Endometrial cancer Flashcards
Define
Malignancy arising from endometrial tissue; 2nd most common gynae malignancy in UK (1% lifetime risk)
- Uncommon in <40yo (mean age 54yo) – if PMB, diagnosis is endometrial cancer until proven otherwise
TYPE 1: 80-85%
- Endometrioid adenocarcinomas- epithelioid, mucinous, secretory
- Oestrogen driven
- Arise from a background of endometrial hyperplasia (e.g. in PRE-MENOPAUSAL women)
- Low grade tumours, superficially invasive
- Mutations (≥ 4 different genes): PTEN, P13KCA, K-RAS, CTNNB1, FGFR2, p53
TYPE 2: 10-15%
- High-grade serous and clear cell carcinomas
- Older women
- More common in African decent
- Arise from the atrophic endometrium (e.g. in POST-MENOPAUSAL women)
- Higher grade, deeper invasion, higher stage
- Less oestrogen dependent, more aggressive and carry worse prognosis
Mutations:
Serous carcinoma: p53, P13KCA (Her-2 amplification)
Clear cell carcinoma: PTEN, CTNNB1, Her-2 amplification
Aetiology – unclear, involves unopposed oestrogen stimulation of endometrium; exogenous or endogenous
Type 1 (85%) – SEM = secretory, endometrioid, mucinous carcinoma
- Younger patients; oestrogen-dependent; superficially invade; low-grade
- ≥4 mutations must accumulate to cause this…
· PTEN PI3KCA K-Ras
· CTNNB1 FGFR2 P53
Type 2 (15%) – SC = uterine papillary serous carcinoma (UPSC), clear cell carcinoma
- Older patients; less oestrogen-dependent; deeper invasion, higher grade
- Mutations associated:
· Serous Carcinoma: p53 (90%) PI3KCA (15%) Her 2 amplification
· Clear Cell Carcinoma: PTEN CTNNB1 Her-2 amplification
Aetiology
1) Endometrial hyperplasia
Characterised by proliferation of endometrial glands, resulting in a greater gland-to-stroma ratio than in a normal endometrium
Occurs when chronically exposed to oestrogen and unopposed by progesterone
2) Increased life-time exposure to oestrogen.
- Oestrogen causes endometrial cells to proliferate when it is unopposed by progesterone
- Hyperoestrogenic states increase endometrial cancer risk
- Obesity
- More likely to have anovulatory menstrual cycles and less likely to get pregnant NOTE: Chronic anovulation is also seen in PCOS
- Diabetes: Insulin and insulin-like growth factor (IGF) stimulate endometrial proliferation
- Tamoxifen use : Used to prevent recurrent breast cancer which is anti-oestrogenic in the breast but stimulatory in the endometrium
NOTE: Cyclical or continuous progestin-containing hormone treatments reduce the risk
- Hereditary predisposition
Associated with Lynch syndrome- autosomal dominant condition caused by mutations in one of the mismatch repair genes MLH1, MSH2, MSH6 or less commonly, PMS2
Lifetime risk of endometrial cancer in women with Lynch syndrome is 40-60%
Cowden syndrome- PTEN TSG mutation
Risk/ Protective Factors
Risk Factors
- OBESITY
- Diabetes/ insulin resistance
- Nulliparity
- Late menopause > 52 years
- Unopposed oestrogen therapy- endogenous or exogenous
- Tamoxifen (selective oestrogen-receptor modulator)
- PCOS - rf for premenopausal women
- Family history of colorectal, endometrial, ovarian or breast cancer
- HNPCC/Lynch syndrome
Protective Factors
- Hysterectomy
- COCP
- Progestin-based contracep tives including injectables
- IUCD
- Copper coil
- LNG-IUS
- Pregnancy
- Smoking
- Prolonged breastfeeding
Symptoms/ Signs
IMPORTANT: endometrial cancer presents at an early stage so it has a good prognosis
POSTMENOPAUSAL BLEEDING
This is a RED FLAG symptom
Benign causes of PMB:
- Unscheduled bleeding on HRT
- Vaginal atrophy
- Spontaneous over activity of ovaries
- Intermenstrual bleeding
- Post-coital bleeding
- Heavy menstrual bleeding
More advanced stages
- Abdominal pain
- Urinary dysfunction
- Bowel disturbances
- Respiratory symptoms
o PV bleeding (i.e. PMB; as opposed to ovarian cancer which is more associated with palpable masses)
o Bulky uterus -> Metastasises to para aortic LNs
Investigations
Bloods
- FBC
- LFTs
- U+Es
- Serum Ca-125 level
Pap smear
TVUSS + hysteroscopy + endometrial biopsy
- TVUSS
- Allows assessment of endometrial thickness
In postmenopausal women:
- If ≤ 4mm- cancer is very unlikely (this thickness is NORMAL)
- If > 4mm- further evaluation by hysteroscopy and/or biopsy needed
- Usually 4 - 10 mm is a grey area and above 10mm is likely
In premenopausal women:
- If > 10mm- further evaluation by hysteroscopy and/or biopsy needed
Endometrial (pipelle) biopsy +/- hysteroscopy – GOLD STANDARD
- Directed biopsy in abnormal areas and histological confirmation
- If inconclusive, then move onto hysteroscopy with biopsy (see below)
- Hysteroscopy with biopsy
- Performed under local anaesthetic in outpatients where possible
- GA may be used if cervical stenosis or if hysteroscopy is poorly tolerated
Visualisation of the endometrium
IMPORTANT: endometrial biopsy should be considered in women 45 years using hormonal contraception who present with persistent problematic bleeding or a change in bleeding pattern.
STAGING
Determined by MRI
Management
Endometrial Hyperplasia
- Simple (without atypia) high dose progestogens with repeat sampling in 3-4 months (LNG-IUS may be inserted)
- Atypia –> Total hysterectomy with bilateral salpingo-oophrectomy
Endometrial Cancer
- SURGERY
- Total hysterectomy with bilateral salpingo-oophrectomy (BSO)
- Performed abdominally or laparoscopically
- And peritoneal washing
- If MRI suggests cervical involvement, a modified radical hysterectomy
- This also removes a cuff of vagina, paracervical and parametrial tissue to ensure adequate excision margins
- If high grade (grade 3) OR type 2 histology, a pelvic or para-aortic node dissection may be performed
Adjuvant treatment
- Postoperative radiotherapy reduces local recurrence rate but does NOT improve survival
- External beam local radiotherapy or brachytherapy (local radiotherapy over vaginal vault for short periods of time) are options
- Chemotherapy is given for advanced or metastatic disease
Hormone treatment
- If not fit for surgery OR wish to avoid for fertility-sparing reasons
- High dose PO or IU progestins
- Useful for women with complex atypical hyperplasia and low-grade stage IA endometrial tumours
- Relapse rates are high
NOTE:
Alternatives to hysterectomy for premenopausal women are ONLY possible for PRECANCEROUS or EARLY-STAGE, LOW-GRADE endometrial cancers.
Hormone therapy (PO progestogens or Levonorgestrel IUS) is associated with moderate response and high relapse rates
Women faced with losing their fertility should be referred to a specialist to discuss ovarian conservation and/or stimulation for egg retrieval and surrogacy
Complications
Complications
Spread and metastases
Prognosis
Moderate-high relapse rates for hormonal treatment
5-year survival for women with endometrial cancer:
Stage I: 88%
Stage II: 75%
Stage III: 55%
Stage IV: 16%
