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 (reflex MLH1-promoter methylation 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 escalates adjuvant chemotherapy; omental and peritoneal staging, by contrast, follows the histotype (serous, carcinosarcoma or undifferentiated), not the p53 result on its own.

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 imaging is transvaginal ultrasound, but ACOG 2026 now recommends transvaginal ultrasound plus endometrial tissue sampling as the initial evaluation for most PMB. Observation on an endometrial thickness ≤4 mm is reserved for a woman with a single bleed, no risk factors and assured follow-up; >4 mm, any persistent/recurrent bleeding regardless of thickness, or any endometrial-cancer risk factor (obesity, diabetes, anovulation) mandates tissue. The ≤4 mm stripe 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 frequently clonally related, but behave as early, curable disease: when the FIGO 2023 IA3 criteria are met (less than 50% myometrial invasion, no substantial LVSI, a unilateral encapsulated ovary and no other metastasis) they are staged IA3 with an excellent prognosis and no adjuvant therapy, 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.