Endometrial carcinoma and fibroids
Endometrial hyperplasia and carcinoma; uterine fibroids and sarcomas
The endometrium proliferates under oestrogen and is held in check by progesterone; prolonged unopposed oestrogen produces hyperplasia and then endometrioid carcinoma, while a separate, oestrogen-independent pathway produces aggressive serous carcinoma in older women. Fibroids are common benign, hormone-dependent smooth muscle tumours, and true uterine sarcomas are rare. CPSP asks risk factors, molecular changes, degenerations and how to tell benign from malignant.
Endometrial hyperplasia
- Cause: unopposed oestrogen: anovulation (PCOS, perimenopause: no corpus luteum, no progesterone), obesity (adipose aromatase), oestrogen-only HRT with a uterus, tamoxifen (agonist on endometrium), oestrogen-secreting granulosa cell tumour.
- Histology: crowded glands of varying size, some cystic, with a gland-to-stroma ratio above 1:1.
| Category | Nuclei | Behaviour |
|---|---|---|
| Hyperplasia without atypia | Like normal proliferative endometrium | Regresses when the stimulus is removed; low cancer risk |
| Atypical hyperplasia (endometrial intraepithelial neoplasia) | Enlarged, rounded, lost polarity | Highest risk: about a quarter to a half have or develop carcinoma |
- Hyperplasia regresses when oestrogen is removed; a neoplasm persists without the stimulus because of clonal genetic change.
- Progestogen (e.g. LNG-IUS) opposes oestrogen-driven growth, down-regulating oestrogen receptors and causing decidualisation and gland atrophy.
Endometrial carcinoma
- The commonest gynaecological cancer in high-income countries; presents early with postmenopausal bleeding, so prognosis is generally good.
| Feature | Type I: endometrioid | Type II: serous (and clear cell) |
|---|---|---|
| Patient | Peri- or postmenopausal, obese, diabetic, hypertensive, nulliparous | Older, thin, no oestrogen excess |
| Background | Atypical hyperplasia | Atrophic endometrium; serous intraepithelial carcinoma |
| Molecular | PTEN loss (commonest), microsatellite instability, PIK3CA, KRAS, β-catenin | TP53 mutation |
| Histology | Glands resembling endometrium; squamous morules | Complex papillae, marked atypia, psammoma bodies |
| Behaviour | Usually low grade, slow | Aggressive, early peritoneal and omental spread |
- Risk factors (oestrogen exposure): obesity, early menarche, late menopause, nulliparity, PCOS, unopposed oestrogen, tamoxifen, diabetes. Insulin lowers hepatic SHBG, raising active oestradiol.
- Protective: combined oral contraceptive (lasting years after stopping), progestogens, high parity, smoking (never advised).
- Lynch syndrome (mismatch repair: MLH1, MSH2, MSH6, PMS2; autosomal dominant) is the commonest inherited cause; endometrial cancer may be the sentinel cancer. Loss of MLH1 staining is usually sporadic from MLH1 promoter hypermethylation; loss of MSH2/MSH6 suggests Lynch. BRCA is not the main risk.
- FIGO staging (classic): IA under half the myometrium; IB half or more; II cervical stroma; III serosa, adnexa, vagina, parametrium or nodes; IV bladder or bowel mucosa or distant spread. On MRI, tumour breaching the junctional zone shows myometrial invasion.
- Carcinosarcoma (malignant mixed Müllerian tumour): malignant epithelium plus malignant mesenchyme, sometimes with cartilage or rhabdomyoblasts; linked to prior pelvic radiation and tamoxifen; behaves as a high-grade carcinoma.
Endometrial polyps and adenomyosis
- Polyp: a localised overgrowth covered by endometrium on three sides, with fibrous stroma and thick-walled vessels in the stalk; common with tamoxifen. Ultrasound shows an echogenic lesion with a single feeding artery.
- Adenomyosis: endometrial glands and stroma deep within the myometrium with surrounding muscle hypertrophy, giving a symmetrically enlarged, boggy, tender uterus with heavy painful periods in multiparous women. MRI: junctional zone 12 mm or more with tiny T2-bright foci. Endometriosis is endometrium outside the uterus.
Leiomyoma (fibroid)
- The commonest benign tumour of the female genital tract: a benign smooth muscle neoplasm, each one monoclonal; multiple fibroids are independent clones. MED12 mutations in about 70%; HMGA2 rearrangements in others. Hereditary leiomyomatosis with renal cancer involves fumarate hydratase.
- Rich in oestrogen and progesterone receptors: grow in reproductive life and pregnancy, shrink after menopause; growth after menopause without HRT is suspicious.
- Firm, whorled, white tumours; expansile growth compresses adjacent myometrium into a pseudocapsule, allowing enucleation at myomectomy. Desmin, SMA and h-caldesmon confirm smooth muscle (vimentin is non-specific; CD10 marks endometrial stroma).
- Position: intramural (commonest); submucous (bulges into the cavity; enlarges the bleeding surface, impairs contraction, causes heaviest bleeding and infertility despite small size); subserous (pressure symptoms).
| Degeneration | Features |
|---|---|
| Hyaline | Commonest; glassy pink acellular areas |
| Cystic | Liquefied hyaline |
| Red (carneous) | Pregnancy: haemorrhagic infarction as growth outstrips supply; pain, low-grade fever, leucocytosis; beefy red |
| Calcific | After menopause; 'popcorn' calcification on X-ray |
| Sarcomatous | Very rare |
- Rare effects: erythrocytosis from tumour erythropoietin; lipoleiomyoma contains fat.
Uterine sarcomas
- Leiomyosarcoma: usually arises de novo, not from a fibroid. Soft, fleshy, haemorrhagic, infiltrative, without whorls. Diagnosis needs two of three: marked atypia, high mitotic count, coagulative tumour cell necrosis (hyaline necrosis in a fibroid does not count).
- Low-grade endometrial stromal sarcoma: bland cells like proliferative stroma, CD10 positive, with tongue-like myometrial invasion and worm-like plugs in veins.
Remember Unopposed oestrogen gives hyperplasia and endometrioid cancer (PTEN); an atrophic endometrium in a thin elderly woman gives serous cancer (TP53).
Exam trap Gland crowding alone is not atypia; the nuclei decide whether hyperplasia is atypical.
Exam trap Fibroids do not commonly turn into sarcoma; leiomyosarcoma usually arises on its own.
Test yourself on this topic
5 of the 31 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 55-year-old woman's rapidly enlarging uterine mass is a soft, fleshy, haemorrhagic tumour with no whorled pattern. Microscopy shows spindle cells with marked atypia and many mitoses. Which additional feature most supports leiomyosarcoma over a leiomyoma?
Answer: Coagulative tumour cell necrosis
Leiomyosarcoma is diagnosed from a combination of diffuse moderate to severe nuclear atypia, a high mitotic count and coagulative tumour cell necrosis, an abrupt transition from viable to dead tumour cells. Two of these three features are usually required. Hyaline necrosis, common in benign fibroids, looks different and is not a sign of malignancy. Desmin and hormone receptors show smooth muscle origin but do not separate benign from malignant tumours.
Leiomyosarcoma criteria
- Marked nuclear atypia
- High mitotic count
- Coagulative tumour cell necrosis
- Two of three usually required
Remember Atypia, mitoses, tumour necrosis: sarcoma.
Exam trap Hyaline necrosis in a benign fibroid is not tumour cell necrosis.
Why the other options are wrong
- Hyaline change between bundles Common benign degeneration.
- Well-defined pseudocapsule Typical of a benign fibroid; sarcomas infiltrate.
- Oestrogen receptor positivity Present in many fibroids too.
- Desmin-positive smooth muscle cells Marks smooth muscle in both benign and malignant tumours.
A 46-year-old woman with symptomatic fibroids is told that they will probably shrink and stop causing bleeding after her menopause. What is the reason?
Answer: Ovarian oestrogen and progesterone fall
Uterine leiomyomas depend on ovarian steroids. They have more oestrogen and progesterone receptors than surrounding myometrium, and both hormones drive their growth, which is why they enlarge in reproductive life and in pregnancy. After menopause, ovarian steroid production falls and fibroids usually shrink. A fibroid that grows after menopause, without hormone therapy, raises concern about sarcoma.
Hormone dependence of fibroids
- Rich in ER and PR
- Grow in reproductive years and pregnancy
- Shrink after menopause
- Postmenopausal growth: think sarcoma
Remember No ovarian steroids, no fibroid growth.
Exam trap A fibroid enlarging after menopause without HRT needs investigation.
Why the other options are wrong
- Blood supply from the uterine arteries stops The uterine arteries continue to supply the uterus.
- Fibroids calcify at age 50 Calcification may occur but is not the cause of shrinkage.
- Pituitary growth hormone falls Not the controlling hormone.
- Fibroid cells undergo apoptosis from FSH High FSH does not cause fibroid apoptosis.
A 44-year-old woman with a very large fibroid uterus has a haemoglobin of 18.5 g/dL despite heavy periods. Oxygen saturation is normal and the kidneys look normal. After hysterectomy her haemoglobin returns to normal. What is the most likely mechanism?
Answer: Erythropoietin secreted by the fibroid
Myomatous erythrocytosis syndrome is a rare paraneoplastic effect of large fibroids. The tumour produces erythropoietin, or a similar factor, which stimulates red cell production, giving erythrocytosis despite menstrual blood loss. Normal saturation excludes a hypoxic cause, and normalisation after hysterectomy confirms that the fibroid was the source. Ureteric compression can sometimes act through renal erythropoietin, but the kidneys here are normal.
Myomatous erythrocytosis
- Large fibroid
- Tumour erythropoietin
- High Hb, normal saturation
- Resolves after removal
Remember High haemoglobin that goes with the uterus: fibroid EPO.
Exam trap Do not assume polycythaemia vera when a large fibroid is present; check erythropoietin.
Why the other options are wrong
- Hypoxia from pressure on the lungs Oxygen saturation is normal.
- Haemoconcentration from blood loss Acute loss does not raise haemoglobin this way.
- Renal ischaemia from ureteric pressure Excluded by normal kidneys.
- JAK2-driven marrow proliferation Would not resolve after hysterectomy.
A 50-year-old perimenopausal woman with heavy irregular bleeding has an endometrial biopsy. It shows crowded proliferative glands of varying size, some cystically dilated, with a gland-to-stroma ratio above 1:1. The nuclei are like those of normal proliferative endometrium. What is the diagnosis?
Answer: Endometrial hyperplasia without atypia
Endometrial hyperplasia is an increase in glands relative to stroma, usually from prolonged unopposed oestrogen, which is common in perimenopausal anovulatory cycles. When the gland nuclei resemble normal proliferative endometrium, it is classed as hyperplasia without atypia, which carries a low risk of progression and usually responds to progestogen. Atypical hyperplasia (endometrial intraepithelial neoplasia) shows enlarged, rounded, vesicular nuclei with nucleoli and has a high risk of coexisting or future carcinoma. Carcinoma requires stromal invasion or confluent glandular growth.
Endometrial hyperplasia
- Gland:stroma ratio > 1:1
- Normal-looking nuclei: without atypia
- Atypical nuclei: EIN, high risk
- Driver: unopposed oestrogen
Remember Crowded glands with ordinary nuclei: hyperplasia without atypia.
Exam trap Gland crowding alone does not make hyperplasia atypical; the nuclei decide.
Why the other options are wrong
- Atypical hyperplasia (EIN) Requires nuclear atypia, which is absent here.
- Well-differentiated endometrioid carcinoma Requires invasion or confluent gland growth.
- Disordered proliferative endometrium only Glands are not crowded beyond a 1:1 ratio in this pattern.
- Secretory endometrium Would show secretory change from progesterone.
A 66-year-old woman with no family history of cancer has endometrioid endometrial carcinoma. Immunohistochemistry shows loss of MLH1 and PMS2 in the tumour. Further testing of the tumour shows a change that makes Lynch syndrome unlikely. What is it?
Answer: MLH1 promoter hypermethylation
About a quarter to a third of endometrial carcinomas lack mismatch repair proteins, but most of those with MLH1 loss are sporadic. In these tumours, the MLH1 gene is silenced by acquired hypermethylation of its promoter in the tumour, not by an inherited mutation, and the patient is usually older with no family history. Finding MLH1 promoter methylation therefore makes Lynch syndrome unlikely and avoids unnecessary germline testing. Loss of MSH2 or MSH6, by contrast, strongly suggests Lynch syndrome.
MLH1 loss in endometrial cancer
- MMR loss in about a quarter to a third
- MLH1 loss usually sporadic
- Cause: promoter hypermethylation
- MSH2/MSH6 loss suggests Lynch
Remember Methylated MLH1 means acquired, not inherited.
Exam trap Loss of a mismatch repair protein on staining is not by itself a diagnosis of Lynch syndrome.
Why the other options are wrong
- Germline MSH2 deletion Would confirm Lynch syndrome.
- Loss of MSH6 staining Would point towards Lynch syndrome, not away.
- Mutation of the PTEN gene Common in endometrioid cancer; does not distinguish sporadic from inherited.
- High tumour mutational burden Found in all mismatch repair-deficient tumours.
Where this sits in the CPSP syllabus
- Obstetrics & Gynaecology, Paper 2: Neoplasia of the female genital tract, Endometrial hyperplasia and carcinoma; uterine fibroids and sarcoma
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