometrial cancer, so every episode is cancer until excluded. In a premenopausal woman, suspect it with persistent abnormal uterine bleeding plus risk factors (obesity, anovulation/PMOS, nulliparity, tamoxifen, Lynch syndrome).
• First-line investigation is transvaginal ultrasound. An endometrial thickness ≤4 mm in a woman with PMB has a very high negative predictive value and may be observed; >4 mm, or any persistent/recurrent bleeding regardless of thickness, mandates tissue. The 4 mm cut-off is the standard SA practice threshold for PMB. It does not apply to tamoxifen users (subendometrial cystic change inflates ET) or to most premenopausal bleeding — sample those directly.
• Tissue diagnosis: outpatient Pipelle biopsy first; a negative or insufficient Pipelle with ongoing bleeding does not exclude cancer — proceed to hysteroscopy and directed biopsy/dilatation & curettage. A focal lesion (polyp, thickened area) needs hysteroscopic, not blind, sampling.
• On the hyperplasia spectrum, atypia is the dividing line. Hyperplasia without atypia carries a low (<5% over ~20 years) cancer risk; atypical hyperplasia / endometrial intraepithelial neoplasia (EIN) carries a ~28% long-term progression risk and, critically, a ~40% rate of concurrent occult carcinoma already present in the uterus — a finding that mandates hysterectomy rather than surveillance.
• Staging work-up once cancer is confirmed: examination, FBC, U&E/creatinine, and imaging tailored to risk — MRI pelvis for myometrial/cervical-stromal invasion, CT chest/abdomen/pelvis for nodal and distant disease in high-grade or non-endometrioid histology. Request molecular classification (POLE sequencing, MMR/p53 immunohistochemistry) on the diagnostic specimen where available; in SA, MMR and p53 IHC are widely accessible and cheap, POLE sequencing is the access bottleneck. Offer Lynch screening (universal MMR-IHC) — it changes the patient's and family's lifetime cancer surveillance.

The advanced assessment — atypical presentations and the severity calls

The diagnosis of "cancer or not" is rarely the difficulty; stratifying risk and reading the atypical presentation is. Several judgement calls recur:

• The thin endometrium is not always reassuring in the high-risk histotype. Serous carcinoma can arise in an atrophic endometrium and present with an endometrial thickness below the 4 mm threshold; the 4 mm rule was validated against the common endometrioid phenotype. Recurrent PMB with a thin stripe, in an older woman, still earns tissue — do not let a reassuring ultrasound close the loop in a woman whose only reassurance is a measurement designed to catch a different disease.
• The obese woman with a non-diagnostic office work-up. Body habitus degrades transvaginal image quality and makes office sampling fail more often; a "technically limited scan, insufficient Pipelle" in a high-BMI woman with persistent bleeding is a hysteroscopy referral, not a discharge.
• Premenopausal endometrial cancer is a Lynch flag. Cancer under ~50, a synchronous or metachronous colorectal cancer, or a suggestive family history (Amsterdam/Bethesda pattern) raises germline mismatch-repair deficiency. The gene-specific lifetime endometrial-cancer risk is substantial — broadly in the order of MLH1 ~34–54%, MSH2 ~21–57%, MSH6 ~16–49%, with PMS2 lower — and in many Lynch women the endometrial cancer is the sentinel (index) malignancy, preceding the colorectal cancer. Identifying it is therefore not academic: it brings forward colonoscopic and (gene-dependent) gynaecological surveillance for the patient and cascades testing to the family.
• Synchronous endometrial–ovarian cancers in a young woman are characteristically two independent low-grade primaries with an excellent prognosis, not stage-IV metastatic disease — a distinction that changes the entire conversation and avoids over-treatment.
• Severity stratification is now an integrated construct. A grade-1, IA endometrioid tumour and a serous IA tumour share an anatomical stage but occupy opposite ends of the risk spectrum; the modern stratification (ESGO/ESTRO/ESP and FIGO 2023) integrates grade + depth of invasion + LVSI (especially substantial/multifocal LVSI) + histotype + molecular class into the risk group that drives adjuvant intensity. The consultant reads all five, not the stage number alone.

Investigations at depth

• Endometrial thickness is a screening filter, not a diagnostic test. Its high NPV in PMB is the basis for the 4 mm rule, but it has poor specificity (most thickened endometria are benign) and fails in three named situations: tamoxifen (subepithelial cystic change inflates ET), the non-endometrioid histotype (can be thin), and premenopausal women (cyclical thickness makes the cut-off meaningless). Know where your test misleads.
• MRI is the local-staging instrument: it quantifies depth of myometrial invasion (the ≥50% threshold) and cervical-stromal involvement, which drive the decision on radicality and adjuvant radiotherapy. CT chest/abdomen/pelvis is reserved for high-grade or non-endometrioid histology to screen for nodal and distant disease; routine CT in low-grade disease over-investigates.
• The molecular work-up has a defined, sequential logic: (1) p53 IHC and the four MMR stains on the diagnostic biopsy (cheap, NHLS-deliverable); (2) POLE hotspot sequencing where accessible; (3) for MMRd tumours, reflex MLH1-promoter methylation ± BRAF to separate sporadic loss from probable Lynch, which then earns germline testing. This can — and should — be run on the Pipelle, so the molecular class is known before the hysterectomy and can inform the surgical plan. The classifier is prognostic and predictive, not merely descriptive: it predicts radiotherapy response (PORTEC-1/2 molecular re-analysis), chemotherapy benefit (PORTEC-3) and immunotherapy benefit (RUBY/NRG-GY018).
• CA-125 is neither sensitive nor specific enough to diagnose endometrial cancer, but a markedly raised level in serous histology flags likely extra-uterine/peritoneal disease and can track response — interpret it as a disease-burden signal, never a screening test.

The differential diagnosis and the mimics that change management

The mimics matter because each diverts management down a different path:

• Atrophic vaginitis / cervical or vulval bleeding — the commonest benign cause of "PMB", but it is a diagnosis of exclusion after tissue, never instead of it.
• Endometrial / endocervical polyps and submucosal fibroids — focal lesions that blind sampling misses; they mandate hysteroscopic directed biopsy, and a polyp in a postmenopausal woman or a tamoxifen user can harbour malignancy.
• Cervical carcinoma extending to the uterus, and the reverse — distinguishing a primary endometrial adenocarcinoma with cervical-stromal involvement from a primary endocervical adenocarcinoma changes staging and the radicality of surgery; p16 and immunoprofiling resolve it.
• Uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma, carcinosarcoma) — a rapidly enlarging uterus, or "fibroid" growth after menopause, is sarcoma until proven otherwise. Morcellation is contraindicated when malignancy is possible, because it disseminates tumour and worsens survival. Carcinosarcoma is now understood as a metaplastic carcinoma (epithelial-driven), is overwhelmingly p53abn, and is staged and treated as high-grade carcinoma, not as a pure sarcoma.
• Tamoxifen-associated change — subendometrial cystic atrophy radiologically mimics a thick, suspicious endometrium; the management pivot is to sample, not measure, and to investigate only symptomatic users.
• Metastasis to the endometrium (breast, gastrointestinal) — rare, but recasts the whole plan; the index of suspicion rises with a relevant primary and unusual histology.

Management

Organise as immediate (the index lesion / surgery) → ongoing (adjuvant) → long-term (surveillance/survivorship), and let the histology and molecular class drive intensity rather than stage alone.

• Immediate / surgical: the backbone is total hysterectomy + bilateral salpingo-oophorectomy. Surgical route is the deliberate contrast with cervical cancer — for endometrial cancer the LAP2 and LACE evidence established that minimally invasive surgery is oncologically equivalent with less morbidity, so laparoscopy is preferred where skills/equipment exist. Sentinel lymph-node mapping with indocyanine green has replaced routine full lymphadenectomy for apparent early disease (FIRES: sensitivity ~97%, NPV ~99.6%), sparing lymphoedema. Full lymphadenectomy never improved survival in the ASTEC/MRC trial and is abandoned as a routine.
• Fertility-sparing (atypical hyperplasia or strictly grade-1, stage-IA, no myoinvasion on MRI, no contraindication): LNG-IUS ± oral progestogen with 3-monthly re-biopsy; complete response ~80–90% but ~1/3 relapse, so definitive hysterectomy is advised once childbearing is complete. This is an MDT decision, not a clinic default.
• Ongoing / adjuvant is where molecular class now intervenes. Vaginal brachytherapy controls vault recurrence in intermediate-risk disease with minimal toxicity. For high-risk disease, adjuvant chemoradiation (the PORTEC-3 regimen) is used — but the 10-year data show the benefit is concentrated in p53abn tumours, while MMRd and POLEmut derive little from added chemotherapy. POLEmut early-stage disease may be safe to de-escalate (omit adjuvant therapy) — a live trial question (RAINBO/PORTEC-4a). SA drug names: doxorubicin/cisplatin or carboplatin–paclitaxel per oncology protocol.
• Long-term / advanced & recurrent: first-line systemic therapy is now carboplatin–paclitaxel plus a PD-1 inhibitor (pembrolizumab — NRG-GY018; or dostarlimab — RUBY), with the most dramatic gains in dMMR/MSI-high tumours. Survivorship: VTE risk, lymphoedema, vaginal/sexual sequelae, and HRT is generally safe in oestrogen-driven low-risk endometrioid disease after treatment is contentious — counsel individually. Manage the obesity, diabetes and hypertension that caused the cancer and cause the cardiovascular death that more survivors actually die of.

Subtype-specific management — what changes by molecular class

For a confirmed early-stage tumour, the molecular class adds to the plan what grade-and-stage alone would not:

• POLEmut, uterus-confined → de-escalate. The natural history is so favourable that adjuvant radiotherapy or chemotherapy adds toxicity without measurable benefit; observation after surgery is the trajectory the field is moving toward (PORTEC-4a's "favourable" arm and the RAINBO-BLUE concept). The caveat: POLE status must actually be sequenced — you cannot de-escalate on an assumption, and where sequencing is unavailable (much of SA) you default to histopathological risk and treat conservatively but not nihilistically.
• MMRd → standard adjuvant by risk, but two extra moves. First, the Lynch pathway (reflex methylation/BRAF, germline referral) which changes the family's surveillance. Second, in advanced/recurrent MMRd disease, immunotherapy is the highest-impact systemic option — and identifying MMRd via cheap IHC is the deliverable SA intervention even where the drug itself is not funded.
• NSMP → the molecular class steps back and the classical risk factors lead. Grade, depth of invasion and substantial LVSI drive the choice between observation, vaginal brachytherapy and pelvic radiotherapy. Because NSMP is ER/PR-positive, it is the group where endocrine maintenance (e.g. progestins, aromatase inhibitors) has a role in advanced/recurrent disease and where fertility-sparing progestin therapy is feasible. Watch the CTNNB1-mutant / L1CAM-high subset, which recurs above its apparent risk.
• p53abn → escalate. Full surgical staging (omentum, peritoneal sampling) as for serous/clear-cell, and adjuvant chemotherapy (the carboplatin–paclitaxel backbone) because this is the class PORTEC-3 showed derives the survival benefit. HER2-positive serous carcinoma is a further actionable subset where anti-HER2 therapy is added to chemotherapy in settings where it is available.

Named regimens, exact agents and how they differ

For fertility-sparing medical therapy the named options and their distinctions are: the levonorgestrel-releasing intrauterine system (LNG-IUS, 52 mg) delivering high local progestin with low systemic exposure; oral medroxyprogesterone acetate (MPA); and oral megestrol acetate (MA), both giving higher systemic dose at the cost of weight gain and thrombotic risk. Pooled complete-response rates across regimens cluster around the 80–90% range, are generally highest for the LNG-IUS (± oral progestin) combination and lower for oral-only regimens, but roughly a third relapse, so the LNG-IUS-containing strategy with 3-monthly re-biopsy and a clear "complete family, then hysterectomy" exit is the defensible plan — an MDT decision, never a clinic default.

Monitoring, complications and the SA choice

• Operative and perioperative: the typical patient is obese, often diabetic and hypertensive, so VTE prophylaxis, careful airway/positioning and glycaemic control are integral. Minimally invasive surgery (LAP2/LACE) is preferred where the skills and equipment exist because it reduces wound and thromboembolic morbidity in exactly this high-BMI population — but the SA reality is that laparoscopic gynae-oncology capacity is concentrated in tertiary units, so an open procedure at a regional centre is an entirely acceptable, evidence-consistent choice when laparoscopy is not available.
• Sentinel-node technique: indocyanine green with near-infrared mapping is the modern standard, but ICG and the camera platform are resourced unevenly in SA. Where SLN is unavailable, side-specific nodal assessment and selective lymphadenectomy guided by frozen section/risk is reasonable; routine full pelvic ± para-aortic lymphadenectomy is not the default, given ASTEC showed no survival benefit and clear lymphoedema harm.
• Adjuvant radiotherapy access is itself a constraint: brachytherapy and external-beam capacity sit in tertiary oncology units with waiting lists, which is a real argument against over-prescribing radiotherapy to low-risk disease and for using the molecular class to spare radiotherapy in those who will not benefit (the PORTEC-4a logic).
• The SA-vs-international divergence in one line: internationally the plan reaches for laparoscopic SLN-mapped surgery, molecular-class-tailored adjuvant therapy and chemo-immunotherapy for advanced disease; in SA the same biological framework is applied but the delivery is triaged — IHC-led classification (deliverable) over POLE sequencing and immunotherapy (often not) — and the consultant's job is to capture the high-value, low-cost wins (Lynch identification, avoiding over-treatment, recognising p53abn) within those constraints.

The evidence & the controversy

The FIGO 2023 restaging is the live controversy and a guaranteed discussion point. It abandons purely anatomical staging: histological type, grade, substantial LVSI and molecular class now move patients between stages — e.g. a uterus-confined POLEmut tumour is downstaged to IAmPOLEmut, while a p53abn tumour with myoinvasion is upstaged to IICmp53abn. The promise is prognostic precision; the objection — voiced by ESGO commentators and in International Journal of Gynecological Cancer ("too much, too soon?") — is that it causes ~20% stage migration, diverges from the 2021 ESGO/ESTRO/ESP risk groups, and demands molecular testing that most of the world, including much of SA, cannot yet deliver. A defensible viva position: adopt the molecular biology (it is real and changes treatment) while acknowledging the staging notation is contested and resource-dependent; report the FIGO 2009 stage alongside it where molecular data are missing.

Adjuvant therapy is being rewritten by molecular class. PORTEC-3's 10-year post-hoc analysis is the pivotal teaching point: adjuvant chemoradiotherapy improved overall survival only modestly across all-comers (74% vs 67%) but dramatically in p53abn tumours (10-yr OS 53% vs 37%, HR 0.52), while POLEmut and MMRd tumours gained essentially nothing. This reframes adjuvant chemotherapy as a p53abn-directed therapy rather than a stage-directed one, and underpins de-escalation trials for POLEmut disease.

The de-escalation evidence has now matured into a positive trial. PORTEC-4a (Lancet Oncology 2025, n=592, randomised 2:1) tested molecular-integrated risk-profile-directed adjuvant therapy against standard vaginal brachytherapy in high-intermediate-risk disease — the first prospective randomised proof that you can act on the molecular class. Roughly 46% of women safely avoided radiotherapy by being assigned to observation on a favourable profile, without compromising control; conversely, women with an unfavourable profile escalated to pelvic radiotherapy had their locoregional recurrence cut from 30.5% to 8.4%. This is the trial that converts the molecular classifier from a prognostic curiosity into a tool that both de-escalates the favourable and escalates the unfavourable — and it directly supports omitting radiotherapy in POLEmut/favourable-profile early disease. It also reframes the older radiotherapy trials: PORTEC-2 had already shown that vaginal brachytherapy is non-inferior to pelvic external-beam radiotherapy for vaginal control in high-intermediate-risk disease with far less toxicity, so the modern question is no longer "which radiotherapy" but "radiotherapy at all, in whom" — answered by molecular profile.

Immunotherapy has redefined advanced disease in just two years. NRG-GY018 (pembrolizumab) and RUBY (dostarlimab) independently showed that adding a PD-1 inhibitor to carboplatin–paclitaxel improves progression-free and overall survival, with the benefit greatest in dMMR/MSI-high tumours (RUBY 24-month PFS 61% vs 16% in dMMR). The mechanism is high tumour mutational burden and neoantigen load in MMRd. The SA access reality completes the picture: these agents are largely unavailable in the public sector, making universal MMR-IHC to identify who would benefit the higher-value, deliverable intervention. The mirror is that for low-grade, early disease over-treatment is the bigger SA harm.

Landmark trials & key evidence

A worked appraisal point — PORTEC-3's p53abn effect. Among p53-abnormal tumours, 10-year overall survival was 53% with chemoradiation versus 37% with radiotherapy alone — an absolute survival gain of 53 − 37 = 16 percentage points, giving a number-needed-to-treat ≈ 1 / 0.16 ≈ 6 to prevent one death at 10 years in that subgroup. Contrast that with the all-comers absolute gain of 74 − 67 = 7 percentage points (NNT ≈ 1/0.07 ≈ 14), most of which is carried by the p53abn patients while POLEmut/MMRd patients are treated for no benefit — the arithmetic that justifies directing adjuvant chemotherapy by molecular class rather than by stage.

Worked viva — how to structure the answer

Examiners give a stem like "a 58-year-old obese woman, postmenopausal bleeding, endometrial biopsy shows grade-1 endometrioid adenocarcinoma; MMR IHC shows loss of MLH1 and PMS2." A high-scoring answer runs:

1. Frame it — "This is an early endometrioid endometrial cancer that is MMR-deficient; the immediate questions are sporadic versus Lynch, the surgical plan, and what the molecular class adds to it."
2. Resolve the molecular class — "MLH1/PMS2 loss is usually sporadic via MLH1-promoter hypermethylation; I would reflex methylation ± BRAF testing, and if unmethylated, refer for germline testing for Lynch. I would also note p53 IHC and, where available, POLE sequencing — and apply the POLEmut > MMRd > p53abn ordering rule if markers conflict."
3. Plan the surgery — "Total hysterectomy and bilateral salpingo-oophorectomy with sentinel-node mapping; laparoscopic where capacity exists, open at a regional unit otherwise. No routine full lymphadenectomy — ASTEC showed no survival benefit and clear lymphoedema harm."
4. Decide adjuvant by class and risk — "Adjuvant intensity follows grade, depth of invasion, LVSI and molecular class. For MMRd I would not expect a chemotherapy benefit on PORTEC-3; for a favourable molecular-integrated profile, PORTEC-4a supports observation rather than reflex radiotherapy."
5. Justify from evidence — TCGA/ProMisE for the taxonomy, PORTEC-3 (chemo is p53abn-directed), PORTEC-4a (de-escalate favourable, escalate unfavourable), RUBY/NRG-GY018 (immunotherapy, dMMR-led).
6. Act on Lynch and survivorship — "Germline referral protects the patient (colorectal/ovarian surveillance) and cascades to the family; I would manage the obesity, diabetes and hypertension that drive both the cancer and the cardiovascular death survivors more often die of, and counsel on the SA access reality that IHC-led classification, not immunotherapy, is the deliverable high-value step."

Exam traps & red flags

• Observing atypical hyperplasia. ~40% already harbour cancer and ~28% progress — atypical hyperplasia/EIN is a hysterectomy diagnosis (unless fertility-sparing is a deliberate MDT plan).
• A negative Pipelle does not exclude cancer. Persistent PMB with a normal/insufficient blind biopsy needs hysteroscopy — blind sampling misses focal lesions.
• Applying the 4 mm cut-off to tamoxifen users or premenopausal women. It is validated for PMB only; tamoxifen distorts ET — sample directly. And remember serous carcinoma can present with a thin endometrium.
• Treating all endometrial cancer as low-risk. Serous, clear-cell and carcinosarcoma (p53abn) behave like high-grade disease and need full staging and chemotherapy regardless of apparent stage.
• Forgetting molecular class changes treatment, not just prognosis. p53abn → chemotherapy benefit; dMMR → immunotherapy benefit and Lynch screening; POLEmut → consider de-escalation.
• Getting the multiple-classifier ordering wrong. POLEmut > MMRd > p53abn — a POLEmut/p53abn tumour is treated as POLEmut (excellent prognosis), not as aggressive disease. Misclassifying over-treats a curable patient.
• Routine full lymphadenectomy. No survival benefit (ASTEC) and causes lymphoedema; SLN mapping is the modern standard.
• Morcellating a presumed fibroid that could be a sarcoma. A rapidly enlarging or post-menopausal "fibroid" is sarcoma until excluded; morcellation disseminates tumour.
• Missing Lynch syndrome. Young patients and dMMR tumours warrant germline referral — it protects the patient (colorectal/ovarian surveillance) and the family, and endometrial cancer is often the sentinel Lynch malignancy.
• De-escalating on an assumption. You cannot omit adjuvant therapy for "probable POLEmut" — POLE must be sequenced; where it cannot be, default to histopathological risk.

Evidence anchors

• The Cancer Genome Atlas — integrated genomic characterization of endometrial carcinoma, Kandoth et al., Nature 2013
• ProMisE molecular classifier (confirmation) — Talhouk et al., Cancer 2017
• FIGO 2023 staging of endometrial cancer — Berek et al., Int J Gynaecol Obstet 2023
• PORTEC-3 10-year outcomes by molecular class — Post et al., Lancet Oncol 2025
• PORTEC-4a — molecular-profile-based adjuvant treatment, Lancet Oncol 2025
• PORTEC-2 — vaginal brachytherapy vs pelvic EBRT, Nout et al., Lancet 2010
• GOG-258 — Matei et al., N Engl J Med 2019
• NRG-GY018 / KEYNOTE-868 (pembrolizumab) — Eskander et al., N Engl J Med 2023
• RUBY (dostarlimab) — Mirza et al., N Engl J Med 2023
• FIRES sentinel-node trial — Rossi et al., Lancet Oncol 2017
• Concurrent carcinoma in atypical hyperplasia (GOG) — Trimble et al., Cancer 2006
• MRC ASTEC — no survival benefit from systematic pelvic lymphadenectomy, Lancet 2009
• GOG LAP2 — laparoscopy non-inferior to laparotomy for uterine-cancer staging, Walker et al., J Clin Oncol 2012
• Management of Endometrial Hyperplasia — RCOG/BSGE Green-top Guideline No. 67 (2016)
• Endometrial cancer mortality & ethnic disparity in South Africa 1999–2018 — PLOS One 2025