PATH 14 - Uterus

Normal uterus

menopause

• HRT

– abnormal cyclical bleeding,

- heavy painful or irregular periods

- IMB (intermenstrual bleeding)

- PMB (post menopausal bleeding)

- infertility

• Proliferative phase – gland and stroma prolif due to oestrogen production by ovarian follicles

• Secretory phase -14 days following ovulation, due to combined oestrogen/prog production by corpus luteum

• Menstrual phase – stromal breakdown following involution of corpus luteum

Bleeding w/o underlying organic condition (no visible cancer, polyp etc)

• Abnormalities in cycle development:
•     - anovulatory cycles (most common)
•     - inadequate luteal phase
•     - irregular or delayed shedding

• Commonest cause of DUB
• Usu occurs near menarche/menopause
• Follicles develop with oestrogen production
• No ovulation – no prog from corpus luteum
• Endometrium proliferates and then when follicles regress
• ---> withdrawal bleeding

• Proliferative endometrium with stromal breakdown
• if prolonged – disordered proliferative
• variably spaced and shaped glands with cystic dilatation
• can eventually lead to hyperplasia/cancer

Ovulation occurs but inadequate  prog secretion by corpus luteum

Either fails to develop or premature regression

Histology: secretory changes but less well developed with glands lacking tortuosity, discordant stromal breakdown

Can be a cause of infertility/spontaneous abortion

• Persistent corpus luteum with prolonged progesterone production
• Often see mixture of proliferative and secretory changes, or irregular secretory development, with stromal breakdown

• Oestrogens -  initially used unapposed in HRT
• Proliferative changes + stromal breakdown as endometrium cannot support continued growth
• --> disordered proliferative
• --> eventual hyperplasia/carcinoma

• Progestins variable effect-  
• Short term: secretory glandular changes and stromal decidualisation
• Long term: downregulation of ER/PR receptors with eventual atrophy
• High dose therapy --> superficial necrosis
• Used in IUCD/Rx DUB and hyperplasia

• Oral contraceptive pill
• Usually combined oestrogen/progesterone but dominated by progesterone effect
• Suppresses ovulation
• Pill effect : simple tubular glands in vascular decidualised stroma +/- stromal breakdown

Minipill and Depo-provera (IM) - progesterone only, similar pill effect

Common, esp perimenopausal, less frequent after 60yrs

Benign, often large and multiple

Increased in tamoxifen treatment

Biphasic growth of benign glands + stroma

Usu non-fntnl (no cyclical change)

Abnormal PV bleeding

May be involved by neoplastic processes

benign endomertial polyp

May be acute or chronic

Often non specific

• Specific forms:
• Neisseria gonorrheae/Chlam (STD),
• TB,
• post-partum/abort,
• pyometra,
• IUCD

• Variable symptoms, may lead to PID (abdo pain, fever, raised WCC)
• often unable to date endometrium

• Common, benign, non-neoplastic
• Deep extension of endometrial glands and stroma into myometrium 
• Assoc w muscle hypertrophy
• Typically occurs late repro years
• Can cause abnormal uterine bleeding/pain
• May cause recurrence of symptoms after endometrial ablation therapy

Endometrial carcinoma

• Mesenchymal tumours
•  - endometrial stromal tumours
•  - smooth muscle tumours

Mixed epithelial and mesenchymal tumours

Other eg lymphoma

Metastases (ovary, breast, colon)

• Most common gynaecological malignancy
• Usually post menopausal (PMB)
• Often confined to uterus at Dx
• Overall good prognosis (80-90% 5YS)
• 2 main types (endometriod vs non-endometrioid)

Stage 1 - confined to uterus (subdivided according to depth of myometrial invasion)

Stage 2- extension to cervix

Stage 3- invasion of serosa, adnexae or positive peritoneal cytology

Stage 4- bladder/bowel invasion or distant metastasis

• Endometrioid subtype
• 80-85%
• oestrogen driven, arising in hyperplasia
• perimenopausal and post menopausal women
• (younger than type 2 )
• Molecular changes:
• PTEN,
• beta catenin,
• MMR gene mutations,
• K-ras
• p53 mutations rare (as opposed to type 2)

Generally good prognosis - low grade/early stage

• Tend to develop disease 15yrs earlier
• most have Lynch syndrome (HNPCC): endometrial Cx as common as Colorectal Cx, 70% lifetime risk

Wikipedia: (Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon Cx as well as other cancers including endometrium, ovary,stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Inherited mutations in DNA mismatch repair.)

• Mutations in DNA mismatch repair genes --> MSI
• (microsatelite instability)

• - MSH 2/6 mutations more common
• generally seen type 1 endometrial carcinoma
• BRCA patients- increased risk?  

Wiki: BRCA mutation genes BRCA1 or BRCA2. Harmful mutations in these genes produce a hereditary breast-ovarian cancer syndrome in affected families. Mutations in BRCA1 and BRCA2 are uncommon, and breast cancer is relatively common, so these mutations consequently account for only five to ten percent of all breast cancer cases in women.

• Causes of hyper-oestrogenism... such as:
• - obesity
• - anovulation (Polycystic ovary syndrome (PCOS) is one of the most common female endocrine disorders) 
• - hormonal therapy (HRT, tamoxifen)
• - oestrogen secreting ovarian tumours
• - relative progestogen deficiency

• - Precursor lesion to type 1 carcinoma
• - oestrogen induced
• - typically perimenopausal (anovulatory cycles)
• - also younger women (PCO) or postmenopausal(excess endogenous or exogenous oestrogen)
• - may present with abnormal bleeding
• - macroscopically thickened endometrium

- Hyperplasia without atypia (low cancer risk)-simple or complex

Atypical hyperplasia (increased cancer risk)-simple or complex-atypia categorised as mild/mod/severe

• Simple hyperplasia without atypia:
• -increased gland to stromal ratio
• -variable sized and shaped glands, often dilated
• -cytologically resembles normal proliferative

• Atypical hyperplasia
• - usu complex
• - v crowded glands with complex infoldings
• - nuclear enlargement,
• - rounding,
• - nucleoli

• Surgery – hysterectomy
• Progestins
• – simple hyperplasia,
• - patients w atypical hyperplasia who are poor surgical candidates or preserving fertility

• 10-15%
• no assoc with raised oestrogen/hyperplasia
• older patients (post-menopausal)
• often high grade serous or clear cell types
• p53 mutations common
• often extrauterine spread
• generally poor prognosis

- endometrial intra-epithelial carcinoma (EIC)/serous carcinoma in situ

- similar molecular pathology to invasive serous carcinoma

- non-invasive replacement of endometrial surface or glandular epithelium by one or more layers of malignant serous cells

- relatively subtle pathology, may be missed

- surgical (hysterectomy, BSO) = bilateral salpingo-oophorectomy (when both ovaries and both Fallopian tubes are removed)

- high risk cases (high grade/deeply invasive) have lymph node dissection +/-omental sampling

- post operative radiotherapy / chemotherapy in some cases

• Smooth muscle tumours
• - leiomyoma (benign, more common)
• - leiomyosarcoma

Endometrial stromal tumours

Very common, often incidental finding

vast majority are benign (leiomyoma or ‘fibroid’)

Often multiple

• typically hormone dependent
• 
• Well circumscribed, clean. No necrosis or haemorrhage..unlike malignant tumours

• 
• histol- uniform... looks like normal myometrium

• Malignant smooth muscle tumour
• <1-2% of all uterine SMT
• rapid growth, especially post menopausal

macro: often single, large, variegated, hemorrhage, necrosis

micro: high cellularity, cellular atypia, infiltrative, mitotic activity, tumour necrosis

aggressive (<50% 5YS)

not responsive to therapy

relatively rare

• Classification:
• - endometrial stromal nodule – circumscribed
• -  endometrial stromal sarcoma (low grade)
• - undifferentiated stromal sarcoma – no resemblance to endometrial stroma

• Most common, low grade malignancy
• Composed of cells resembling endometrial stroma
• Infiltrative growth
• Ttreatment: surgery, high dose progestins
• Indolent growth, late recurrence, can metastasize

• Malignant mixed mullerian tumours (MMMT)
• -Epithelial malignancy with a malignant mesenchymal component
• -Shares some molecular findings and risk factors with type 1 endometrioid carcinoma
• -Often polypoid mass
• - epithelial component often serous
• - homologous or heterologous stroma (eg chondrosarcoma/rhabdomyosarcoma)
• - poor prognosis

• - most patients with abnormal uterine bleeding have benign conditions
• - endometrial carcinoma is usually low grade, low stage and has a good prognosis .
• ....but aggressive variants occur
• - always consider family history (colorectal Cx too)
• - most mesenchymal tumours are benign