Endometrial Carcinoma

Endometrial carcinoma is the commonest gynaecological malignancy in the developed world and the second commonest (after cervical cancer) in India. It is the prototype "oestrogen-driven" cancer, and its defining clinical clue — postmenopausal bleeding (PMB) — makes it one of the most repeatedly tested gynae-oncology topics in NEET PG. This note builds the topic around the Type I/Type II dichotomy, the PMB workup, FIGO staging, and the progestin-vs-surgery management split.

Definition and overview

Endometrial carcinoma is a malignant epithelial tumour arising from the glandular lining (endometrium) of the uterine corpus. It is largely a disease of postmenopausal women (peak 55–65 years), and roughly 90% present with abnormal uterine bleeding, usually PMB. Because bleeding appears early, most cases (≈75%) are diagnosed at FIGO Stage I — which is why endometrial cancer carries a relatively favourable overall prognosis compared with ovarian cancer.

High-yield: Any postmenopausal bleeding is endometrial carcinoma until proven otherwise. The single most important investigation in a PMB woman is endometrial sampling (biopsy), not just ultrasound.

Classification — the Type I vs Type II dualistic model

The classic Bokhman dualistic model divides endometrial cancer into two biologically distinct types. This table is a perennial NEET PG favourite.

Feature	Type I	Type II
Histology	Endometrioid adenocarcinoma	Serous (UPSC), clear cell, carcinosarcoma
Oestrogen dependence	Yes (oestrogen-driven)	No (oestrogen-independent)
Precursor lesion	Atypical hyperplasia / EIN	Endometrial intraepithelial carcinoma (serous)
Background endometrium	Hyperplastic	Atrophic
Typical patient	Younger, obese, perimenopausal	Older, thin, postmenopausal
Grade	Low grade (G1/G2)	High grade
Molecular marker	PTEN, KRAS, microsatellite instability, β-catenin	p53 mutation, HER2/neu
Prognosis	Good	Poor
Proportion	~80%	~10–20%

High-yield: Type I = PTEN/MMR/microsatellite instability; Type II (serous) = p53 mutation. Uterine papillary serous carcinoma behaves like ovarian serous cancer (spreads transcoelomically, peritoneal disease, raised CA-125).

TCGA molecular classification (newer, increasingly asked)

The Cancer Genome Atlas reclassified endometrial cancer into four molecular groups, now incorporated into FIGO 2023 staging:

1. POLE ultramutated → best prognosis
2. MSI-high / hypermutated (MMR-deficient; Lynch-associated)
3. Copy-number low (no specific molecular profile, "NSMP")
4. Copy-number high (p53-abnormal / serous-like) → worst prognosis

High-yield: POLE-mutated tumours have the best prognosis; p53-abnormal the worst. This is the modern "exam upgrade" over the old Type I/II split.

Etiology and risk factors

The unifying theme for Type I is unopposed oestrogen — oestrogen stimulation of the endometrium without the protective, maturing effect of progesterone.

Risk factors (unopposed-oestrogen states):

• Obesity — peripheral aromatisation of androgens to oestrone in adipose tissue (strongest modifiable risk factor)
• Nulliparity
• Early menarche, late menopause (>52 years)
• PCOS — chronic anovulation → unopposed oestrogen (commonest cause in young women)
• Diabetes mellitus and hypertension (the classic triad with obesity)
• Oestrogen-only HRT (no progestin in a woman with a uterus)
• Tamoxifen — anti-oestrogen in breast, but agonist on the endometrium
• Oestrogen-secreting tumours — granulosa cell tumour of the ovary, thecoma
• Lynch syndrome (HNPCC) — autosomal dominant MMR defect; lifetime endometrial cancer risk up to 40–60%

Protective factors: Combined oral contraceptive pills (progestin component), multiparity, smoking (lowers oestrogen — not recommended!), physical activity, levonorgestrel-IUS.

High-yield: In a woman with breast cancer on tamoxifen who develops PMB → think endometrial carcinoma. Tamoxifen acts as an endometrial oestrogen agonist.

High-yield: Lynch syndrome women should be offered prophylactic hysterectomy + BSO after childbearing. Endometrial cancer is often the sentinel (first) cancer in Lynch syndrome women.

Precursor lesion — endometrial hyperplasia / EIN

The WHO 2014 system simplified hyperplasia into two categories based on the presence of cytological atypia, which determines cancer risk:

Category	Risk of progression to cancer	Management
Hyperplasia without atypia	~1–3%	Progestin (oral / LNG-IUS), reassess
Atypical hyperplasia / EIN	~25–40% (and ~40% have coexisting cancer at hysterectomy)	Total hysterectomy (fertility-sparing progestin only if desired)

Pathophysiology

Persistent oestrogenic stimulation → endometrial gland proliferation → simple hyperplasia → complex hyperplasia → atypical hyperplasia/EIN → well-differentiated endometrioid carcinoma. PTEN loss is an early event; KRAS and β-catenin mutations follow. Type II serous cancers arise de novo from atrophic endometrium via p53 mutation (TP53), bypassing the hyperplasia pathway.

Spread of endometrial carcinoma:

1. Direct extension — to myometrium (depth of invasion is the key prognostic factor), cervix, then beyond uterus.
2. Lymphatic — to pelvic and para-aortic nodes. (Fundal tumours can drain directly to para-aortic nodes via the infundibulopelvic/ovarian channel.)
3. Transcoelomic / transtubal — peritoneal seeding, characteristic of serous type.
4. Haematogenous (late) — lungs, liver, bone.

High-yield: Depth of myometrial invasion and tumour grade are the most important histological prognostic factors and drive the need for lymphadenectomy.

Clinical features

• Postmenopausal bleeding — the cardinal symptom (≈90%). Only ~10% of PMB is due to cancer, but cancer must always be excluded.
• Perimenopausal/premenopausal: intermenstrual bleeding, menorrhagia, irregular heavy bleeding (especially in obese/PCOS women).
• Pyometra / haematometra — pus or blood collection if cervical os is stenosed (elderly).
• Abnormal cervical smear showing endometrial/glandular cells in a postmenopausal woman.
• Late disease: pelvic pain, mass, weight loss.

Clinical approach flow:

PMB → History & examination (rule out atrophic vaginitis, cervical/vulval lesions, exogenous hormones) → Transvaginal ultrasound for endometrial thickness → Endometrial biopsy (office) / Hysteroscopy + D&C if biopsy inadequate → Histology confirms → Imaging (MRI pelvis) for staging → Surgical staging.

Diagnosis and investigation of choice

Transvaginal ultrasound (TVS)

First-line screening tool in PMB. Measures endometrial thickness (ET).

• ET ≤ 4 mm in a postmenopausal woman → cancer very unlikely (high negative predictive value); reassure unless bleeding persists/recurs.
• ET > 4 mm (some use 5 mm) → mandatory endometrial sampling.

High-yield: A postmenopausal endometrial thickness cut-off of ≤4 mm essentially rules out endometrial carcinoma. But the cut-off does not apply to women on tamoxifen (endometrium is artefactually thickened) — those need direct sampling.

Endometrial biopsy — the investigation of choice

Tissue diagnosis is mandatory. Options:

• Office endometrial biopsy (Pipelle/Karman) — first-line, OPD, no anaesthesia. High sensitivity for cancer.
• Hysteroscopy with directed biopsy / fractional curettage — gold standard if office biopsy is non-diagnostic, sampling fails (cervical stenosis), or focal lesion/polyp suspected. Hysteroscopy allows direct visualisation of focal lesions a blind Pipelle may miss.
• Fractional curettage historically used to assess cervical involvement.

High-yield: Pipelle/office endometrial biopsy is the first-line tissue test; hysteroscopy + biopsy is the gold standard for a definitive/focal diagnosis. Pap smear is not a screening test for endometrial cancer.

Staging investigations

• MRI pelvis — best for assessing myometrial invasion depth and cervical involvement.
• CT chest/abdomen/pelvis — for distant/nodal spread.
• CA-125 — useful baseline, especially in serous histology (extrauterine disease).

FIGO staging (surgical staging)

Endometrial carcinoma is surgically staged (unlike cervical cancer, which was traditionally clinically staged). Memorise the milestones.

Stage	Extent
I	Confined to the uterine corpus (IA: <½ myometrial invasion; IB: ≥½ invasion)
II	Invades cervical stroma, no extra-uterine spread
III	Local/regional spread — IIIA: serosa/adnexa; IIIB: vagina/parametrium; IIIC: pelvic (IIIC1) or para-aortic (IIIC2) nodes
IV	IVA: bladder/bowel mucosa; IVB: distant metastases (including inguinal nodes, intra-abdominal)

High-yield (staging milestones): Cervical stromal invasion = Stage II; pelvic/para-aortic nodes = Stage IIIC; bladder/bowel mucosa = Stage IVA. Positive peritoneal cytology alone no longer upstages the disease (changed in FIGO 2009).

Mnemonic for Stage progression — "Uterus → Cervix → Around → Away": I = uterine corpus, II = cervix, III = around (adnexa/vagina/nodes), IV = away (mucosa/distant).

Management and drug of choice

Surgery — the cornerstone

The standard primary treatment is total hysterectomy + bilateral salpingo-oophorectomy (TH + BSO) with surgical staging (peritoneal washings, pelvic ± para-aortic lymph node assessment, often via sentinel lymph node mapping with indocyanine green). Minimally invasive (laparoscopic/robotic) surgery is preferred where feasible.

• Low-risk (Stage IA, G1/G2 endometrioid): TH + BSO; lymphadenectomy may be omitted.
• Intermediate/high-risk: add full surgical staging ± adjuvant therapy.

Adjuvant therapy

• Radiotherapy — vaginal brachytherapy (reduces local recurrence) ± external beam pelvic RT for higher-risk/node-positive disease.
• Chemotherapy — carboplatin + paclitaxel for advanced (Stage III/IV) or serous/clear cell histology.
• Immunotherapy — pembrolizumab (esp. in MMR-deficient/MSI-high advanced disease); pembrolizumab + lenvatinib in MMR-proficient advanced disease.

Hormonal / fertility-sparing therapy — progestins

For young women with atypical hyperplasia or well-differentiated (G1) Stage IA endometrioid carcinoma who desire fertility, conservative management with high-dose progestins is acceptable:

• Oral medroxyprogesterone acetate / megestrol acetate, or
• Levonorgestrel-releasing intrauterine system (LNG-IUS / Mirena)
• Serial endometrial sampling every 3–6 months; definitive hysterectomy after childbearing or if no response.

High-yield: The drug of choice for fertility-sparing treatment of low-grade Stage IA endometrioid carcinoma / atypical hyperplasia is a progestin (medroxyprogesterone acetate or LNG-IUS). Progestins are also the palliative hormonal agent in advanced/recurrent oestrogen-receptor-positive disease.

Complications

• Local recurrence — commonest site is the vaginal vault (hence vaginal brachytherapy).
• Distant metastases — lung (commonest distant site), liver, bone.
• Lymphoedema of lower limbs after lymphadenectomy/pelvic RT.
• Surgical/radiotherapy morbidity — bladder/bowel injury, radiation cystitis/proctitis.
• Pyometra with risk of perforation in obstructed cases.
• Treatment-related: VTE (obese, malignant, post-surgical patients).

Key differentials

Causes of postmenopausal bleeding to differentiate from carcinoma:

Cause	Distinguishing clue
Atrophic vaginitis/endometritis	Commonest cause of PMB overall; thin endometrium, dry atrophic vagina
Endometrial/cervical polyp	Focal lesion on hysteroscopy/saline sonography
Endometrial hyperplasia	Thickened endometrium, no invasion on biopsy
Exogenous hormones / tamoxifen	Drug history
Cervical carcinoma	Visible/friable cervical lesion, contact bleeding
Oestrogen-secreting ovarian tumour	Adnexal mass + hyperplasia (granulosa cell tumour)

Also distinguish uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma) — rapidly enlarging uterus, arises from myometrium/stroma, poorer prognosis, not oestrogen-screened by ET cut-off.

Recently asked / exam angle

• Single-best clue: "Obese, diabetic, hypertensive, nulliparous postmenopausal woman with bleeding" → endometrial carcinoma (the obesity-DM-HTN triad).
• Investigation of choice in PMB → endometrial biopsy (Pipelle); ultrasound ET cut-off ≤4 mm.
• Tamoxifen + PMB → endometrial carcinoma; remember tamoxifen is an endometrial agonist, and ET cut-off does not apply.
• p53 mutation → serous (Type II); PTEN/MSI → endometrioid (Type I). TCGA: POLE = best, p53-abnormal = worst.
• Staging milestones: cervical stroma = II, nodes = IIIC, bladder/bowel mucosa = IVA. Peritoneal cytology no longer upstages.
• Fertility-sparing therapy drug = progestin (MPA / LNG-IUS) for G1 IA endometrioid.
• Lynch syndrome = endometrial cancer is often the index malignancy; screen with MMR/IHC.
• Commonest site of recurrence = vaginal vault.
• Granulosa cell tumour of ovary → unopposed oestrogen → endometrial hyperplasia/carcinoma association.
• Endometrial cancer is surgically staged; cervical cancer (older system) was clinically staged — a classic contrast MCQ.

Rapid revision

1. PMB = endometrial carcinoma until proven otherwise; investigation of choice = endometrial biopsy.
2. Type I = endometrioid, oestrogen-driven, PTEN/MSI, good prognosis; Type II = serous/clear cell, p53, atrophic background, poor prognosis.
3. TCGA molecular groups: POLE (best) > MSI-H > NSMP > p53-abnormal (worst).
4. Strongest modifiable risk factor = obesity (peripheral aromatisation to oestrone); classic triad = obesity + diabetes + hypertension + nulliparity.
5. Tamoxifen is an endometrial oestrogen agonist → increases endometrial cancer risk.
6. Lynch syndrome (HNPCC, MMR defect) → up to 40–60% lifetime risk; offer prophylactic hysterectomy + BSO.
7. Postmenopausal endometrial thickness ≤4 mm virtually excludes cancer (except on tamoxifen).
8. Atypical hyperplasia/EIN → 40% coexisting cancer → hysterectomy (or progestin if fertility desired).
9. Standard treatment = TH + BSO + surgical staging (± sentinel node mapping).
10. Drug of choice for fertility-sparing G1 Stage IA = progestin (MPA / LNG-IUS).
11. FIGO milestones: cervical stroma = II, pelvic/para-aortic nodes = IIIC, bladder/bowel mucosa = IVA; cytology no longer upstages.
12. Commonest recurrence site = vaginal vault → vaginal brachytherapy; most cases diagnosed early (Stage I) → good prognosis.