Endometrial carcinoma is a malignant neoplasm arising from the glandular epithelium of the uterine lining, most commonly presenting as abnormal uterine bleeding in postmenopausal women.

Exam domain	One-glance essentials
Definition / diagnosis	*Endometrial carcinoma is malignancy arising from the endometrial lining, most commonly endometrioid adenocarcinoma* ^[1]^[2] It often presents early with abnormal bleeding and is surgically staged ^[1]
Epidemiology / risks	Key risks are obesity, chronic anovulation or PCOS, diabetes, nulliparity, tamoxifen, unopposed oestrogen, and Lynch syndrome ^[2] Continuous combined hormonal contraception and parity reduce risk through progestogenic exposure ^[2]
Core mechanism	Unopposed oestrogen → endometrial hyperplasia → endometrioid carcinoma in many cases ^[2] Other molecular pathways produce non-endometrioid aggressive cancers that are less linked to oestrogen ^[1]
Clinical picture	*Postmenopausal bleeding is the hallmark*; premenopausal patients may have persistent intermenstrual, irregular, or heavy bleeding ^[1]^[2] Advanced disease may cause pelvic pain, discharge, weight loss, anaemia, or pressure symptoms ^[1]
Investigations	TVUS assesses the endometrium, but endometrial biopsy establishes diagnosis ^[1]^[2] Hysteroscopy targets focal disease; MRI evaluates local extent and CT assesses extrauterine spread when indicated ^[1]
Management	*Total hysterectomy with bilateral salpingo-oophorectomy and stage-directed nodal assessment is standard for operable disease* ^[1] Radiotherapy, chemotherapy, hormonal therapy, or immunotherapy are selected by stage, histology, molecular features, recurrence, and fitness ^[1]^[2]
Complications	Complications include myometrial and cervical invasion, nodal or distant spread, bleeding, anaemia, pain, and thromboembolism ^[1] Treatment may cause lymphoedema, bladder or bowel morbidity, infertility, and premature menopause ^[1]^[2]
Prevention / follow-up	Maintain healthy weight, treat chronic anovulation with endometrial protection, and identify Lynch syndrome for patient and family prevention ^[2] Investigate PMB promptly; there is no population screening test for average-risk asymptomatic women ^[1]
Exam traps	A thin stripe alone does not close PMB assessment: ACOG 2026 recommends TVUS plus tissue sampling for most patients Do not use cervical cytology to exclude endometrial cancer ^[1]

References

^[1] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (pp. 21–22 — endometrial cancer staging and spread) ^[2] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p. 34 — risk factors and Lynch syndrome)

Endometrial Cancer

Faculty molecular-classification checklist (pathology deck pp. 22–32): integrate pathogenic POLE exonuclease-domain variants, MMR, p53 and histology. For multiple classifiers, POLEmut takes precedence over MMRd/p53abn, and MMRd over p53abn. A POLE variant of uncertain significance does not qualify. NSMP requires exclusion of the other classes; grade and ER status further refine its risk. p53 must be reported as wild-type or abnormal, including overexpression, null and cytoplasmic patterns. ER/PR guide endocrine treatment; assess HER2 in relevant advanced/recurrent disease. ESGO–ESTRO–ESP 2025.

Endometrial cancer (also referred to as carcinoma of the corpus uteri) is a malignant neoplasm arising from the endometrium — the glandular lining of the uterine body (corpus). The name itself tells you where it lives: endo- (within) + metr- (uterus) + -ial (pertaining to).

It is the most common gynaecological malignancy in developed countries and the most common malignancy of the female genital tract in Hong Kong ^[1]^[2]. The vast majority present with postmenopausal bleeding (PMB), which is why the clinical mantra is:

Postmenopausal bleeding is endometrial cancer until proven otherwise.

Key Distinction

Do not confuse endometrial cancer with cervical cancer. Endometrial cancer arises from the body of the uterus (corpus uteri), whereas cervical cancer arises from the cervix. They have entirely different risk factors, pathogenesis, screening strategies, and management.

2. Epidemiology

Common in high-income populations; global rank differs from rankings in individual countries. Do not label it the fourth most common female cancer worldwide.
Predominantly a disease of affluent, developed nations — the "Western" cancer — because of its strong association with obesity and unopposed oestrogen exposure.
Median age at diagnosis: ~60–63 years; ~90% of cases occur in women > 50 years.

Hong Kong Cancer Registry data: corpus uteri cancer is the most common gynaecological cancer in HK, and its incidence has been rising steadily over the past two decades ^[1]^[2].
The rising trend mirrors increasing rates of obesity, metabolic syndrome, later childbearing, and lower parity in the HK population.
Age-standardised incidence rate in HK: approximately 14–16 per 100,000 women per year (and climbing).
Mortality is comparatively lower than ovarian cancer because endometrial cancer tends to present early (PMB brings patients to the doctor).

Predominantly a disease of postmenopausal women ^[1]^[2].
Peak incidence: 55–65 years.
~5% of cases occur before age 40 — these are usually low-grade, Type I cancers in the setting of PCOS, obesity, or anovulation; they may be candidates for fertility-sparing treatment.
Pre-menopausal endometrial cancer should always raise suspicion for Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) ^[1]^[3].

3. Risk Factors

The unifying theme for the vast majority of risk factors is unopposed oestrogen exposure — that is, oestrogen acting on the endometrium without the counterbalancing, differentiating effect of progesterone. Progesterone causes endometrial secretory differentiation and sloughing; without it, oestrogen drives relentless proliferation → hyperplasia → atypia → carcinoma.

The Oestrogen–Progesterone Balance

Think of the endometrium as a field of grass. Oestrogen is fertiliser — it makes the grass grow thick and tall. Progesterone is the lawnmower — it mows the grass back each cycle. If you keep pouring on fertiliser but never mow, the grass becomes overgrown and eventually chaotic (hyperplasia → atypia → cancer). Every risk factor below either increases the "fertiliser" or removes the "lawnmower."

Category	Risk Factor	Mechanism / Explanation
Age	Predominantly a disease of postmenopausal women	Cumulative oestrogen exposure over a lifetime; post-menopausal state allows peripheral aromatisation to become the dominant oestrogen source (especially in obesity)
Excessive endogenous oestrogens	Early menarche	More years of cyclic oestrogen exposure
	Late menopause	Same — extended reproductive window
	Nulliparity	Pregnancy provides 9 months of high progesterone (the "lawnmower"); nulliparity = fewer progesterone-dominant intervals
	Obesity	Adipose tissue contains aromatase, which converts adrenal androgens (androstenedione) → oestrone (E1). Obesity also ↑ bioavailable oestrogen by ↓ SHBG. Additionally, obesity → insulin resistance → hyperinsulinaemia → ↓ SHBG + direct mitogenic effect of insulin/IGF-1 on endometrium
	Polycystic ovarian syndrome (PCOS)	Chronic anovulation = no corpus luteum = no progesterone; also associated with hyperinsulinaemia and obesity
	Oestrogen-secreting tumours (ovarian granulosa cell tumours) ^[1]^[2]	Direct autonomous oestrogen production by tumour → endometrial hyperstimulation
	Endometrial hyperplasia	Precursor lesion (especially atypical hyperplasia / endometrial intraepithelial neoplasia [EIN]) — sits on the hyperplasia–cancer continuum
Exogenous oestrogen	Unopposed oestrogen therapy ^[1]^[2]	HRT with oestrogen-only in a woman with an intact uterus → no progesterone to oppose proliferative effect. Risk ↑ 2–10× depending on dose and duration. Adding progesterone to HRT eliminates this risk — this is why combined HRT is standard for women with a uterus.
	Tamoxifen therapy ^[1]^[2]	Tamoxifen is a selective oestrogen receptor modulator (SERM). In breast tissue it is an oestrogen antagonist (hence its use in breast cancer). But in the endometrium it acts as a partial agonist → stimulates endometrial proliferation → ↑ risk of endometrial hyperplasia, polyps, and cancer (RR ~2–7× after 5 years of use). This is one of the important side effects to counsel breast cancer patients about.
Genetic / Familial	Lynch syndrome (lifetime risk 15–60%) ^[1]^[2]^[3]	Germline mutation in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Endometrial cancer is the most common extracolonic malignancy in Lynch syndrome — sometimes even the sentinel cancer that leads to the diagnosis. Screening: pelvic exam + endometrial biopsy Q1y from 30–35y, with prophylactic TAH+BSO after completion of childbearing (~40y) ^[3].
	Family history of breast, ovarian, and colorectal cancer ^[1]^[2]	Overlap with Lynch syndrome and BRCA-related cancer family syndrome
Metabolic / Miscellaneous	Diabetes mellitus ^[1]^[2]	Hyperinsulinaemia → ↓ SHBG → ↑ free oestrogen; insulin itself is mitogenic; also frequently coexists with obesity
	Hypertension ^[1]^[2]	Epidemiological association — likely confounded by metabolic syndrome / obesity, though some evidence of independent risk

Protective Factor	Mechanism
Combined oral contraceptive pill (COCP)	Provides regular progesterone → opposes oestrogen-driven proliferation; risk reduction persists ≥ 10 years after discontinuation
Multiparity	More cumulative progesterone exposure during pregnancies
Breastfeeding	Lactational amenorrhoea = suppressed oestrogen via hypothalamic-pituitary axis
Levonorgestrel IUS (Mirena)	Local progesterone delivery directly to endometrium → atrophy
Smoking	Anti-oestrogenic effect (accelerates oestrogen metabolism and ↓ body weight); this is one of the few cancers where smoking is paradoxically protective — but obviously not a recommended strategy!
Physical activity	↓ obesity, ↓ insulin resistance, ↓ bioavailable oestrogen

High Yield – Risk Factors from Lecture

Risk factors can be classified into age, and then oestrogen (from exogenous, endogenous sources), essentially lifestyle factors ^[2]. Don't forget oestrogen-secreting tumours (ovarian granulosa cell tumours) and that unopposed oestrogen is giving oestrogen without progesterone ^[2]. The commonest syndrome associated with endometrial cancer is Lynch syndrome (up to 60% lifetime risk) ^[2].

4. Anatomy and Function

The uterus is a hollow, pear-shaped, muscular organ sitting in the pelvis between the bladder (anterior) and rectum (posterior). It is divided into:

Fundus: the dome-shaped top above the insertion of the fallopian tubes
Body (corpus): the main bulk — this is where endometrial cancer arises
Isthmus: the narrow constriction between body and cervix
Cervix: the lower cylindrical portion opening into the vagina

Serosa (perimetrium): visceral peritoneum covering the uterus
Myometrium: thick smooth muscle layer (~90% of uterine wall). Cancer invading through this layer carries prognostic significance (depth of myometrial invasion is a key staging parameter).
Endometrium: the innermost mucosal layer, composed of:
- Functionalis layer: the superficial layer that proliferates under oestrogen, differentiates under progesterone, and sheds during menstruation
- Basalis layer: the deep, permanent regenerative layer that does not shed — it is from here that the endometrium regenerates after each cycle

Myometrial invasion depth: determines staging (Stage IA = < 50% invasion, Stage IB = ≥ 50% invasion). Deeper invasion = closer to serosa, closer to lymphatic/vascular channels → higher risk of lymph node metastasis.
Cervical stromal involvement: upstages to Stage II.
Lymphatic drainage:
- Fundus and upper body: drain to para-aortic lymph nodes (via the ovarian/infundibulopelvic ligament vessels) and to external iliac nodes
- Lower body and isthmus: drain to obturator, internal iliac, and external iliac nodes
- This dual drainage pattern is why both pelvic and para-aortic lymph node dissection may be considered in surgical staging.
Peritoneal cavity: the uterus opens into the peritoneal cavity via the fallopian tubes → tumour cells can shed through the tubes → peritoneal/omental spread (transtubal dissemination).

During the proliferative phase (follicular, days 1–14), rising oestrogen from developing ovarian follicles stimulates endometrial glandular and stromal proliferation. After ovulation, the corpus luteum produces progesterone, which causes the endometrium to enter the secretory phase — glands become tortuous and secrete glycogen, stroma becomes decidualised, and proliferation ceases. If no pregnancy occurs, the corpus luteum regresses → progesterone withdrawal → menstruation (shedding of the functionalis layer).

The pathological state in Type I endometrial cancer is one where this cycle is broken: persistent oestrogen without progesterone → the endometrium proliferates continuously without ever differentiating or shedding → hyperplasia → accumulation of mutations → cancer.

5. Aetiology and Pathophysiology

The Dualistic Model of Endometrial Cancer

Endometrial cancer is classically divided into two types based on clinicopathological and molecular features. This is the Bokhman dualistic model (1983), it is retained here to explain historical literature. Faculty CMB pathology explicitly replaces it with molecular classification for current risk assessment; morphology alone cannot reliably assign molecular class.

Feature	Type I (Endometrioid)	Type II (Non-endometrioid)
Frequency	~80% of cases	~20% of cases
Histology	Endometrioid adenocarcinoma	Serous, clear cell, carcinosarcoma
Grade	Usually low grade (G1–G2)	Usually high grade (G3)
Precursor lesion	Atypical hyperplasia / EIN	Endometrial intraepithelial carcinoma (serous EIC) / atrophic endometrium
Oestrogen-related?	Yes — oestrogen-dependent	No — oestrogen-independent
Patient profile	Younger, obese, metabolic syndrome	Older, thin, post-menopausal
Molecular features	PTEN loss (most common), PIK3CA, KRAS, CTNNB1 (β-catenin), MSI-high, ARID1A	TP53 mutation (> 90%), HER2 amplification, widespread copy number alterations
Behaviour	Indolent, usually confined to uterus at diagnosis	Aggressive, often advanced at diagnosis
Prognosis	Good (5-year survival ~85%)	Poor (5-year survival ~40–50%)

Pathogenesis: Normal endometrium → simple hyperplasia → complex hyperplasia → atypical hyperplasia (AH) / endometrial intraepithelial neoplasia (EIN) → endometrioid carcinoma.

This is a stepwise progression driven by chronic unopposed oestrogen, analogous to the adenoma–carcinoma sequence in colorectal cancer. Each step accumulates additional genetic hits:

PTEN inactivation (~40–80% of endometrioid cancers): PTEN is a tumour suppressor that negatively regulates the PI3K/AKT/mTOR signalling pathway. Loss of PTEN → unchecked PI3K signalling → cell proliferation and survival. PTEN mutations are found even in the earliest hyperplastic lesions, suggesting this is an early/initiating event.
MSI (microsatellite instability) (~20–30%): due to epigenetic silencing (promoter hypermethylation) of MMR genes (especially MLH1) → defective DNA mismatch repair → accumulation of frameshift mutations. This is also the mechanism in Lynch syndrome (but there it is a germline MMR mutation rather than epigenetic silencing) ^[3].
PIK3CA mutations (~30–40%): activating mutations in the catalytic subunit of PI3K → further activation of the PI3K/AKT/mTOR pathway.
KRAS mutations (~15–30%): activating RAS-MAPK signalling → cell proliferation.
CTNNB1 (β-catenin) mutations (~20–25%): activating Wnt/β-catenin signalling → proliferation, especially in squamous morules (the squamous differentiation component of endometrioid carcinomas).
ARID1A mutations (~30–40%): loss of chromatin remodelling function.

Pathogenesis: Atrophic endometrium → serous endometrial intraepithelial carcinoma (serous EIC) → serous carcinoma. This does not go through the hyperplasia-atypia continuum.

Key molecular features:

TP53 mutations (> 90% of serous carcinomas): p53 is the "guardian of the genome"; its loss allows cells to proliferate despite DNA damage → genomic instability → aggressive behaviour.
HER2/neu (ERBB2) amplification (~25–30% of serous): potential therapeutic target (trastuzumab).
Widespread copy number alterations (CNAs): chromosomal instability is the hallmark.
These tumours are typically oestrogen receptor (ER) and progesterone receptor (PR) negative — hence they do not respond to hormonal therapy and are not driven by oestrogen.

The Cancer Genome Atlas (TCGA) molecular classification has revolutionised our understanding and is increasingly incorporated into clinical practice. It divides endometrial cancer into four molecular subtypes:

Subtype	Key Feature	Frequency	Prognosis
POLE ultramutated	Somatic mutations in the proofreading domain of DNA polymerase ε (POLE) → extremely high mutation burden → strong immune response	~7%	Excellent (best prognosis despite sometimes high-grade histology)
MSI-hypermutated (dMMR)	Deficient mismatch repair (MLH1 methylation or Lynch syndrome) → high mutation burden, microsatellite instability	~28%	Intermediate (may respond to immune checkpoint inhibitors)
Copy-number low (p53 wild-type)	No specific driver; PTEN, PIK3CA, CTNNB1 mutations common; most "classic" low-grade endometrioid tumours	~39%	Intermediate to good
Copy-number high (p53 abnormal / serous-like)	TP53 mutation, chromosomal instability, HER2 amplification; includes most serous and high-grade endometrioid	~26%	Poor (worst prognosis)

Why Molecular Classification Matters Clinically

A high-grade endometrioid cancer that is POLE-mutated has an excellent prognosis despite its scary histology — it may not need adjuvant therapy. Conversely, a low-grade endometrioid cancer that is p53-abnormal behaves aggressively. Molecular classification allows us to refine prognosis and tailor adjuvant treatment beyond histology alone. The 2023 FIGO staging now incorporates molecular classification.

6. Classification

Epithelial tumours of the uterine corpus:

A. Endometrioid carcinoma (~80%)

Grade 1: ≤ 5% solid (non-squamous, non-morular) growth pattern
Grade 2: 6–50% solid growth pattern
Grade 3: > 50% solid growth pattern
Variants: with squamous differentiation, villoglandular, secretory, with mucinous differentiation

B. Serous carcinoma (~5–10%)

Always considered high grade (no grading applied)
Papillary architecture with psammoma bodies
Characteristically aggressive, even with minimal myometrial invasion — can spread to peritoneum and omentum early (behaves like ovarian serous carcinoma)

C. Clear cell carcinoma (~1–5%)

Always considered high grade
Named for cells with abundant clear (glycogen-rich) cytoplasm
Tubulo-cystic, papillary, or solid patterns
Aggressive behaviour similar to serous

D. Carcinosarcoma (malignant mixed Müllerian tumour / MMMT) (~3–5%)

Contains both malignant epithelial (carcinoma) and malignant mesenchymal (sarcoma) components
Now classified as a metaplastic carcinoma (the sarcomatous component is thought to derive from the carcinomatous component via epithelial-mesenchymal transition)
Extremely aggressive

E. Other rare types: mucinous carcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, neuroendocrine carcinoma, mixed carcinoma

The old 4-tier classification (simple/complex ± atypia) has been simplified:

Old Classification	New Classification	Cancer Risk
Simple hyperplasia without atypia	Hyperplasia without atypia	< 5% progression to cancer
Complex hyperplasia without atypia	Hyperplasia without atypia	< 5%
Simple atypical hyperplasia	Atypical hyperplasia / EIN	~30–60% progression
Complex atypical hyperplasia	Atypical hyperplasia / EIN	~30–60% progression

Atypical hyperplasia / EIN (endometrial intraepithelial neoplasia) is the direct precursor to Type I endometrioid carcinoma. Up to 40–60% of women with AH on biopsy are found to already harbour concurrent carcinoma in the hysterectomy specimen.

“Non-aggressive” here means low-grade endometrioid carcinoma. Substantial LVSI differs from absent/focal LVSI.

Stage	Defining pattern
IA1	Non-aggressive; confined to polyp/endometrium
IA2	Non-aggressive; <50% myometrial invasion, absent/focal LVSI
IA3	Selected low-grade uterine and unilateral ovarian disease; criteria below
IB	Non-aggressive; ≥50% myometrial invasion, absent/focal LVSI
IC	Aggressive histology confined to polyp/endometrium
IIA / IIB	Non-aggressive with cervical stromal invasion / substantial LVSI
IIC	Aggressive histology with myometrial invasion
IIIA1 / IIIA2	Adnexa, unless IA3 criteria met / uterine subserosa or serosa
IIIB1 / IIIB2	Vagina or parametria / pelvic peritoneum
IIIC1 / IIIC2	Pelvic / para-aortic nodes up to renal vessels; suffix i = micro-, ii = macrometastasis
IVA / IVB / IVC	Bladder/bowel mucosa / extrapelvic peritoneum / distant disease

IA3 requires all: low-grade endometrioid histology at both sites, <50% myometrial invasion, no substantial LVSI, no other metastases, and a unilateral ovarian tumour confined within an intact capsule. Otherwise ovarian spread is IIIA1. FIGO 2023 staging paper.

Molecular classification can modify early-stage labels: pathogenic POLEmut disease confined to the uterine corpus or extending to the cervix is IAm_POLEmut; p53abn with any myometrial invasion, with or without cervical invasion, is IICm_p53abn. MMRd/NSMP do not change the anatomical stage. Stage III–IV keeps its stage with molecular status recorded. NCI current staging.

The table below is the legacy FIGO 2009 anatomical framework, retained to interpret older lectures and trials. It is not the complete FIGO 2023 classification:

Stage	Description
I	Confined to corpus uteri
IA	Tumour limited to endometrium or invades < 50% of myometrium
IB	Invades ≥ 50% of myometrium
II	Invades cervical stroma (but not beyond uterus)
III	Local and/or regional spread
IIIA	Invades serosa and/or adnexae (direct extension or metastasis)
IIIB	Vaginal involvement and/or parametrial involvement
IIIC1	Metastasis to pelvic lymph nodes
IIIC2	Metastasis to para-aortic lymph nodes (± pelvic nodes)
IV	Invades bladder/bowel mucosa and/or distant metastasis
IVA	Invades bladder and/or bowel mucosa
IVB	Distant metastasis (including inguinal lymph nodes, intra-abdominal metastasis, lung, liver, bone)

Use FIGO 2023 labels for current staging

FIGO 2023 incorporates histological aggressiveness, LVSI and molecular classification. Stage I–II subdivisions therefore cannot be assigned from depth of invasion alone. Pelvic peritoneal disease is IIIB2; peritoneal metastases beyond the pelvis are IVB; distant metastases (including lung, liver parenchyma, bone and extra-regional nodes) are IVC. Bladder/bowel mucosal invasion remains IVA. Uterine-confined POLE-mutated disease is classified IAm_POLEmut; p53-abnormal disease with myometrial invasion is IICm_p53abn. Do not relabel the legacy table as 2023 without these changes. (2025 ESGO–ESTRO–ESP guideline.)

Understanding how endometrial cancer spreads is essential for understanding staging and clinical features:

How female cancers spread [1]

Direct extension / Local invasion:
- Through myometrium → serosa → peritoneal cavity
- Downward into cervical stroma (Stage II)
- Into parametrium, vagina (Stage IIIB)
- Into adjacent organs: bladder, rectum (Stage IVA)
Lymphatic spread (most important route for regional spread):
- Pelvic lymph nodes: obturator → internal iliac → external iliac → common iliac
- Para-aortic lymph nodes (especially from fundal tumours via ovarian vessels in the infundibulopelvic ligament)
- Risk of lymph node metastasis correlates with: depth of myometrial invasion, tumour grade, LVSI, histological type
Transtubal / Peritoneal spread:
- Tumour cells can exfoliate through the fallopian tubes into the peritoneal cavity → omental deposits, peritoneal carcinomatosis
- This is particularly characteristic of serous carcinoma (which behaves like ovarian serous cancer)
- Positive peritoneal cytology (now removed from FIGO staging but still reported)
Haematogenous spread (late, FIGO 2023 Stage IVC):
- Lung (most common distant site)
- Liver
- Bone
- Brain (rare)

8. Clinical Features

Cancer is not the commonest cause of abnormal vaginal bleeding — many many more benign causes exist ^[2]. However, endometrial cancer must always be excluded, particularly in postmenopausal women.

The cardinal symptom of endometrial cancer is abnormal vaginal bleeding — especially postmenopausal bleeding (PMB).

~90% of endometrial cancers present with abnormal vaginal bleeding. Because this is an early symptom (even small tumours confined to the endometrium will bleed), most endometrial cancers are diagnosed at an early stage (75% at Stage I), which accounts for the relatively good overall prognosis.

Symptom	Pathophysiological Basis	Details
Postmenopausal bleeding (PMB)	Tumour (friable, neovascularised, ulcerated surface) erodes endometrial blood vessels → bleeding into the uterine cavity → drains via the cervical os → PV bleeding. In a postmenopausal woman, the endometrium should be atrophic and thin; any bleeding is abnormal and demands investigation.	~90% of endometrial cancers present with PMB. However, only ~10% of women with PMB have endometrial cancer — the most common cause of PMB is actually atrophic vaginitis/endometritis. Still, it must be excluded.
Abnormal premenopausal bleeding	Same mechanism of tumour-related bleeding, but presents as intermenstrual bleeding (IMB), menorrhagia (heavy menstrual bleeding), or irregular bleeding in premenopausal women. In younger women, it is often attributed to dysfunctional uterine bleeding (anovulatory cycles), which delays diagnosis.	~5% of endometrial cancers occur in women < 40. PCOS patients with prolonged amenorrhoea followed by heavy irregular bleeding should raise suspicion.
Abnormal vaginal discharge	Tumour necrosis and secondary infection → purulent or blood-stained discharge. Large tumours may outgrow their blood supply → central necrosis → foul-smelling discharge.	May be watery, mucoid, purulent, or blood-tinged.
Pyometra / Haematometra	If tumour obstructs the cervical canal (or in elderly women with cervical stenosis) → accumulation of pus (pyometra) or blood (haematometra) within the uterine cavity → uterine distension.	Presents with lower abdominal pain, uterine tenderness, fever (if infected). May be an incidental finding.
Pelvic pain / pressure	Advanced disease with uterine enlargement, myometrial invasion, or spread to adjacent structures (parametrium, nerves). In early disease, pain is uncommon.	Late symptom; if present, consider locally advanced disease.
Urinary symptoms	Anterior extension to bladder → frequency, urgency, haematuria (Stage IVA). Ureteric compression by bulky pelvic disease → hydronephrosis → flank pain, renal impairment.	Late feature.
Rectal symptoms	Posterior extension to rectosigmoid → tenesmus, altered bowel habit, rectal bleeding (Stage IVA).	Late feature.
Constitutional symptoms	Advanced/metastatic disease → cancer cachexia mediated by inflammatory cytokines (TNF-α, IL-6) → anorexia, weight loss, fatigue.	Late feature; uncommon in early disease.
Symptoms of metastatic disease	Lung metastases → dyspnoea, cough, haemoptysis. Liver metastases → right upper quadrant pain, jaundice. Bone metastases → bone pain, pathological fracture.	Stage IVC (2023); uncommon at presentation for Type I, but may occur at presentation for Type II (especially serous).

Sign	Pathophysiological Basis	Details
Often no abnormal findings on examination	Early endometrial cancer (confined to endometrium/superficial myometrium) does not alter the external appearance of the uterus or pelvis.	Most cases are diagnosed at an early stage where physical examination is entirely normal. The diagnosis is made on investigation (ultrasound and biopsy).
Uterine enlargement	Tumour bulk within the uterine cavity or invading the myometrium → uterine enlargement palpable on bimanual examination.	Irregular, firm, bulky uterus on bimanual palpation. May be difficult to distinguish from fibroids in a premenopausal woman.
Blood at the cervical os	Blood draining from the uterine cavity through the cervix → visible on speculum examination.	On speculum: blood at or from the external os, but the cervix itself appears grossly normal (unlike cervical cancer where you may see a cervical mass/ulcer).
Cervical involvement	Tumour extending downward into cervical stroma → visible cervical mass/irregularity on speculum, or palpable on digital examination.	Stage II disease.
Vaginal involvement	Direct extension or metastatic deposit in vagina → visible/palpable vaginal nodule(s), especially in the suburethral area or vaginal cuff (post-hysterectomy).	Stage IIIB.
Parametrial thickening / fixation	Tumour extending through the myometrium into the parametrium → loss of normal mobility of the uterus on bimanual examination.	Restricted uterine mobility or "frozen pelvis" on examination = locally advanced disease.
Adnexal mass	Direct extension to ovary/fallopian tube, or synchronous ovarian pathology (endometrioid ovarian cancer can co-occur with endometrial cancer in ~5% of cases).	Stage IIIA (if ovarian spread).
Ascites	Peritoneal carcinomatosis → fluid accumulation in peritoneal cavity.	Stage IVB. Shifting dullness on percussion, fluid thrill.
Lymphadenopathy	Metastatic spread to inguinal lymph nodes (Stage IVC in FIGO 2023) → palpable groin nodes. Pelvic/para-aortic nodes are not palpable.	Rare as a presenting sign.
Lower limb oedema	Pelvic lymph node metastasis or direct parametrial invasion compressing iliac veins → impaired venous/lymphatic drainage → lower limb oedema (usually unilateral initially).	Advanced disease.
Pallor	Chronic blood loss (prolonged abnormal vaginal bleeding) → iron deficiency anaemia → pallor of conjunctivae, nail beds.	Very common at presentation; check for anaemia.
Obesity, features of metabolic syndrome	These are risk factors rather than signs of the cancer itself, but they are commonly present in patients with Type I endometrial cancer (central obesity, acanthosis nigricans from insulin resistance, hirsutism in PCOS).	Observe the patient's body habitus — a clinical clue.

Clinical Approach to Abnormal Vaginal Bleeding

Classify based on anatomy → start from bottom, and move upwards: vagina → cervix → endometrium → ovaries ^[2]. For each level, think benign and malignant causes. The most common cause of endometrial bleeding is irregular ovulation causing irregular periods ^[2]. But always exclude malignancy — especially in the postmenopausal, obese, or high-risk patient.

Key Clinical Pearl — Early Detection

Unlike ovarian cancer (which typically presents late), endometrial cancer usually presents early because the uterine cavity is a "closed space" that drains through the cervix — even a small tumour causes bleeding that the patient notices. This is why 75% of cases are Stage I at diagnosis and the overall prognosis is favourable (5-year survival ~80%).

9. Precursor Lesions — Endometrial Hyperplasia

Since the hyperplasia → atypia → carcinoma continuum is central to understanding Type I endometrial cancer, it deserves its own section:

Endometrial hyperplasia is an abnormal proliferation of endometrial glands with an increase in the gland-to-stroma ratio. It results from chronic, unopposed oestrogen stimulation.

Category	Histological Features	Risk of Progression to Cancer
Hyperplasia without atypia	Gland crowding, cystic dilatation, but no nuclear atypia. Architecture may be simple or complex.	< 5% over 20 years
Atypical hyperplasia / EIN	Gland crowding with nuclear atypia (enlarged nuclei, prominent nucleoli, loss of polarity). This is the critical distinguishing feature.	~30–60% (and up to 40% already have coexistent carcinoma in the hysterectomy specimen)

Nuclear atypia reflects accumulated genetic mutations (especially PTEN loss) that have pushed the cell toward malignant transformation. Without atypia, the proliferation is just "overgrowth" that usually regresses with progesterone therapy. With atypia, the cells have already undergone neoplastic transformation and are on the verge of (or already at) cancer.

This is so high-yield it warrants a dedicated section. The commonest syndrome associated with endometrial cancer is Lynch syndrome ^[2].

Lynch syndrome (HNPCC) = germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM) ^[3].
Lifetime risk of endometrial cancer in Lynch syndrome: 15–60% — endometrial cancer is the most common extracolonic malignancy in Lynch syndrome ^[1]^[2]^[3].
Endometrial cancer may even be the first/sentinel malignancy that leads to diagnosis of Lynch syndrome.
Lynch-associated endometrial cancers tend to occur at a younger age (median ~50 vs ~63 for sporadic) and may be of lower uterine segment location (a clinical clue).
Screening for Lynch syndrome: Universal tumour testing with IHC for MMR proteins (MLH1, MSH2, MSH6, PMS2) and/or MSI testing is increasingly recommended for all endometrial cancers — similar to the approach in colorectal cancer ^[3].
Cancer screening in Lynch syndrome carriers ^[3]:
- Colorectal: colonoscopy Q1–2y from 20–25y
- Endometrial/ovarian: pelvic exam + endometrial biopsy Q1y from 30–35y; prophylactic TAH+BSO at the end of childbearing (~40y)*
- Gastric, urinary: as per guidelines

High Yield Summary

Definition: Malignant neoplasm of the endometrium; most common gynaecological cancer in HK and developed countries.

Epidemiology: Predominantly postmenopausal women (peak 55–65y). Rising incidence in HK due to obesity/metabolic syndrome.

Risk Factors (think "unopposed oestrogen"):

Endogenous: obesity (aromatase), PCOS (anovulation), early menarche, late menopause, nulliparity, oestrogen-secreting tumours (granulosa cell)
Exogenous: unopposed oestrogen HRT, tamoxifen (partial agonist in endometrium)
Genetic: Lynch syndrome (15–60% lifetime risk) — most important hereditary cause
Metabolic: DM, HTN (metabolic syndrome cluster)

Classification:

Type I (80%): Endometrioid, oestrogen-dependent, arises from atypical hyperplasia/EIN, PTEN/MSI/PIK3CA, good prognosis
Type II (20%): Serous/clear cell/carcinosarcoma, NOT oestrogen-dependent, arises from atrophic endometrium, TP53 mutation, poor prognosis

Molecular subtypes (TCGA): POLEmut (excellent), MSI-H/dMMR (intermediate), CN-low (intermediate-good), CN-high/p53abn (poor)

Clinical presentation: Postmenopausal bleeding (~90%) — most present early (Stage I) → overall good prognosis. Pre-menopausal: IMB, menorrhagia, irregular bleeding. Examination often normal in early disease.

Spread: Direct → lymphatic → transtubal/peritoneal → haematogenous (lung > liver > bone)

Active Recall - Endometrial Cancer (Definition to Clinical Features)

^[1] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p19, Risk factors and HK Cancer Registry) ^[2] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p1, p34 — common causes, risk factors, anatomy-based classification) ^[3] Senior notes: Ryan Ho GI.pdf (p182–183, Lynch syndrome, HNPCC, cancer screening recommendations)

Differential Diagnosis of Endometrial Cancer

Uterine sarcoma: postmenopausal growth or atypical bleeding/mass warrants evaluation; rapid growth is not diagnostic and MRI cannot reliably exclude leiomyosarcoma. Pathology considers atypia, mitotic activity and tumour-cell necrosis. Low-grade stromal sarcoma shows infiltrative tongues/vascular invasion, with molecular testing supporting classification.
Mucosal melanoma: vulvovaginal bleeding or a mass may be amelanotic. Biopsy with S100/SOX10 and melanocytic markers helps identify it; management needs a specialist melanoma/gynaecological MDT.
Gestational trophoblastic neoplasia: unexplained bleeding after any pregnancy requires hCG assessment. Choriocarcinoma often has markedly raised hCG; PSTT/ETT may produce relatively little hCG despite substantial disease. See gestational trophoblastic disease.

Source: CMB82 What not to miss in Gynecological cancers, pp. 3–11. These are differential-diagnosis red flags, not interchangeable endometrial-carcinoma pathways.

Endometrial cancer does not present with a pathognomonic sign. It presents with abnormal vaginal bleeding — most commonly postmenopausal bleeding (PMB), or irregular/heavy menstrual bleeding in premenopausal women. It can also present as a pelvic mass or be found incidentally on imaging. Therefore, the differential diagnosis is really the differential of:

Postmenopausal bleeding (PMB) — the most common and most important clinical scenario
Abnormal uterine bleeding (AUB) in premenopausal women
Pelvic mass (when endometrial cancer presents as an enlarged uterus)

Cancer is not the commonest cause → many many more benign causes ^[1]. Per-vaginal bleeding — separate answer into benign / malignant ^[1]. Classify based on anatomy → start from bottom, and move upwards: vagina → cervix → endometrium → ovaries ^[1].

Clinical Approach to Abnormal Vaginal Bleeding DDx

The lecture explicitly teaches an anatomical approach, starting from below and moving upward: vagina → cervix → endometrium → ovaries ^[1]. At each level, think of benign and malignant causes. This is the most systematic and least-likely-to-miss approach for exams and clinical practice.

PMB is the hallmark presentation of endometrial cancer. However, only ~10% of women with PMB actually have endometrial cancer. The other 90% have benign causes. Nevertheless, you must always exclude malignancy.

Anatomical Approach (Bottom-Up)

Anatomical Site	Benign Causes	Malignant Causes	Key Features / Why It Bleeds
Vulva / Vagina	Atrophic vaginitis (most common cause of PMB overall — ~60–70%), trauma, vaginal infection, vulvar dermatoses	Vulvar carcinoma, vaginal carcinoma (rare), vaginal metastasis (e.g. from endometrial or cervical cancer)	Atrophic vaginitis: Post-menopausal oestrogen withdrawal → vaginal epithelium thins and loses glycogen → becomes fragile, dry, inflamed → bleeds with minimal contact (intercourse, wiping). On speculum: thin, pale, friable mucosa with petechiae.
Cervix	Cervical polyp, cervicitis (infection), cervical ectropion (rare post-menopause)	Cervical carcinoma	Cervical polyp: Benign pedunculated growth from endocervical canal; bleeds because it is fragile and vascular. Visible on speculum. Cervical cancer: Irregular friable mass visible on speculum; typically postcoital bleeding (contact bleeding) rather than spontaneous PMB, but can overlap.
Endometrium	Endometrial polyp, endometrial hyperplasia (without atypia), endometrial atrophy (atrophic endometritis), endometritis (infection)	Endometrial carcinoma, endometrial stromal sarcoma	Endometrial polyp: Localised overgrowth of endometrial glands + stroma; bleeds because the surface is fragile and the polyp may outgrow its blood supply → surface erosion. Endometrial atrophy: Paradoxically, an atrophic thin endometrium can bleed because the thin vessels are fragile. Endometrial hyperplasia: Thickened, oestrogen-driven endometrium that sheds irregularly.
Myometrium	Uterine leiomyoma (fibroid) — though usually regress post-menopause; adenomyosis (rare post-menopause)	Uterine leiomyosarcoma	Fibroid: Submucosal fibroids distort the endometrial cavity and increase surface area → abnormal bleeding. Uncommon cause of PMB since fibroids atrophy after menopause. If a "fibroid" grows post-menopause, think leiomyosarcoma.
Ovary / Fallopian Tube	Oestrogen-secreting ovarian tumours (granulosa cell tumour, thecoma) → cause endometrial hyperplasia/cancer indirectly	Ovarian carcinoma (rarely presents with PV bleeding), fallopian tube carcinoma	Granulosa cell tumour: Autonomously produces oestrogen → endometrial stimulation → hyperplasia → bleeding. This is a cause of PMB and a risk factor for endometrial cancer itself.
Exogenous / Systemic	HRT-related breakthrough bleeding, anticoagulant therapy, bleeding diathesis (coagulopathy)	—	HRT: Especially in early months of starting HRT; breakthrough bleeding is common. If persistent, must exclude endometrial pathology. Anticoagulants: Don't cause bleeding de novo, but unmask underlying pathology — always investigate.

Critical Rule

Postmenopausal bleeding is most worrying, must require referral to be seen within a week ^[2]. Even though the most common cause is atrophic vaginitis (benign), you must exclude endometrial cancer. Never attribute PMB to "atrophy" without investigation — ACOG 2026 recommends ultrasound plus endometrial sampling for most PMB patients (see Diagnosis).

In premenopausal women, endometrial cancer is much rarer (~5% of cases occur before age 40), but it must still be considered in women with risk factors (obesity, PCOS, Lynch syndrome, tamoxifen use, prolonged anovulation).

The most common cause of endometrial bleeding is irregular ovulation causing irregular periods ^[1].

Change in menstrual pattern (irregular, prolonged, intermenstrual, irregular) is how endometrial cancer presents in premenopausal women — slightly different to cervical cancer (postcoital contact bleeding) ^[2].

The FIGO PALM-COEIN classification is the standard framework for abnormal uterine bleeding (AUB) in nongravid women of reproductive age ^[1]:

Category	Cause	Structural (PALM) or Non-structural (COEIN)	Relationship to Endometrial Cancer
P	Polyp	Structural	Endometrial polyps are benign but may harbour focal hyperplasia or carcinoma (especially in postmenopausal women on tamoxifen). Must biopsy if suspicious.
A	Adenomyosis	Structural	Endometrial glands within the myometrium. Causes menorrhagia/dysmenorrhoea. Not a precursor to endometrial cancer.
L	Leiomyoma (fibroid)	Structural	Submucosal fibroids cause heavy bleeding by distorting the endometrial cavity. Not premalignant, but must distinguish from leiomyosarcoma.
M	Malignancy and hyperplasia	Structural	This is endometrial cancer/hyperplasia itself.
C	Coagulopathy	Non-structural	Von Willebrand disease, platelet disorders, anticoagulant use → heavy menstrual bleeding.
O	Ovulatory dysfunction	Non-structural	Most common cause ^[1]. Anovulation → no progesterone → unopposed oestrogen → irregular shedding of endometrium. Common in PCOS, perimenopause, hypothyroidism. Chronic anovulation is also a risk factor for endometrial cancer.
E	Endometrial	Non-structural	Primary disorders of endometrial haemostasis (e.g. ↑ prostaglandins, ↑ fibrinolysis).
I	Iatrogenic	Non-structural	IUDs, hormonal contraception, anticoagulants.
N	Not otherwise classified	Non-structural	Catch-all for rare causes.

When to Suspect Endometrial Cancer in a Premenopausal Woman

Think endometrial cancer if the premenopausal woman has: obesity + PCOS + prolonged anovulation, tamoxifen use, Lynch syndrome family history, age > 40 with persistent AUB unresponsive to medical treatment, or persistent unexplained AUB. There is no universal premenopausal ultrasound thickness cutoff.

Advanced endometrial cancer or cancer with haematometra/pyometra can present as a pelvic mass. The DDx of a pelvic mass is important because uterine fibroid, ovarian mass and cancer are important differential diagnoses of pelvic mass ^[4]^[5].

Classify according to gynaecological and non-gynaecological. Non-gynaecological: separate into gastrointestinal, urological, retroperitoneal ^[3].

Category	Differential	Key Distinguishing Features
Gynaecological — Uterine	Uterine fibroid (leiomyoma)	Most common pelvic mass in women. Firm, irregular, mobile uterine mass. On USS: well-circumscribed, whorled hypoechoic mass. Key distinction: fibroids should shrink post-menopause; if growing post-menopause → suspect leiomyosarcoma or endometrial cancer filling the cavity.
	Adenomyosis	Diffusely enlarged, boggy, tender uterus. Typically causes dysmenorrhoea + menorrhagia.
	Endometrial cancer	Enlarged uterus filled with tumour ± blood/pus. Heterogeneous endometrial mass on USS with myometrial invasion.
	Uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma)	Rare. Rapidly growing "fibroid" in post-menopausal woman. LDH elevated. Cannot reliably distinguish from fibroid on imaging pre-operatively.
	Haematometra / Pyometra	Uterine cavity distended with blood/pus (cervical stenosis ± cancer obstructing cervical canal). Presents with pain, fever, enlarged tender uterus.
Gynaecological — Ovarian/Tubal	Ovarian cyst (functional, endometrioma, dermoid, cystadenoma)	Adnexal mass separate from uterus on bimanual exam. USS: cystic, unilocular (simple cyst) or complex features.
	Ovarian cancer	Adnexal mass with solid components, ascites, CA-125 elevated.
	Ectopic pregnancy	Don't forget about pregnancy → especially for teenage girls ^[3]. Positive β-hCG. Adnexal mass/tenderness.
Non-gynaecological — GI	Colorectal cancer / diverticular mass	Bowel symptoms (altered habit, rectal bleeding). Palpable per rectum.
	Appendiceal abscess	RIF mass, fever, preceding RIF pain.
Non-gynaecological — Urological	Distended bladder (urinary retention)	Midline, dull to percussion, disappears after catheterisation.
	Pelvic kidney	Usually incidental, asymptomatic.
Non-gynaecological — Retroperitoneal	Retroperitoneal sarcoma, lymphoma	Fixed, hard mass. Constitutional symptoms.
Other	Pseudocyst related to previous surgeries ^[3]	History of previous abdominal surgery; cystic mass on imaging.

D. Other Important Differentials to Consider in the Context of Endometrial Cancer

~5% of endometrial cancers have a synchronous primary ovarian cancer (usually both endometrioid histology).
This is particularly common in younger women.
Must be distinguished from endometrial cancer metastatic to the ovary (Stage IIIA) — the distinction affects staging, prognosis, and treatment. Clues to synchronous primaries (rather than metastasis): both low-grade, minimal myometrial invasion, different molecular profiles.

Endocervical adenocarcinoma can extend upward and mimic endometrial cancer.
Immunohistochemistry helps: cervical adenocarcinoma is typically p16-positive (HPV-driven) and ER/PR-negative, while endometrioid endometrial cancer is p16-negative and ER/PR-positive.

Rare. Breast cancer, colorectal cancer, gastric cancer can metastasise to the endometrium.
Always consider if the histology is unusual for a primary endometrial cancer.

Lynch syndrome ^[6]: endometrial cancer may be the sentinel cancer. Consider simultaneous screening for colorectal cancer (colonoscopy) and other Lynch-associated cancers.
Cowden's disease (PTEN germline mutation): associated with multiple hamartomas, thyroid disease, breast cancer, and risk of CA endometrium ^[7].
Inflammatory myopathies (dermatomyositis/polymyositis): associated with malignancy including cervical, ovarian cancers; endometrial cancer is less commonly reported but is part of the paraneoplastic spectrum ^[8].

Key DDx Principle for Exams

Do not diagnose atrophic vaginitis or "hormonal" bleeding without excluding endometrial cancer first. ACOG April 2026 recommends TVUS plus endometrial sampling for most patients with PMB, revising the old ultrasound-only ≤4 mm triage. Persistent/recurrent bleeding, focal lesions and inadequate samples require further evaluation. Premenopausal sampling is risk- and symptom-based. ACOG update.

Feature	Endometrial Cancer	Atrophic Vaginitis	Endometrial Polyp	Cervical Cancer	Uterine Fibroid
Typical age	Postmenopausal (55–65)	Postmenopausal	Any age, common peri/postmenopausal	40–55 (squamous), any age	Reproductive age (shrinks post-menopause)
Bleeding pattern	PMB, irregular heavy	Scanty, postcoital, continuous spotting	IMB, PMB	Postcoital contact bleeding	Menorrhagia, IMB
Pain	Usually painless (early)	Dyspareunia	Usually painless	May have pelvic pain	Dysmenorrhoea, pressure
Speculum	Blood at os, cervix looks normal	Thin, pale, friable vaginal mucosa	May see polyp at os	Visible cervical mass/ulcer	Normal cervix
TVUSS	Thickened, irregular endometrium; ± myometrial invasion	Thin endometrium ( < 4 mm)	Focal echogenic mass in cavity; feeding vessel on Doppler	Cervical mass	Well-defined hypoechoic myometrial mass
Biopsy	Malignant glands	N/A	Benign glands and stroma	Malignant squamous or glandular cells	N/A (smooth muscle on histology)
CA-125	May be mildly elevated (not diagnostic)	Normal	Normal	Normal (unless advanced)	Normal or slightly elevated
Risk factor overlap	Obesity, unopposed oestrogen, nulliparity, Lynch	Oestrogen deficiency (opposite!)	Tamoxifen, HRT	HPV infection (completely different)	Oestrogen-dependent (like Type I endo CA)

Cervical vs Endometrial Cancer – A Common Source of Confusion

Students often confuse the presentations. Remember: Endometrial cancer presents with menstrual-related bleeding (IMB, menorrhagia, PMB) — it is uterine bleed. Cervical cancer classically presents with postcoital contact bleeding ^[2]. The risk factors are completely different: endometrial = oestrogen-driven; cervical = HPV-driven. However, there can be overlap in presentation, and both must be considered in any woman with abnormal PV bleeding.

Tumour markers are not diagnostic of endometrial cancer but may help in the overall clinical picture:

Marker	Relevance	Notes
CA-125	May be elevated in advanced endometrial cancer (especially serous type with peritoneal spread). Also elevated in ovarian cancer, endometriosis, ascites, pleural effusion ^[9].	CA-125 is increased during menses → test done during first half of menstrual cycle ^[9]. Not used for screening or diagnosis of endometrial cancer. May be used for monitoring response/recurrence in serous type.
HE4	Serum marker that may complement CA-125 in distinguishing benign from malignant endometrial pathology.	Less affected by benign conditions than CA-125. Sometimes used alongside CA-125 in risk stratification algorithms.
β-hCG	Must be checked to exclude pregnancy (especially ectopic) in premenopausal women with PV bleeding. Also elevated in gestational trophoblastic disease.	Don't forget about pregnancy ^[3].

High Yield Summary

DDx of Endometrial Cancer = DDx of Abnormal PV Bleeding, approached anatomically:

Vulva/Vagina: Atrophic vaginitis (most common cause of PMB!), trauma, vulvar/vaginal carcinoma
Cervix: Cervical polyp, cervicitis, cervical carcinoma (contact bleeding, HPV-driven — different from endometrial CA)
Endometrium: Polyp, hyperplasia (without atypia), atrophic endometritis, endometrial cancer, endometrial stromal sarcoma
Myometrium: Fibroid (submucosal), adenomyosis, leiomyosarcoma
Ovary: Granulosa cell tumour (oestrogen-secreting → stimulates endometrium), ovarian cancer
Systemic: HRT-related, anticoagulants, coagulopathy

Key distinctions:

Endometrial CA = menstrual-type bleeding (PMB, IMB, menorrhagia); cervical CA = postcoital contact bleeding
Atrophic vaginitis = most common cause of PMB but must exclude cancer before attributing to this
PALM-COEIN for premenopausal AUB; most common cause = ovulatory dysfunction
Pelvic mass DDx: gynaecological (fibroids, ovarian masses, endo CA) vs non-gynaecological (GI, urological, retroperitoneal)
Always exclude pregnancy in premenopausal women
Lynch syndrome: endometrial CA may be the sentinel cancer → screen for CRC and other Lynch tumours

Active Recall - Differential Diagnosis of Endometrial Cancer

References

^[1] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p1 — common causes, anatomical approach, PALM-COEIN) ^[2] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p35 — symptom recognition, cervical vs endometrial bleeding patterns, PMB referral urgency) ^[3] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p17 — DDx for pelvic mass, pregnancy, pseudocyst) ^[4] Lecture slides: GC 118. Pelvic mass ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p71 — summary: fibroid, ovarian mass, cancer as DDx of pelvic mass) ^[5] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p40 — RMI, CA-125 limitations) ^[6] Senior notes: Ryan Ho GI.pdf (p182–183 — Lynch syndrome, extracolonic tumours, screening) ^[7] Senior notes: Ryan Ho Rheumatology.pdf (p169 — Cowden's disease, risk of CA endometrium + breast) ^[8] Senior notes: Ryan Ho Neurology.pdf (p194 — inflammatory myopathies associated with malignancy) ^[9] Senior notes: Maksim Medicine Notes.pdf (p337 — tumour markers, CA-125 interpretation)

Diagnosis of Endometrial Cancer

PMB update — April 2026: ACOG now recommends TVUS plus endometrial tissue sampling for most patients with postmenopausal bleeding. Its previous ultrasound-only reassurance pathway for an endometrium ≤4 mm has been revised. Older faculty notes use a 5 mm sampling threshold; label that as the older pathway. Persistent/recurrent bleeding, a focal lesion or inadequate assessment requires tissue evaluation regardless of stripe thickness. This is an ACOG update; local pathways may differ. ACOG announcement.

Unlike cervical cancer (Pap smear/HPV screening) or colorectal cancer (colonoscopy/FIT), there is no population-based screening programme for endometrial cancer. Why? Because the disease itself provides its own "screening symptom" — postmenopausal bleeding — which brings women to medical attention early. The vast majority (~75%) present at Stage I and have excellent survival. The cost-effectiveness of screening asymptomatic women has not been demonstrated.

For Lynch syndrome, specialist counselling may include periodic endometrial biopsy and risk-reducing surgery after childbearing; screening has not established a mortality benefit and does not replace prompt investigation of symptoms ^[6].

The diagnosis of endometrial cancer requires tissue — histological confirmation from endometrial biopsy is mandatory. Imaging alone is never sufficient for diagnosis.

There is no formal "diagnostic criteria" checklist like the Amsterdam criteria for Lynch syndrome. The diagnosis is made by:

Clinical suspicion: woman with abnormal vaginal bleeding (especially PMB), with or without risk factors
Imaging suggestive of endometrial pathology: transvaginal ultrasound (TVUSS) showing thickened endometrium
Histological confirmation: endometrial sampling (Pipelle biopsy, hysteroscopy + curettage) showing malignant glandular epithelium

The histological report must include:

Histological type (endometrioid, serous, clear cell, carcinosarcoma, etc.)
Grade (G1, G2, G3 for endometrioid; serous and clear cell are always high-grade by definition)
Depth of myometrial invasion (if hysterectomy specimen)
Lymphovascular space invasion (LVSI)
Cervical stromal involvement
Immunohistochemistry: ER, PR status; p53 status; MMR protein expression (MLH1, MSH2, MSH6, PMS2) for Lynch screening
Molecular classification (if available): POLE, MMR/MSI, p53, copy-number status

The clinical pathway depends on the presentation:

C. Investigation Modalities — Detailed Breakdown

History — this is your first and most important "investigation":

Recognise the symptoms ^[10]: change in menstrual pattern, prolonged bleeding, intermenstrual bleeding, irregular bleeding, postmenopausal bleeding ^[10]
Postmenopausal bleeding is most worrying, must require referral to be seen within a week ^[2]
Risk factor assessment: obesity, PCOS, nulliparity, HRT use, tamoxifen, Lynch syndrome family history, DM, HTN
Exclude non-endometrial causes: postcoital bleeding (cervical), dyspareunia (atrophic vaginitis), bowel/bladder symptoms (advanced disease)
Exclude pregnancy in premenopausal women

Physical Examination:

General: BMI, pallor (anaemia from chronic blood loss), signs of metabolic syndrome
Abdominal: masses, ascites, hepatomegaly (advanced disease)
Speculum: inspect vulva, vagina (atrophy? lesions?), cervix (mass? polyp? blood at os?). In early endometrial cancer, you typically see blood at the os but the cervix looks normal.
Bimanual: uterine size, mobility, tenderness; adnexal masses; parametrial thickening

Why TVUSS is the first-line imaging investigation: TVUSS is non-invasive, widely available, inexpensive, and highly sensitive for detecting endometrial thickening. It places the probe directly in the vagina (close to the uterus) → excellent resolution of the endometrium.

The older faculty threshold was ET ≥5 mm ^[10]^[11]. Current ACOG 2026 initial assessment generally combines ultrasound and sampling; thickness alone should not exclude biopsy.

Finding	Interpretation	Action
ET < 4–5 mm (postmenopausal)	Thin, atrophic endometrium. Risk of endometrial cancer is very low (NPV > 99% for a threshold of 4 mm, ~96% for 5 mm).	Thin endometrium lowers risk but is not a blanket exemption from sampling under ACOG 2026. Persistent/recurrent bleeding or high clinical risk requires tissue assessment.
ET ≥ 5 mm (postmenopausal)	Thickened endometrium — may represent hyperplasia, polyp, or cancer.	Endometrial sampling required ^[10]^[11].
Focal intracavitary mass	Likely endometrial polyp or submucosal fibroid.	Hysteroscopy + directed biopsy is ideal (Pipelle may miss a focal lesion).
Irregular/heterogeneous endometrium	Suspicious for malignancy — irregular thickening, areas of mixed echogenicity, disrupted endometrial-myometrial junction (suggesting myometrial invasion).	Urgent endometrial sampling.
Fluid in endometrial cavity	May indicate haematometra, pyometra (cervical stenosis), or intracavitary pathology. Measure ET excluding the fluid stripe.	Investigate the cause of fluid; sample the endometrium.
Myometrial invasion (advanced USS)	Disruption of the junctional zone, irregular endo-myometrial interface.	Suggestive of invasive cancer; MRI is better for assessing invasion depth for staging.

Know which pathway the threshold comes from

The faculty's 5 mm cutoff and the previous ACOG ≤4 mm reassurance rule describe older ultrasound-led pathways. Do not merge them into an imprecise “4–5 mm” current rule. ACOG 2026 recommends ultrasound plus sampling for most PMB presentations; a thin stripe alone cannot safely close the assessment.

Limitation of TVUSS

Remember: Type II serous carcinoma can arise from atrophic endometrium and may NOT cause significant endometrial thickening. Therefore, if a postmenopausal woman has persistent or recurrent PMB with a thin endometrium on TVUSS, she still needs endometrial sampling. Do not be falsely reassured by a "thin" stripe.

Premenopausal women: Endometrial thickness varies with the menstrual cycle (thinnest during menses, thickest in the secretory phase — can be 8–14 mm normally). There is no universally accepted ET threshold for premenopausal women. Instead, indications for biopsy are based on clinical risk factors and persistent symptoms rather than a single ET measurement. If USS is performed, it should ideally be in the early proliferative phase (days 4–6) when ET is thinnest.

3. Endometrial Sampling — The Diagnostic Cornerstone

From the uterus, common investigations would be to take biopsy from the endometrial lining ^[11].

There are several methods of obtaining endometrial tissue. The choice depends on the clinical scenario:

Endometrial sampling via Pipelle ^[11]: a thin (3 mm diameter) flexible plastic tube is inserted through the cervix into the uterine cavity. Suction is applied by withdrawing the internal piston, and a strip of endometrium is aspirated.

Aspect	Details
Setting	Can be done in clinic ^[11] — no anaesthesia needed (though can be uncomfortable). Quick ( < 5 minutes).
Sensitivity	~90–95% for detecting endometrial cancer in postmenopausal women with diffuse disease. Lower sensitivity for focal lesions (polyps, focal cancers) — may miss 5–15% of cancers.
Advantages	Simple, inexpensive, outpatient, no anaesthesia, low complication rate.
Limitations	Blind procedure — samples only a strip of endometrium; may miss focal pathology. May be non-diagnostic if insufficient tissue obtained (e.g. atrophic endometrium, cervical stenosis preventing passage).
When to use	Age over 40 — careful!! Need endometrial sampling (endometrial aspirate with samplers e.g. Pipelle) ^[10]. First-line for diffuse endometrial thickening or when focal pathology is not suspected.
When NOT to rely on it	If Pipelle is non-diagnostic, or focal intracavitary lesion on USS, or clinical suspicion remains high despite benign Pipelle → proceed to hysteroscopy + biopsy.

Hysteroscopy is gold standard for uterine lesion ^[10]^[11]. A hysteroscope (a thin telescope with a camera) is inserted through the cervix into the uterine cavity, allowing direct visualisation of the endometrial surface.

Aspect	Details
Setting	Can be done in clinic under minor sedation if just doing a look around and minor scraping, or under GA if wanting to perform a full polypectomy ^[11].
What it shows	Direct visualisation of: endometrial surface (colour, vascularity, irregularity), polyps, submucosal fibroids, areas of thickening/abnormality, cervical canal. Directed biopsies taken from suspicious areas.
Sensitivity	> 95% for endometrial cancer when combined with directed biopsy. Superior to Pipelle for focal lesions (polyps, focal cancers).
Advantages	See-and-treat approach (e.g. polypectomy at the same time). Allows directed biopsy of the most abnormal-looking areas. Can visualise the entire cavity.
Limitations	More invasive than Pipelle. Requires equipment, trained operator, and often a procedure room. Rare risks: perforation (~0.1%), infection, fluid overload (from distension medium).
When to use	Focal intracavitary lesion on USS; Pipelle non-diagnostic; persistent bleeding despite reassuring Pipelle; suspected submucosal fibroid or polyp requiring removal; pre-operative assessment.

Hysteroscopic findings suggestive of endometrial cancer:

Irregular, polypoid, or papillary mass(es)
Abnormal vascularity (tumour neovascularisation)
Friable tissue that bleeds on contact
Necrotic or ulcerated areas

Historically the standard, now largely replaced by outpatient Pipelle and hysteroscopy. Still used:

When cervical stenosis prevents Pipelle/hysteroscope passage
When combined with hysteroscopy under GA (hysteroscopy + D&C)
Disadvantage: blind, may miss focal lesions (same limitation as Pipelle but more tissue obtained)

Which Biopsy Method to Choose?

First-line in most clinical scenarios: Pipelle (quick, cheap, outpatient). If Pipelle is non-diagnostic, inconclusive, or there is a focal lesion on USS → hysteroscopy + directed biopsy (gold standard ^[10]^[11]). Think of Pipelle as the "triage" test and hysteroscopy as the "definitive" investigation.

Once tissue is obtained, the pathologist provides the definitive diagnosis. Key elements of the histopathology report:

Element	What It Tells You	Clinical Relevance
Histological type	Endometrioid, serous, clear cell, carcinosarcoma, etc.	Combine morphology with molecular classification; Bokhman Type I/II is a historical teaching model.
Grade (endometrioid only)	G1 ( ≤ 5% solid), G2 (6–50%), G3 ( > 50% solid)	Higher grade = worse prognosis, more aggressive behaviour, may alter adjuvant therapy.
Depth of myometrial invasion	< 50% vs ≥ 50% (on hysterectomy specimen)	Key staging parameter (IA vs IB). ≥ 50% invasion = higher risk of lymph node metastasis.
LVSI	Lymphovascular space invasion present or absent	Independent prognostic factor; substantial LVSI upstages in 2023 FIGO.
Cervical stromal involvement	Present or absent	If present → Stage II.
ER / PR status	Oestrogen/progesterone receptor expression	ER/PR positive = better prognosis; relevant for hormonal therapy (progestins for recurrence, or fertility-sparing Mx).
p53 IHC	Wild-type versus abnormal pattern (overexpression, null with intact internal controls, or cytoplasmic staining)	An abnormal pattern supports TP53 alteration; interpret with POLE/MMR to assign the molecular class. Do not report merely “p53 positive/negative”.
MMR protein IHC (MLH1, MSH2, MSH6, PMS2)	All 4 expressed (proficient) vs loss of 1 or more (deficient)	Loss of MMR proteins → suspect Lynch syndrome or sporadic MSI. If MLH1 lost → check MLH1 promoter methylation (if present = sporadic; if absent = likely Lynch → germline testing). This is the basis for universal MMR testing in endometrial cancers ^[6].
POLE mutation testing (if available)	POLE exonuclease domain mutation	POLE-mutated = excellent prognosis regardless of grade; may de-escalate adjuvant therapy.

Universal MMR/MSI testing is increasingly recommended on ALL endometrial cancers to identify Lynch syndrome — endometrial cancer may be the sentinel cancer that leads to the diagnosis, enabling cascade screening of family members for colorectal and other cancers ^[6].

5. Pre-operative / Staging Investigations

Once endometrial cancer is confirmed on biopsy, further investigations are needed to assess the extent of disease and fitness for surgery:

Blood test: CBP, RFT, LFT ^[12].

Test	Rationale
CBP (Complete Blood Picture)	Assess for anaemia from chronic blood loss (the patient has been bleeding). Also baseline before surgery.
RFT (Renal Function Tests)	Baseline renal function; detect hydronephrosis from ureteric obstruction in advanced disease.
LFT (Liver Function Tests)	Baseline; detect liver metastases (elevated ALP, GGT, bilirubin).
Glucose / HbA1c	Many patients have diabetes/metabolic syndrome (risk factor and comorbidity affecting surgical fitness).
Clotting profile	Pre-operative assessment; assess for coagulopathy contributing to bleeding.
Group and save / crossmatch	Pre-operative.

Tumour markers ^[12]:

Marker	Role in Endometrial Cancer
CA-125	May be elevated in advanced/serous endometrial cancer. Useful for monitoring treatment response and detecting recurrence in serous type. Not diagnostic. Normal CA-125 does not exclude endometrial cancer. CA-125 is for ovarian cancer, and adenocarcinoma in general ^[13] — in endometrial cancer, it is a supplementary investigation.
HE4	May complement CA-125; sometimes used in the ROMA algorithm alongside CA-125 for adnexal mass risk stratification, but less established in endometrial cancer specifically.

Tumour Markers Are NOT Diagnostic

CA-125 is not used to diagnose endometrial cancer. It is sometimes measured pre-operatively (especially if serous type or advanced disease) and can be useful for monitoring treatment response/recurrence. A normal CA-125 does not exclude cancer.

Imaging: CT / MRI / PET-CT to assess renal tract / extent of spread / lymph node involvement ^[12].

Modality	What It Assesses	When to Use
MRI Pelvis	Best imaging modality for local staging: depth of myometrial invasion (T2-weighted: tumour is intermediate signal against dark myometrium), cervical stromal involvement, parametrial extension, vaginal involvement. Also good for lymph node assessment (pelvic and para-aortic).	Standard pre-operative staging investigation in confirmed endometrial cancer. MRI allows the surgeon to plan the extent of surgery (e.g. whether lymph node dissection is needed based on suspected depth of invasion).
CT Chest / Abdomen / Pelvis	Distant metastases: lung (most common distant site), liver, peritoneal disease, lymphadenopathy (pelvic and para-aortic). Less accurate than MRI for local myometrial invasion assessment.	Often combined with MRI pelvis: MRI pelvis for local staging + CT chest/abdomen for distant staging. This is the standard combination in many centres.
PET-CT (or PET-MRI)	Highly sensitive for detecting lymph node metastases and distant disease. Combines metabolic (FDG uptake) and anatomical information.	Reserved for suspected advanced disease, recurrence, or when conventional imaging is equivocal. PET-MR if you have the money ^[13]. Not routinely used for early-stage disease.
Chest X-ray	Basic screen for lung metastases or pre-operative chest assessment.	May be used as a simple alternative to CT chest in low-risk, early-stage disease.
TVUSS (if not already done)	May assess myometrial invasion (junctional zone disruption) as a preliminary local assessment.	Already done as part of the initial diagnostic workup; MRI is superior for surgical planning.

MRI Pelvis — Key Findings in Endometrial Cancer:

MRI Finding	Significance
T2-weighted: intermediate-signal mass within the high-signal endometrial cavity	The tumour itself
Disruption of the junctional zone (the dark T2 line between endometrium and myometrium)	Suggests myometrial invasion; measure the depth of invasion relative to total myometrial thickness
Tumour invades ≥50% of myometrium	Important risk feature; FIGO 2023 stage also depends on histology, LVSI and molecular class
Tumour extending into cervical stroma	Stage II (disruption of the dark cervical stromal ring on T2)
Serosal/adnexal involvement	Usually IIIA, but FIGO 2023 IA3 permits a precisely defined low-grade uterine/ovarian presentation
Enlarged lymph nodes (short axis > 10 mm, round, necrotic)	Suspicious for nodal metastasis
Dynamic contrast-enhanced (DCE) MRI	Tumour enhances less than normal myometrium in early phase → helps delineate the tumour-myometrial interface and assess invasion depth

Since endometrial cancer patients are frequently obese with metabolic comorbidities (DM, HTN, cardiac disease), a thorough pre-operative assessment is essential:

Assessment	Purpose
Anaesthetic review	Airway assessment (obesity-related difficult airway), cardiopulmonary fitness
ECG	Baseline cardiac assessment; many patients have HTN/cardiac disease
Echocardiogram (if indicated)	If cardiac symptoms or significant comorbidity
Pulmonary function tests (if indicated)	If respiratory comorbidity
Optimisation	Diabetes control, anaemia correction (iron/transfusion), VTE risk assessment (high risk due to cancer + obesity + surgery)

A modern technique increasingly used in endometrial cancer surgery:

Indocyanine green (ICG) or blue dye/technetium-99m injected into the cervix
Lymphatic drainage traced to the first draining ("sentinel") node in the pelvis
SLN removed and sent for ultra-staging (serial sectioning + IHC → detects micrometastases and isolated tumour cells)
If SLN is negative → full lymphadenectomy may be avoided (reducing lymphoedema risk)
Increasingly adopted as an alternative to systematic pelvic lymphadenectomy in apparent early-stage disease

Phase	Investigation	Purpose
Initial Assessment	History + Examination	Clinical suspicion, risk factor identification, exclude non-uterine causes
First-line Imaging	Transvaginal USS	Assess thickness, focal lesions and myometrium; usually combine with sampling in PMB (ACOG 2026)
Tissue Diagnosis	Pipelle endometrial aspirate (outpatient)	First-line endometrial sampling ^[10]^[11]
	Hysteroscopy + directed biopsy (gold standard) ^[10]^[11]	If Pipelle non-diagnostic, focal lesion, or high clinical suspicion
Histopathology	H&E + IHC (ER, PR, p53, MMR) + Molecular (POLE)	Definitive diagnosis, typing, grading, molecular classification, Lynch screening
Staging	MRI Pelvis	Local staging: myometrial invasion depth, cervical involvement, parametrial extension
	CT Chest/Abdomen (± Pelvis)	Distant staging: lung, liver, peritoneal, lymph node metastases
	PET-CT/PET-MRI	Advanced or equivocal cases
Bloods	CBP, RFT, LFT, glucose, clotting	Baseline, comorbidity assessment, fitness for surgery ^[12]
Tumour Markers	CA-125 (± HE4)	Monitoring (not diagnostic), especially in serous type ^[12]^[13]
Pre-op Fitness	Anaesthetic review, ECG, etc.	Assess surgical fitness (high comorbidity burden in this population)

High Yield Summary

Diagnosis of Endometrial Cancer — Key Points:

No population-based screening — the symptom (PMB) itself prompts investigation; Lynch carriers require specialist risk counselling; periodic biopsy may be considered, with limited screening-outcome evidence.
PMB: ACOG 2026 recommends TVUS plus endometrial sampling for most patients; the faculty 5 mm threshold is older teaching.
Endometrial sampling: Pipelle (outpatient, first-line, ~90–95% sensitivity) → if non-diagnostic or focal lesion → Hysteroscopy + directed biopsy (gold standard) ^[10]^[11].
Histopathology must report: type, grade, myometrial invasion depth, LVSI, cervical involvement, ER/PR, p53, MMR IHC.
Universal MMR testing on all endometrial cancers → detect Lynch syndrome.
Staging: MRI pelvis (local) + CT chest/abdomen (distant) ± PET-CT.
Bloods: CBP, RFT, LFT, glucose. Tumour markers: CA-125 for monitoring (not diagnosis).
Type II serous cancer can arise from thin/atrophic endometrium — do not be falsely reassured by thin ET on TVUSS if clinical suspicion is high or bleeding persists.

Active Recall - Diagnosis of Endometrial Cancer

References

^[2] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p35 — symptom recognition, PMB referral urgency) ^[6] Senior notes: Ryan Ho GI.pdf (p182–183 — Lynch syndrome screening, endometrial surveillance in Lynch carriers) ^[10] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p7, p20 — recognise symptoms, investigations: age > 40 Pipelle, PMB TVUSS ≥ 5 mm, gold standard hysteroscopy) ^[11] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p11, p36 — Pipelle in clinic, hysteroscopy gold standard, TVUSS threshold 5 mm) ^[12] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p13 — bloods CBP/RFT/LFT, tumour markers, imaging CT/MRI/PET-CT) ^[13] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p21 — CA-125 for adenocarcinoma, MRI best for local staging, PET-MR)

Management of Endometrial Cancer

Adjuvant treatment is stage- and molecular-risk based. POLE mutation supports omission of adjuvant therapy in appropriately classified uterine-confined stage I–II disease; it does not mean observation for every stage III–IV POLE-mutated cancer. Use the 2025 ESGO–ESTRO–ESP risk groups, incorporating histology, LVSI, nodal status and molecular subtype.
Primary advanced/recurrent disease requiring systemic treatment: carboplatin–paclitaxel plus pembrolizumab or dostarlimab, then maintenance with the same checkpoint inhibitor, is an established first-line option in both dMMR and pMMR disease. Benefit is particularly large in dMMR. These are alternative regimens, not two checkpoint inhibitors given together. (Pembrolizumab approval; dostarlimab expanded indication.)
After previous systemic therapy: dMMR/MSI-H disease may receive single-agent PD-1 treatment if checkpoint-inhibitor naïve; pMMR disease may receive pembrolizumab–lenvatinib. Evidence from a pre-immunotherapy population does not establish automatic reuse after progression on first-line PD-1 treatment. Selected indolent ER-positive disease can receive endocrine therapy. (NCI treatment review.)
Staging edition matters: FIGO 2023 IVB = extrapelvic peritoneal spread; IVC = distant metastases. Older FIGO 2009 teaching tables used IVB for both. Medically inoperable localised disease can still receive definitive brachytherapy ± EBRT; inability to undergo surgery does not itself imply palliative treatment.

Before diving into the specifics, understand the overarching philosophy of endometrial cancer management:

Surgery is the cornerstone — goal again is to do surgery on everyone ^[14]. The primary treatment for endometrial cancer at any stage (when feasible) is surgical. Surgery is both therapeutic (removes the tumour) and diagnostic/staging (provides the definitive histopathological staging from the specimen).
Adjuvant therapy is risk-stratified — after surgery, the decision to give radiotherapy (RT), chemotherapy, or both depends on the risk group (determined by stage, grade, histological type, LVSI, molecular subtype).
Minimally invasive surgery is standard for early disease — unlike CA cervix, we have randomised trials demonstrating that for endometrial cancer, laparoscopic surgery is just as good as open ^[14]. This is a key teaching point: the LACE and LAP2 trials showed equivalent oncological outcomes with less morbidity for laparoscopic vs open hysterectomy in early-stage endometrial cancer.
Fertility-sparing management is an option for a select group of young women with low-grade, early-stage disease who wish to preserve fertility.
Non-surgical management (primary RT ± chemotherapy) is reserved for patients who are medically unfit for surgery or have inoperable advanced disease.

A. Surgical Management — The Primary Treatment

TH BSO ± lymphadenectomy (abdominal / laparoscopic) ^[14]^[15]

The standard operation is:

Component	What It Means	Why
Total Hysterectomy (TH)	Removal of the entire uterus (body + cervix)	Removes the primary tumour. Total (not subtotal) hysterectomy is needed because the cervix must be examined histologically for stromal invasion (Stage II).
Bilateral Salpingo-Oophorectomy (BSO)	Removal of both fallopian tubes and ovaries	(1) Ovaries are a common site of microscopic metastasis (even when grossly normal). (2) Removes the source of oestrogen production (important in oestrogen-driven Type I cancers). (3) Detects synchronous ovarian cancer (~5%).
± Lymphadenectomy / Lymph Node Assessment	Removal or sampling of pelvic ± para-aortic lymph nodes	Determines nodal stage (IIIC1/C2). The extent of lymph node dissection is determined by the pre-operative risk assessment (see below).
Peritoneal washings	Collection of peritoneal fluid for cytology	No longer part of FIGO staging (removed in 2009), but still commonly collected and reported. Positive cytology may influence adjuvant therapy decisions.

Breakdown of "TH": "Total" = Latin totus (whole) — the entire uterus including the cervix is removed. This is distinguished from a "subtotal" hysterectomy where the cervix is left behind (not appropriate for cancer). "Hyster-" = Greek hystera (uterus); "-ectomy" = Greek ektome (cutting out).

BSO breakdown: "Bilateral" = both sides; "salpingo-" = Greek salpinx (tube/trumpet, referring to the fallopian tube); "oophor-" = Greek oophoron (egg-bearing, i.e. ovary); "-ectomy" = excision.

Early disease (confined to the uterus) → laparoscopic hysterectomy is definitive treatment ^[14].

Approach	Indications	Advantages	Limitations
Laparoscopic / Robotic-assisted	Early disease confined to uterus ^[14]^[15]. Standard of care for Stage I–II in most centres.	Shorter hospital stay, less blood loss, fewer wound complications (important in obese patients), faster recovery, equivalent oncological outcomes (LACE trial, LAP2 trial).	Technically challenging in very large uteri, morbid obesity (though robotic platform helps), or suspected advanced disease requiring extensive debulking.
Open (Laparotomy)	Advanced disease requiring extensive debulking, very large uterus, suspected peritoneal disease, or when laparoscopic approach is not feasible.	Better access for cytoreduction, lymph node dissection in difficult cases.	Longer recovery, more wound complications (especially in obese patients), higher morbidity.

Why Laparoscopic Is Safe in Endometrial Cancer But NOT in Cervical Cancer

Unlike CA cervix, we have randomised trials demonstrating that for endometrial cancer, laparoscopic surgery is just as good as open ^[14]. The LACC trial showed that minimally invasive radical hysterectomy for cervical cancer had WORSE oncological outcomes (higher recurrence, lower survival) than open surgery — likely due to tumour spillage from the uterine manipulator and CO2 pneumoperitoneum effects on cervical tumour dissemination. However, in endometrial cancer, the tumour is contained within the uterine cavity (not on the cervical surface), so these concerns do not apply. The uterus is removed intact and the tumour is not exposed to the peritoneal cavity.

Depending on risk of LN metastasis (determined by grading preoperatively by MRI), will decide number of lymph nodes to remove ^[14]:

The risk of lymph node metastasis depends on:

Depth of myometrial invasion: < 50% → low risk (~5%); ≥ 50% → higher risk (~15–25%)
Grade: G1 → low risk; G3 → higher risk
Histological type: Serous/clear cell/carcinosarcoma → high risk regardless of apparent stage
LVSI: Present → higher risk
Tumour size: > 2 cm → higher risk

Strategy	When	What Is Done
No lymph node assessment	Low-risk disease: Grade 1–2 endometrioid, < 50% myometrial invasion on MRI, no LVSI, tumour ≤ 2 cm	Hysterectomy + BSO only. Risk of nodal disease is < 5%. The GOG-99 and PORTEC studies showed that lymphadenectomy does not improve survival in low-risk disease but does increase morbidity (lymphoedema, lymphocysts).
Pelvic lymph nodes only ^[14]	Intermediate-risk: deeper invasion or higher grade but apparently confined to uterus	Pelvic lymphadenectomy (obturator, internal/external iliac, common iliac nodes).
Pelvic + para-aortic lymph nodes ^[14]	High-risk: G3, deep myometrial invasion, serous/clear cell type, cervical involvement, or suspicious lymph nodes on imaging	Full pelvic + para-aortic lymphadenectomy (up to the renal vessels). Fundal tumours drain directly to para-aortic nodes via the infundibulopelvic ligament — hence the need for para-aortic dissection in high-risk cases.
Sentinel Lymph Node (SLN) Mapping	Increasingly used as an alternative to systematic lymphadenectomy in apparent early-stage disease	ICG or blue dye injected into cervix; SLN identified and excised; ultra-staged with serial sections + IHC. If SLN negative → avoid full lymphadenectomy → reduces lymphoedema. FIRES trial and SENTOR study support this approach. Becoming standard of care in many centres.

B. Adjuvant Therapy — Post-operative Risk Stratification

After surgery, the final surgical-pathological staging and risk grouping determines adjuvant treatment. If LN +ve, need post-op chemo ± RT. If high-risk group, even if LN −ve, can consider brachytherapy ± chemotherapy. If LN not done, give external RT if high risk ^[14]^[15].

These teaching groups are not a substitute for the complete 2025 molecular-risk algorithm above.

Risk Group	Criteria	Adjuvant Treatment
Low Risk	Stage IA, endometrioid, G1–G2, LVSI negative; OR completely resected uterine-confined stage I–II POLEmut disease	Observation only — no adjuvant therapy needed. Excellent prognosis (> 95% 5-year survival).
Intermediate Risk	Stage IA, endometrioid G3; OR Stage IB, endometrioid G1–G2, LVSI negative	Vaginal brachytherapy (VBT) alone — reduces vaginal cuff recurrence (the most common site of local recurrence) without the systemic side effects of EBRT or chemo.
High-Intermediate Risk	Stage IB, endometrioid G3, LVSI negative; OR Stage I–II with substantial LVSI; OR Stage II	EBRT ± vaginal brachytherapy — PORTEC-1 and GOG-99 trials defined this group. EBRT reduces pelvic recurrence but does not improve overall survival (because recurrences can be salvaged). Adding VBT boosts vaginal cuff control. Some centres now consider chemotherapy for this group (PORTEC-3 showed benefit of chemoRT over RT alone in high-risk).
High Risk	Stage III (any); Stage I–II serous, clear cell, carcinosarcoma; Stage I–II p53-abnormal; node-positive disease (stage IIIC, not stage I–II)	Chemotherapy ± EBRT ^[14]^[15]. PORTEC-3 trial showed that combined chemoRT (cisplatin during RT then carboplatin/paclitaxel adjuvant) improved failure-free survival in high-risk endometrial cancer compared to RT alone. This is the current standard for high-risk disease.
Advanced / Metastatic (FIGO 2023 IVB–IVC)	Extrapelvic peritoneal or distant metastases	Carboplatin–paclitaxel plus an appropriate PD-1 inhibitor, with biomarker-directed alternatives (see above). RT may be used for palliation (bleeding, pain).

Types of Adjuvant Therapy Explained

"Brachy-" = Greek brachys (short/close). Brachytherapy delivers radiation from a source placed directly inside the body — in this case, a cylinder placed into the vaginal vault.

Aspect	Details
What	A radioactive source (usually iridium-192) in a vaginal cylinder delivers high-dose radiation to the vaginal cuff and upper vagina.
Why	The vaginal cuff is the most common site of local recurrence after hysterectomy for endometrial cancer. VBT sterilises microscopic residual disease at the vaginal margin.
Advantages	Targeted, minimal toxicity to bowel/bladder (unlike EBRT), outpatient procedure, fewer GI/GU side effects.
Indications	Intermediate-risk disease; also used as a boost with EBRT in high-intermediate risk.
Side effects	Vaginal dryness, stenosis, mild dyspareunia. Minimal systemic toxicity.

Aspect	Details
What	Pelvic radiation delivered from an external machine to cover the pelvis (and sometimes para-aortic region).
Why	Sterilises microscopic disease in the pelvic lymph node basins, parametrium, and vaginal cuff.
Indications	High-intermediate and high-risk disease; if LN not done, give external RT if high risk ^[14]^[15] — because you don't know the nodal status, EBRT covers the pelvic nodes empirically.
Side effects	Acute: diarrhoea, cystitis, fatigue. Chronic: bowel stricture, radiation proctitis, lymphoedema, bone marrow suppression.

Why EBRT If Lymph Nodes Not Done?

If LN not done, need external RT to cover the pelvis ^[14]. The logic: if you did NOT perform lymphadenectomy, you do not know whether the pelvic lymph nodes harbour metastatic disease. EBRT covers the pelvic node basins prophylactically. If lymphadenectomy WAS performed and nodes are negative, you can de-escalate to VBT alone (or observation in low-risk). This is why adequate surgical staging (including lymph node assessment) helps avoid unnecessary RT.

Aspect	Details
Standard regimen	Carboplatin + Paclitaxel (Q3 weekly, typically 6 cycles). This is the backbone of systemic therapy for endometrial cancer.
Why these drugs?	Carboplatin: platinum-based DNA crosslinker → prevents DNA replication → cell death. Paclitaxel ("taxel" from Taxus = yew tree): stabilises microtubules → prevents mitotic spindle disassembly → cells arrested in mitosis → apoptosis. Together they are synergistic against gynaecological cancers.
Indications	If LN +ve, need post-op chemo ± RT ^[14]^[15]. Also for: Stage III–IV, serous/clear cell/carcinosarcoma, high-risk molecular subtype (p53-abnormal), recurrent disease.
Side effects	Myelosuppression (neutropenia, thrombocytopenia), peripheral neuropathy (paclitaxel), nephrotoxicity (carboplatin — less so than cisplatin), alopecia, nausea/vomiting.

PORTEC-3 trial (landmark): Compared adjuvant EBRT alone vs chemoRT (concurrent cisplatin + sequential carboplatin/paclitaxel) in high-risk endometrial cancer. Results: chemoRT improved failure-free survival (particularly in serous cancers and Stage III disease), with a trend toward improved overall survival. This has made combined chemoRT the standard for high-risk disease.

Aspect	Details
Agents	Medroxyprogesterone acetate (MPA) or megestrol acetate (high dose, oral); Levonorgestrel IUS (Mirena).
Mechanism	Progesterone opposes oestrogen-driven proliferation → induces secretory differentiation and apoptosis of endometrial glands → tumour regression. Only works in ER/PR-positive, low-grade endometrioid cancers (Type I).
Indications	(1) Fertility-sparing management of young women with Grade 1 endometrioid cancer/atypical hyperplasia confined to the endometrium (Stage IA, no myometrial invasion). (2) Palliative treatment in recurrent/metastatic ER-positive disease in patients unfit for chemotherapy. (3) Primary treatment in medically unfit patients who cannot undergo surgery.
Contraindications	Type II cancers (serous, clear cell — ER/PR negative, will not respond). High-grade disease. Any myometrial invasion.
Response rate	~70–80% complete response in well-selected cases (Grade 1, ER/PR-positive, no invasion).

Setting	Treatment and selection
Primary advanced/recurrent cancer requiring systemic treatment	Carboplatin–paclitaxel + pembrolizumab or dostarlimab, followed by maintenance with the selected PD-1 inhibitor, regardless of MMR status.
dMMR/MSI-H disease after prior treatment, checkpoint-inhibitor naïve	Single-agent pembrolizumab or dostarlimab can be appropriate.
pMMR advanced/recurrent disease after prior systemic treatment	Pembrolizumab + lenvatinib; account for prior immunotherapy, fitness and toxicity. This is not the routine replacement for first-line chemo-immunotherapy.

Sources and sequencing qualifications are given in the current treatment section above.

Agent	Mechanism	Indication
Trastuzumab (anti-HER2)	Monoclonal antibody against HER2/ERBB2 → blocks HER2 signalling → inhibits tumour growth.	HER2-positive serous endometrial cancer (~25–30% are HER2-amplified). Added to carboplatin/paclitaxel.
Everolimus / Temsirolimus (mTOR inhibitors)	Inhibit PI3K/AKT/mTOR pathway — frequently activated in endometrioid cancers (PTEN loss → PI3K hyperactivity).	Recurrent endometrial cancer; often combined with hormonal therapy (letrozole + everolimus).

This applies to a very select group of patients:

Eligibility Criteria (strict):

Age: young woman desiring future fertility
Histology: Grade 1 endometrioid adenocarcinoma (confirmed on hysteroscopy + curettage)
No myometrial invasion on MRI (Stage IA, confined to endometrium)
ER/PR positive
No extrauterine disease
No contraindications to progestin therapy
Willing to undergo close surveillance

Protocol:

High-dose progestins: oral MPA (400–600 mg/day) or megestrol (160–320 mg/day), ± levonorgestrel IUS (Mirena)
Repeat endometrial sampling at 3–6 months to assess response
If complete response (no residual cancer/atypia on biopsy) → attempt conception (with or without assisted reproductive technology)
After completion of childbearing → definitive TH + BSO (cancer recurrence rate is ~30–40% even after initial complete response)
If no response or progression at 6 months → proceed to hysterectomy

Fertility-Sparing Is Temporary, Not Curative

Fertility-sparing management is a bridge to allow childbearing — it is NOT definitive treatment. The recurrence rate is high (~30–40%), and all patients should ultimately undergo hysterectomy after completing their family. Close surveillance with repeat biopsies is mandatory.

Many endometrial cancer patients are obese with significant comorbidities (DM, HTN, cardiac disease, respiratory disease) and may not tolerate surgery. Options:

Option	Details
Primary radiotherapy (EBRT ± brachytherapy)	Can achieve local control with cure intent. Less effective than surgery but reasonable alternative. 5-year survival ~60–70% for early-stage disease treated with RT alone.
Hormonal therapy (progestins)	For Grade 1 ER/PR-positive disease. Palliative/disease control in those truly unfit for any other treatment.
Optimise and operate	Consider aggressive medical optimisation (weight loss, cardiac workup, anaesthetic input) → some patients initially deemed "unfit" can be made fit for minimally invasive surgery.

Scenario	Management
Stage III (pelvic/para-aortic LN, adnexal/serosal involvement)	Surgical debulking (TH + BSO + lymphadenectomy + omentectomy if serous) → adjuvant chemotherapy (carboplatin/paclitaxel) ± EBRT.
Stage IVA (bladder/bowel invasion)	Consider pelvic exenteration if localised and patient fit. Otherwise, chemoRT or palliative chemotherapy.
FIGO 2023 IVB–IVC (extrapelvic peritoneal/distant disease)	Systemic treatment as above: carboplatin–paclitaxel + pembrolizumab or dostarlimab, then maintenance; selected HER2-positive serous disease may receive trastuzumab-based treatment. Consider endocrine therapy for indolent ER-positive disease and RT for symptom control.
Vaginal cuff recurrence (isolated)	If no prior RT → curative salvage RT (EBRT + brachytherapy) — 5-year survival ~50–70%. If prior RT → consider surgical resection or reirradiation (limited).
Distant recurrence	Systemic therapy as above ± palliative care.

Stage	Surgery	Adjuvant Therapy
IA, G1–G2, endometrioid, LVSI−	TH + BSO (laparoscopic); no LN assessment needed	Observation
IA G3, or IB G1–G2	TH + BSO + SLN or pelvic LN	VBT (intermediate risk); EBRT ± VBT if high-intermediate
IB G3, or Stage II	TH + BSO + pelvic ± para-aortic LN	EBRT ± VBT ± chemotherapy
Stage III	TH + BSO + full LN + cytoreduction	Chemotherapy ± RT ^[14]^[15]
Serous / Clear cell / Carcinosarcoma (any stage)	TH + BSO + full staging (LN + omentectomy + peritoneal biopsies)	Chemotherapy ± RT (treat like ovarian cancer staging); add trastuzumab if HER2+ serous
Stage IVB–IVC (2023)	Consider surgery for palliation/debulking	Systemic chemotherapy ± immunotherapy ± targeted therapy ± palliative RT
Young, Grade 1, no invasion, fertility desired	No surgery initially	Progestins → surveillance → definitive surgery after childbearing
Medically unfit	—	Primary RT or hormonal therapy

Timeframe	Surveillance
Years 1–3	Every 3–4 months: history, physical exam (speculum + bimanual), vaginal cuff cytology (not routine everywhere). Symptom-directed imaging.
Years 3–5	Every 6 months
After 5 years	Annually
What to monitor	Vaginal cuff recurrence (most common site of local recurrence), pelvic symptoms, distant recurrence symptoms (cough, bone pain), late RT effects, lymphoedema.
Imaging	Not routine unless symptomatic. CT/PET if recurrence suspected.
CA-125	May be monitored in serous type (if elevated at baseline).

High Yield Summary

Management of Endometrial Cancer — Exam Essentials:

Surgery is the primary treatment: TH + BSO ± lymphadenectomy ^[14]^[15].
Laparoscopic hysterectomy for early disease ^[14] — proven equivalent to open in RCTs (unlike cervical cancer where open is superior).
Lymph node assessment: risk-stratified by pre-op MRI grading ^[14] — low risk: none or SLN; intermediate: pelvic LN only; high risk: pelvic + para-aortic LN ^[14].
Adjuvant therapy:
- LN +ve → chemo ± RT ^[14]^[15]
- LN −ve, high risk → brachytherapy ± chemo ^[14]^[15]
- LN not done → external RT ^[14]^[15]
- Low risk, LN −ve → observation
Chemotherapy backbone: carboplatin + paclitaxel.
Immunotherapy: pembrolizumab (± lenvatinib) for dMMR/MSI-H or pMMR advanced/recurrent disease.
Fertility-sparing: Grade 1 endometrioid, no invasion, ER/PR+, progestins → surveillance → definitive surgery after childbearing.
Molecular classification now guides adjuvant therapy: POLE-mutated → may de-escalate; p53-abnormal → escalate.

Active Recall - Management of Endometrial Cancer

References

^[6] Senior notes: Ryan Ho GI.pdf (p182–183 — Lynch syndrome management, prophylactic TAH+BSO, cancer screening) ^[14] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p40 — treatment: TH BSO ± lymphadenectomy, laparoscopic surgery, LN risk stratification, post-op adjuvant therapy algorithm) ^[15] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p22 — FIGO staging, treatment: TH BSO ± lymphadenectomy, adjuvant chemo/RT based on LN status and risk)

Complications of Endometrial Cancer

Complications of endometrial cancer can be categorised into three groups:

Complications of the disease itself (untreated or advanced endometrial cancer)
Complications of treatment (surgery, radiotherapy, chemotherapy, hormonal therapy, immunotherapy)
Complications of recurrence

Understanding why each complication occurs — tracing it back to the pathophysiology or the mechanism of injury from treatment — is far more useful than rote memorisation.

A. Complications of the Disease Itself

These complications arise from the tumour's local effects, regional spread, and distant metastasis. Think about what the tumour is doing anatomically and how it disrupts normal physiology.

Complication	Mechanism	Clinical Features
Chronic blood loss → Iron deficiency anaemia	The tumour is friable and highly vascular (angiogenesis is a hallmark of cancer). It continuously bleeds into the uterine cavity → chronic PV blood loss → progressive iron depletion → microcytic hypochromic anaemia.	Pallor, fatigue, dyspnoea on exertion, tachycardia. May be severe at presentation — always check Hb.
Haematometra / Pyometra	Tumour (or age-related cervical stenosis in elderly women) obstructs the cervical canal → blood (haematometra) or infected fluid (pyometra) accumulates under pressure in the uterine cavity. Trapped fluid becomes a culture medium for bacteria → secondary infection.	Enlarged, tender uterus; lower abdominal pain; fever and sepsis (if pyometra). May present as an acute abdomen if uterine perforation occurs.
Uterine perforation	Tumour invades through the full thickness of the myometrium and serosa, or a pyometra ruptures through a thinned, tumour-weakened uterine wall.	Acute abdomen, peritonitis, free fluid on imaging. Surgical emergency.
Ureteric obstruction → Hydronephrosis → Renal impairment	Tumour or bulky pelvic lymph nodes compress or invade the ureters (which run through the parametrium close to the uterine arteries — "water under the bridge"). Bilateral obstruction → post-renal acute kidney injury.	Flank pain, rising creatinine, oliguria/anuria. TVUSS or CT shows dilated renal collecting system. May require ureteric stenting or nephrostomy.
Vesicovaginal or rectovaginal fistula	Advanced tumour (Stage IVA) invading through the bladder or rectal wall creates an abnormal communication.	VVF: continuous urinary incontinence, pneumaturia. RVF: passage of faeces/flatus per vagina, recurrent UTIs. Devastating impact on quality of life.
Pelvic pain and nerve compression	Tumour invades parametrium, pelvic sidewall, or compresses the lumbosacral plexus or obturator nerve.	Pelvic pain, sciatica-like leg pain, lower limb weakness/numbness.
Lower limb swelling ^[16]	Due to lymphatic invasion impeding lymphatic return ^[16]. Bulky pelvic lymph node metastases or direct tumour invasion of iliac vessels → obstruction of lymphatic and venous drainage from the lower limbs.	Unilateral or bilateral lower limb oedema. May also be caused by DVT (see below).
Deep vein thrombosis (DVT) / Pulmonary embolism (PE)	Virchow's triad: (1) Cancer is a hypercoagulable state (tumour secretes tissue factor, inflammatory cytokines → activate coagulation cascade). (2) Pelvic mass compresses iliac veins → venous stasis. (3) Immobility (advanced disease).	Unilateral leg swelling/pain (DVT); acute dyspnoea, pleuritic chest pain, haemodynamic collapse (PE). Endometrial cancer patients are at high VTE risk — thromboprophylaxis is essential peri-operatively.

Endometrial cancer most commonly metastasises to lung > liver > bone (haematogenous) and peritoneum (transtubal/direct) ^[17].

Site of Metastasis	Complications	Mechanism
Lung	Dyspnoea, cough, haemoptysis, pleural effusion	Common primary sites for lung secondaries include uterus ^[18]. Tumour deposits replace lung parenchyma or cause malignant pleural effusion (tumour implants on pleural surface → increased capillary permeability + lymphatic obstruction → fluid accumulation).
Liver	Right upper quadrant pain, hepatomegaly, jaundice, ascites, deranged LFTs	Tumour replaces hepatocytes → impaired synthetic function; obstructs intrahepatic bile ducts → cholestasis; portal hypertension from tumour infiltration → ascites.
Bone	Bone pain, pathological fracture, malignant hypercalcaemia, cord compression ^[17]	Endometrial cancer bone mets are usually osteolytic (tumour secretes factors that activate osteoclasts → bone resorption → structural weakening → fracture; osteoclast activation → calcium release → hypercalcaemia). Vertebral mets may collapse or extend posteriorly into the spinal canal → cord compression (oncological emergency).
Peritoneum	Ascites, bowel obstruction, carcinomatosis	Particularly common in serous type (transtubal dissemination). Tumour implants on peritoneal surfaces → exudative ascites, omental caking, bowel surface deposits → mechanical obstruction.
Brain (rare)	Headache, seizures, focal neurological deficits, personality change	Space-occupying lesion → raised intracranial pressure and local brain compression. More common in advanced/serous type.

Complication	Mechanism
Cancer cachexia	Pro-inflammatory cytokines (TNF-α, IL-6, IL-1) produced by tumour and host immune response → skeletal muscle wasting, adipose tissue loss, anorexia. Late feature of advanced disease.
Anaemia of chronic disease	Inflammatory cytokines → hepcidin upregulation → iron sequestration in macrophages → reduced iron availability for erythropoiesis. Superimposed on iron deficiency from chronic blood loss.
Hypercoagulability (Trousseau syndrome)	Tumour-derived tissue factor and mucins activate the coagulation cascade → migratory thrombophlebitis, DVT/PE, DIC.
Dermatomyositis / Polymyositis (rare)	Paraneoplastic inflammatory myopathy. Endometrial cancer is an uncommon association, but gynaecological cancers (especially cervical and ovarian) are recognised associations in this locality. The mechanism involves cross-reactive immune response between tumour antigens and muscle antigens.

B. Complications of Treatment

1. Complications of Surgery (TH + BSO ± Lymphadenectomy)

Total hysterectomy with bilateral salpingo-oophorectomy, ± lymphadenectomy ^[14]. As with any major pelvic surgery, complications can be classified by timing:

Complication	Mechanism	Notes
Bleeding	Injury to uterine artery, ovarian vessels, or presacral venous plexus during dissection.	Risk increases with bulky uterus, obesity (difficult exposure), prior surgery (adhesions).
Injury to adjacent organs	Ureter, bladder, and bowel are in close anatomical proximity to the uterus. The ureter runs within 1–2 cm of the uterine artery ("water under the bridge") and is at risk during clamping of the uterine pedicles. Bladder is adherent to the anterior lower uterine segment (especially if prior caesarean sections).	Ureteric injury: most feared complication — if unrecognised → urinoma, hydronephrosis, renal loss. Bladder injury: if recognised → primary repair; if not → vesicovaginal fistula. Bowel injury: rare unless adhesions or advanced tumour; if recognised → primary repair; if not → faecal peritonitis.
Anaesthetic complications	Obese patients with metabolic comorbidities → higher risk of difficult airway, aspiration, cardiovascular instability under anaesthesia.	Thorough pre-operative optimisation is essential.

Complication	Mechanism	Notes
Haemorrhage	Reactionary (within 24h — slipped ligature, dislodged clot) or secondary (days 7–14 — infection eroding a vessel).	Watch for tachycardia, hypotension, abdominal distension, vaginal bleeding. May require return to theatre.
Infection	Wound infection (especially in obese patients), pelvic abscess/collection, urinary tract infection (from catheterisation), chest infection.	Prophylactic antibiotics given at induction. Risk factors: obesity, DM, immunosuppression, prolonged surgery.
Venous thromboembolism (DVT/PE)	Cancer surgery + pelvic dissection + immobility + obesity = extremely high VTE risk. Virchow's triad is fully activated.	This is the most important preventable cause of post-operative death in gynaecological cancer surgery. VTE prophylaxis is mandatory: mechanical (TED stockings, pneumatic compression) + pharmacological (LMWH) for ≥ 28 days post-operatively.
Vaginal cuff dehiscence	The vaginal vault is sutured closed after hysterectomy. If healing is poor (infection, early resumption of activity, tissue ischaemia) → the suture line breaks down → vaginal evisceration (bowel protruding through the vagina).	Rare but dramatic. More common with laparoscopic hysterectomy (electrothermal tissue damage at the cuff). Presents with sudden vaginal pressure, bleeding, or visible bowel. Surgical emergency.
Ileus / Bowel obstruction	Post-operative ileus is common after pelvic surgery (bowel handling, peritoneal irritation → temporary bowel dysmotility). Adhesive small bowel obstruction can occur later.	Abdominal distension, nausea, absent bowel sounds. Usually resolves with conservative management.
Urinary retention	Disruption of autonomic nerve supply to the bladder during pelvic dissection (particularly after radical hysterectomy or extensive parametrial dissection).	Usually transient. Catheter drainage until bladder function recovers.

Complication	Mechanism	Notes
Lymphoedema	Removal of pelvic ± para-aortic lymph nodes disrupts lymphatic drainage from the lower limbs → lymph fluid accumulates in subcutaneous tissues. Lymphoedema: ↑risk if axillary RT ^[19] — the same principle applies to pelvic lymphadenectomy ± pelvic RT.	Chronic, progressive leg swelling. Affects 5–25% of patients after pelvic lymphadenectomy. Worsened by adjuvant pelvic RT (fibrosis of remaining lymphatic channels). Management: compression garments, manual lymphatic drainage, physiotherapy, skin care (prevent cellulitis).
Lymphocyst	Lymphatic fluid accumulates in a closed space after lymphadenectomy → cystic collection in the pelvis.	Usually asymptomatic and self-resolving. If symptomatic (pain, ureteric compression, infection) → percutaneous drainage ± sclerotherapy.
Surgical menopause	BSO removes the ovaries → abrupt loss of oestrogen (in premenopausal women). Unlike natural menopause (gradual decline), surgical menopause is immediate and more severe.	Vasomotor symptoms (hot flushes, night sweats), vaginal dryness, mood disturbance, accelerated bone loss (osteoporosis), cardiovascular risk increase. HRT is generally contraindicated in endometrial cancer survivors (oestrogen-dependent cancer), though low-dose vaginal oestrogen for urogenital symptoms may be considered in selected cases.
Adhesions → bowel obstruction	Post-surgical inflammatory response → fibrous adhesions between loops of bowel and pelvic structures.	Late presentations with colicky abdominal pain, vomiting, absolute constipation. May require surgical adhesiolysis.
Vaginal cuff granulation / shortened vagina	Healing by secondary intention at the vaginal cuff → granulation tissue. Loss of uterine length → shorter vagina.	May cause post-coital spotting. Granulation tissue treated with silver nitrate cautery. Shortened vagina may cause dyspareunia.
Sexual dysfunction	Multifactorial: shortened vagina, vaginal dryness (surgical menopause), psychological impact, altered body image, partner relationship changes.	Common but under-reported. Sensitive counselling, vaginal dilators, lubricants, psychosexual support.

SLN Mapping Reduces Lymphadenectomy Complications

Sentinel lymph node mapping (ICG-guided) is increasingly replacing systematic pelvic lymphadenectomy in apparent early-stage disease. By removing only the first draining node(s), the risk of lymphoedema and lymphocyst formation is significantly reduced while maintaining staging accuracy. This is a major quality-of-life improvement for patients.

2. Complications of Radiotherapy

Both external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) have side effects. The key principle is that radiation damages rapidly dividing cells — this includes tumour cells but also normal tissues in the radiation field (bowel mucosa, bladder urothelium, vaginal epithelium, bone marrow).

Complication	Mechanism	Management
Radiation proctitis / enteritis	Bowel mucosa in the pelvic radiation field is damaged → inflammation, oedema, mucosal ulceration. Small bowel and rectosigmoid are most affected.	Diarrhoea, tenesmus, rectal bleeding, abdominal cramps. Mx: low-residue diet, loperamide, topical steroids (rectal).
Radiation cystitis	Bladder urothelium is damaged → inflammation, haemorrhagic cystitis.	Dysuria, frequency, haematuria. Mx: hydration, anticholinergics, occasionally hyperbaric oxygen for refractory cases.
Vaginal inflammation and discharge	Vaginal mucosa in the brachytherapy field is irradiated → mucosal inflammation.	Vaginal discharge, discomfort. Mx: sitz baths, topical oestrogen (if permissible).
Fatigue	Systemic inflammatory response to radiation, bone marrow suppression, psychological factors.	Very common (~80%). Mx: graded exercise, energy conservation.
Myelosuppression	Pelvic bone marrow (a major haematopoietic site in adults) is in the radiation field → reduced red cell, white cell, and platelet production.	Monitor CBP. May require dose modification or treatment breaks.
Skin reaction (EBRT)	Radiation dermatitis — erythema, desquamation of skin in the treatment field.	Skin care, aqueous cream, avoid irritants.

Complication	Mechanism	Management
Radiation fibrosis of bowel	Chronic radiation damage → fibroblast activation → collagen deposition → bowel wall fibrosis and stricturing. Damaged submucosal vasculature → chronic ischaemia → mucosal fragility.	Chronic diarrhoea, rectal bleeding, bowel stricture → obstruction, fistula formation (rectovaginal, enterovaginal). May require surgical intervention.
Vaginal stenosis	Radiation-induced fibrosis of the vaginal wall → narrowing and shortening of the vagina.	Dyspareunia, difficulty with vaginal examination. Prevention is key: regular use of vaginal dilators post-RT + topical oestrogen.
Vaginal dryness and atrophy	Radiation destroys vaginal epithelium and glandular tissue → loss of lubrication and elasticity. Exacerbated by surgical menopause (no oestrogen).	Lubricants, vaginal moisturisers, low-dose vaginal oestrogen (if oncologically safe).
Pelvic insufficiency fracture	Radiation damages osteoblasts and vasculature of pelvic bones → osteoporosis → insufficiency fractures of sacrum, pubic rami.	Pelvic pain, difficulty walking. MRI/bone scan for diagnosis. Mx: analgesia, calcium/vitamin D, bisphosphonates.
Secondary malignancy	Radiation-induced DNA damage in normal tissues → long-term risk of second cancers (e.g. rectal cancer, bladder cancer, sarcoma) in the irradiated field. Latency: typically 5–20 years.	Rare but important. Risk ~1–2% over 20 years. Surveillance.
Ureteric stricture	Radiation fibrosis encasing the ureters → progressive narrowing → hydronephrosis.	Monitoring of renal function. May require stenting.

Brachytherapy Has Fewer Complications Than EBRT

Vaginal brachytherapy (VBT) delivers radiation to a small, targeted volume (the vaginal cuff) → minimal dose to bowel, bladder, and bone marrow. This is why VBT has significantly fewer GI/GU side effects than EBRT and is preferred for intermediate-risk disease where only vaginal cuff recurrence (not pelvic node coverage) is the concern.

Complication	Drug	Mechanism
Myelosuppression (neutropenia, thrombocytopenia, anaemia)	Both (more with carboplatin)	Platinum and taxanes damage rapidly dividing haematopoietic progenitor cells in bone marrow. Neutropenia → risk of febrile neutropenia (oncological emergency — fever + ANC < 0.5 × 10⁹/L → broad-spectrum antibiotics immediately).
Peripheral neuropathy	Paclitaxel > carboplatin	Paclitaxel: stabilises microtubules in peripheral nerve axons → disrupts axonal transport → distal sensory neuropathy (glove-and-stocking distribution: numbness, tingling, burning in fingers and toes). May be cumulative and partially irreversible. Carboplatin: damages dorsal root ganglia.
Nephrotoxicity	Carboplatin (less than cisplatin)	Platinum compounds are directly toxic to renal tubular epithelial cells. Carboplatin is dosed by AUC using the Calvert formula (based on GFR) to minimise renal toxicity. Pre-hydration is less critical than with cisplatin but renal function must be monitored.
Nausea and vomiting	Both (carboplatin = moderately emetogenic)	Platinum stimulates enterochromaffin cells in GI tract → 5-HT3 release → triggers chemoreceptor trigger zone (CTZ) and vomiting centre. Mx: triple antiemetic regimen (5-HT3 antagonist + dexamethasone + NK1 antagonist).
Alopecia	Paclitaxel	Damage to rapidly dividing hair follicle matrix cells → hair loss. Usually reversible after treatment completion. Scalp cooling may reduce severity.
Hypersensitivity reactions	Both (paclitaxel > carboplatin)	Paclitaxel: dissolved in Cremophor EL (polyoxyethylated castor oil) → can trigger anaphylactoid reactions. Pre-medication with dexamethasone + diphenhydramine + ranitidine. Carboplatin: true allergic reactions (Type I hypersensitivity) increase with repeated cycles (> 6 cycles).
Cardiotoxicity	Rare with this regimen	Not a major concern with carboplatin/paclitaxel (unlike doxorubicin). Paclitaxel can cause transient bradycardia and AV block.

Complication	Mechanism	Notes
Immune-related adverse events (irAEs)	Anti-PD-1 antibodies release the "brakes" on the immune system → T cells attack not only tumour but also normal tissues → autoimmune-like inflammation in virtually any organ.	Colitis (diarrhoea, bloody stool), hepatitis (↑ transaminases), pneumonitis (cough, dyspnoea), thyroiditis (hypo- or hyperthyroidism), dermatitis (rash, pruritus), hypophysitis, myocarditis (rare but fatal), nephritis. Graded 1–4; Grade ≥ 3 requires holding immunotherapy + high-dose steroids.
Hypertension (lenvatinib)	Lenvatinib inhibits VEGF signalling → loss of VEGF-mediated nitric oxide production in endothelium → vasoconstriction → hypertension.	Very common (~60%). Must monitor BP and treat aggressively (ACE-i, ARB, CCB).
Palmar-plantar erythrodysesthesia (lenvatinib)	Multi-kinase inhibitor toxicity to rapidly dividing cells in palms and soles → pain, swelling, blistering of hands and feet ("hand-foot syndrome").	Dose reduction may be required. Emollient cream, cooling.
Proteinuria / Nephrotic syndrome (lenvatinib)	VEGF inhibition → damage to glomerular endothelium → proteinuria.	Monitor urine protein. May require dose reduction or discontinuation if severe.

Complication	Mechanism
Weight gain	Progestins stimulate appetite and promote fluid retention and fat deposition.
Venous thromboembolism	Progestins (especially at high doses) increase hepatic synthesis of clotting factors → prothrombotic state. Cancer itself is already a hypercoagulable state → additive VTE risk.
Mood changes, depression	Progestins affect CNS neurotransmitter systems (serotonin, GABA).
Breakthrough bleeding	Progestin-induced endometrial decidualisation can cause irregular shedding.
Incomplete treatment / recurrence	Fertility-sparing progestin treatment has a ~30–40% recurrence rate even after initial complete response. This is a "complication" of conservative management — definitive surgery (hysterectomy) remains necessary after childbearing.

Recurrence Pattern	Clinical Features	Management Principles
Vaginal cuff recurrence (most common local site)	Postmenopausal bleeding or blood-stained discharge, palpable/visible nodule at vaginal apex.	If no prior RT → salvage RT (EBRT + brachytherapy) is potentially curative (5-year survival ~50–70%). If prior RT → surgical resection or reirradiation (limited options).
Pelvic recurrence (pelvic sidewall, nodes)	Pelvic pain, lower limb oedema (lymphatic/venous obstruction), ureteric obstruction → hydronephrosis.	Chemoradiation if radiation-naïve. Systemic chemotherapy if prior RT. Consider pelvic exenteration in selected, centralised recurrences.
Distant recurrence (lung, liver, bone, brain, peritoneum)	Organ-specific symptoms (see metastatic complications above).	Systemic chemotherapy (carboplatin/paclitaxel), immunotherapy (dMMR/MSI-H: pembrolizumab; pMMR: pembrolizumab + lenvatinib), targeted therapy (HER2+ serous: trastuzumab), hormonal therapy (low-grade ER+ recurrence), palliative RT (bone mets, brain mets, bleeding).

Understanding prognosis contextualises why complications at each stage matter:

Surgically staged. If treated early, both [cervical and endometrial cancer] have good prognosis ^[20].

Stage	Extent of Disease	5-Year Survival
I	Uterus	90%
II	Cervix	75%
III	Outside uterus	45%
IV	Bladder/rectum or distant metastasis	10%

^[15]^[20]

Corpus cancer — symptomatic at early stage (abnormal bleeding). If treated early, both have good prognosis. ^[20]

Why Early Detection Matters — The Survival Cliff

The drop from 90% 5-year survival (Stage I) to 10% (Stage IV) is dramatic. This is why the mantra "postmenopausal bleeding = endometrial cancer until proven otherwise" exists — early detection saves lives. Most complications of advanced disease (ureteric obstruction, fistulae, bone mets, cachexia) are avoidable if the cancer is caught and treated at Stage I.

Finding endometrial cancer in a patient should always prompt consideration of Lynch syndrome screening, because the diagnosis carries implications far beyond the endometrial cancer itself ^[6]:

Commonest syndrome associated with endometrial cancer is Lynch syndrome (up to 60% lifetime risk) ^[1]
If Lynch syndrome is confirmed via tumour MMR IHC → germline testing:
- The patient is at high risk of metachronous colorectal cancer (lifetime risk 40–80%), ovarian cancer (6–12%), gastric, urinary tract, and other cancers ^[6]
- Cascade genetic testing of first-degree relatives → identification of at-risk family members → preventive screening (colonoscopy, endometrial surveillance, etc.)
- This turns one patient's diagnosis into a life-saving intervention for an entire family

High Yield Summary

Complications of Endometrial Cancer — Key Points:

Disease complications:

Chronic anaemia (blood loss), haematometra/pyometra (cervical obstruction), ureteric obstruction → hydronephrosis, VTE (cancer hypercoagulability), lower limb oedema (lymphatic invasion)
Metastatic: lung (most common distant site), bone (pain, fracture, hypercalcaemia, cord compression), liver, peritoneum (serous type), brain (rare)

Surgical complications:

Intra-op: bleeding, ureteric/bladder/bowel injury
Early: VTE (most important preventable death), infection, vaginal cuff dehiscence, ileus
Late: lymphoedema (major QoL issue after lymphadenectomy ± RT), surgical menopause, sexual dysfunction, adhesions

RT complications:

Acute: radiation proctitis/enteritis, cystitis, fatigue, myelosuppression
Chronic: bowel fibrosis/stricture, vaginal stenosis, pelvic insufficiency fracture, secondary malignancy
Brachytherapy has fewer complications than EBRT — preferred for intermediate risk

Chemotherapy complications (carboplatin/paclitaxel):

Myelosuppression (febrile neutropenia), peripheral neuropathy (paclitaxel — may be irreversible), nephrotoxicity, nausea, alopecia

Immunotherapy complications:

Immune-related adverse events (colitis, hepatitis, pneumonitis, thyroiditis, myocarditis)
Lenvatinib: hypertension, hand-foot syndrome, proteinuria

Prognosis: Stage I = 90% 5-year survival; Stage IV = 10%. Early detection through prompt investigation of PMB is key.

Active Recall - Complications of Endometrial Cancer

References

^[1] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p34 — Lynch syndrome, risk factors) ^[6] Senior notes: Ryan Ho GI.pdf (p182–183 — Lynch syndrome extracolonic tumours, screening, prophylactic surgery) ^[14] Lecture slides: Block C - Abnormal vaginal bleeding_ gynaecological cancer.pdf (p40 — treatment: TH BSO ± lymphadenectomy, adjuvant therapy algorithm) ^[15] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p21–22 — staging, spread, 5-year survival by stage) ^[16] Lecture slides: Block C - Pelvic mass_ ovarian cancer and cysts; uterine fibroid; pelvic imaging.pdf (p10 — lower limb swelling due to lymphatic invasion) ^[17] Senior notes: Maksim Medicine Notes.pdf (p55 — bone metastasis: 4 complications, management) ^[18] Senior notes: Ryan Ho Respiratory.pdf (p151 — secondary lung tumours, common primaries include uterus) ^[19] Senior notes: Ryan Ho Urogenital.pdf (p210 — lymphoedema after lymphadenectomy ± RT) ^[20] Lecture slides: GC 112. Abnormal vaginal bleeding Gynaecological cancer.pdf (p23 — summary: corpus cancer symptomatic at early stage, good prognosis if treated early)

Endometrial Carcinoma

References

Endometrial Cancer

2. Epidemiology

3. Risk Factors

4. Anatomy and Function

5. Aetiology and Pathophysiology

The Dualistic Model of Endometrial Cancer

6. Classification

How female cancers spread [1]

8. Clinical Features

9. Precursor Lesions — Endometrial Hyperplasia

Active Recall - Endometrial Cancer (Definition to Clinical Features)

Differential Diagnosis of Endometrial Cancer

Anatomical Approach (Bottom-Up)

D. Other Important Differentials to Consider in the Context of Endometrial Cancer

Active Recall - Differential Diagnosis of Endometrial Cancer

References

Diagnosis of Endometrial Cancer

C. Investigation Modalities — Detailed Breakdown

3. Endometrial Sampling — The Diagnostic Cornerstone

5. Pre-operative / Staging Investigations

Active Recall - Diagnosis of Endometrial Cancer

References

Management of Endometrial Cancer

A. Surgical Management — The Primary Treatment

B. Adjuvant Therapy — Post-operative Risk Stratification

Types of Adjuvant Therapy Explained

Active Recall - Management of Endometrial Cancer

References

Complications of Endometrial Cancer

A. Complications of the Disease Itself

B. Complications of Treatment

1. Complications of Surgery (TH + BSO ± Lymphadenectomy)

2. Complications of Radiotherapy

Active Recall - Complications of Endometrial Cancer

References

On this page

Endometrial Carcinoma

1. Definition

2. Epidemiology

Global Perspective

Hong Kong Perspective

Age Distribution

3. Risk Factors

Risk Factor Table

Protective Factors (the "anti-oestrogen" list)

4. Anatomy and Function

Gross Anatomy of the Uterus

Layers of the Uterine Wall (Outside → Inside)

Why Anatomy Matters for Endometrial Cancer

The Endometrial Cycle (Relevant Pathophysiology)

5. Aetiology and Pathophysiology

The Dualistic Model of Endometrial Cancer

Type I — Endometrioid Adenocarcinoma: The Oestrogen-Driven Pathway

Type II — Serous, Clear Cell, Carcinosarcoma: The TP53-Driven Pathway

Modern Molecular Classification (TCGA 2013, WHO 2020)

6. Classification

Histological Classification (WHO 2020)

Hyperplasia Classification (WHO 2014/2020)

Current FIGO 2023: anatomical and histological groups

Legacy FIGO 2009: interpreting older teaching

7. Pathways of Spread

8. Clinical Features

Overview

Symptoms

Signs

9. Precursor Lesions — Endometrial Hyperplasia

What Is Endometrial Hyperplasia?

Classification and Cancer Risk

Why Nuclear Atypia Is the Key Feature

10. Relationship to Lynch Syndrome

11. Summary of the Pathophysiology–Clinical Feature Connection

Active Recall - Endometrial Cancer (Definition to Clinical Features)

References

Faculty CMB82: rare malignancies not to miss

Framing the DDx: What Are We Actually Differentiating?

A. Differential Diagnosis of Postmenopausal Bleeding

B. Differential Diagnosis of Abnormal Uterine Bleeding in Premenopausal Women

C. Differential Diagnosis of Pelvic Mass (When Endometrial Cancer Presents as Uterine Enlargement)

D. Other Important Differentials to Consider in the Context of Endometrial Cancer

1. Synchronous Ovarian and Endometrial Cancer

2. Cervical Cancer Extending into the Uterine Body

3. Extrauterine Cancers Metastatic to the Endometrium

4. Cancer-Associated Conditions That May Coexist

Diagnostic Approach to Narrowing the DDx

E. Quick-Reference: Distinguishing Endometrial Cancer from Its Common Mimics

F. Tumour Markers in the DDx Context

Active Recall - Differential Diagnosis of Endometrial Cancer

Diagnostic Principles — There Is No "Screening Test" for Endometrial Cancer

A. Diagnostic Criteria

B. Diagnostic Algorithm

C. Investigation Modalities — Detailed Breakdown

1. History and Physical Examination

2. Transvaginal Ultrasound (TVUSS)

3. Endometrial Sampling — The Diagnostic Cornerstone

a) Pipelle Endometrial Aspirate (Office/Outpatient)

b) Hysteroscopy + Directed Biopsy / Curettage

c) Dilatation and Curettage (D&C)

4. Histopathology and Immunohistochemistry (IHC)

5. Pre-operative / Staging Investigations

a) Blood Tests

b) Tumour Markers

c) Imaging for Staging

6. Pre-operative Assessment of Fitness

7. Sentinel Lymph Node (SLN) Mapping

D. Summary: Investigation Pathway at a Glance

Active Recall - Diagnosis of Endometrial Cancer

Current treatment decisions (reviewed September 2026)

Guiding Principles

Management Algorithm

A. Surgical Management — The Primary Treatment

1. Standard Surgical Procedure

2. Surgical Approach: Laparoscopic vs Open

3. Lymph Node Assessment

B. Adjuvant Therapy — Post-operative Risk Stratification

Adjuvant principles (simplified; older anatomical stage labels below)

Types of Adjuvant Therapy Explained