Endometrial Cancer Types and Risks

ENDOMETRIAL CANCER ENDOMETRIAL CANCER also endometrial polyps and endometrial hyperplasia also endometrial polyps and endometrial hyperplasia Dr Jane Wilcock BSc FRCG SFHEA PGCertMedEd. MAHEd. Endometrial cancer review 26:7 193-199Macnab W. and Mehasseb M. K. Obstetrics, Gynaecology and Reproductive Medicine2016 Endometrial Cancer: ESMO Clinical Practice Guidelines Ann Oncol 2013; 24 (Suppl 6): vi33-vi38. N. Colombo, E. Preti, F. Landoni, S. Carinelli, A. Colombo, C. Marini, C. Sessa

The Ten Most Common Cancers in Females, Numbers of New Cases, UK, The Ten Most Common Cancers in Females, Numbers of New Cases, UK, 2015 2015 This chart excludes non-melanoma skin cancer because of known under-reporting http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence/common-cancers-compared#heading-Two

Epidemiology/risks Epidemiology/risks In the world cervical cancer is most common cancer and endometrial second. 50% new gynae cancers and rising incidence: increasing lifespan, obesity, less hysterectomies for benign conditions 95%>40years 80% 60-70years old. Lifetime risk 1 in 40 Presents early with PMB usually

Endometrial cancer type1 Endometrial cancer type1 80%: from glandular epithelium adenocarcinoma 50% complex atypical hyperplasia have endometrial cancer Obesity Nulliparity Insulin resistance Oestrogen (unopposed oestrogen; granulosa cell ovarian ca-5% rare, sex chord stroma derivation slow growing) Genetic abnormalities in mismatch repair or tumour suppressor genes Can be oestrogen and progesterone receptor positive (interact); loss of receptors occurs in carcinogenesis. Not yet useful in treatment but gaining a place in staging algorithms

Endometrial cancer type2 Endometrial cancer type2 Unusual and a homogenous group of female hormone receptor negative cancers with a poorer prognosis serous endometrial cancer clear cell squamous Carcinosarcoma (malignant mixed Mullerian) Undifferentiated Endometrial stromal sarcomas ESS Not the same risk factors as type1 Mutations of p53 tumour suppressor gene common Often peritoneal spread ( like ovarian cancer) Metastases: lung, breast, ovary, GIT

Obesity, oestrogen and tamoxifen Obesity, oestrogen and tamoxifen Up to 50% of endometrial cancers in developed world 2-4x increased risk adipocytes secrete oestrogen plus increased insulin levels due to resistance and increased insulin growth factor-1 (IGF-1) both anabolic hormones stimulating cell growth State of play: limited evidence so far that lowering weight reduces cancer risk Tamoxifen (selective oestrogen receptor modulator) as an adjuvant therapy in breast cancer increases endometrial pathology including cancer State of play: no evidence that routine screening if no abnormal bleeding improves detection of endometrial cancer. Less tamoxifen being used as aromatase inhibitors have substituted (letrozole). Aromatase synthesises oestrogen in adipocytes.

Endometrial hyperplasia Endometrial atypical hyperplasia Endometrial cancer Type1

<5% of endometrial cancer is associated with genetic inheritance <5% of endometrial cancer is associated with genetic inheritance Tumour suppressor genes p53, PTEN gene can be associated Mismatch repair genes (MMR) BRACA1 and 2 not associated with endometrial cancer Lynch II syndrome, HNPCC (hereditary non-polyposis colon cancer) is associated Autosomal dominant with mutation DNA MMR genes 50% F develop endometrial cancer as first cancer rather than CRC 10% risk of other cancers If at risk offered after completed family hysterectomy and BSO or endometrial annual imaging and biopsy

Diagnosis Diagnosis Low prevalence prevents imaging as screening being practical 90% PMB Of women with PMB 10% will have cancer Persistent vaginal discharge Premenopausal women: IMB, abnormal calls at cervical screening, PCO women at increased risk Investigation History, FH, hormonal use, examination including PV and speculum to assess cervix, 2WW referral TV USS: endometrial thickness postmenopausal has high NPV so<5mm is reassuring; <3mm more so

Investigation Hysteroscopy and endometrial sampling 80% F in OPC Pipelle: detects ca postmenopausal women99.6% and pre-menopause 91% Endometrial hyperplasia 81% sensitive (identify cases correctly) and specificity 98% (identify those without hyperplasia correctly) MDT: CXR, CT scan, MRI for cervix and myometrial invasion Spread is to LNs, trans-tubal to ovaries and peritoneum, lungs Treatment is hysterectomy and BSO, can be laparoscopic and robotic Adjuvant or later stage radiotherapy: external or brachytherapy Controversies about lymph node dissection study on carboplatin and paclitaxel ongoing Progesterone therapy no a cure all: 40% recurrence after initial response in younger women wanting to retain their uterus

survival survival 5 year survival 80%; most recurrences in first 3 years post op Stage1 disease 85-90% Future therapy: PTEN is a protein produced in oestrogen high environments and regulates cell growth. Mutations of PTEN occur in many endometrial cancer type1 and if PTEN errors then signalling pathways (mTOR) are stimulates to cell division and growth. Temsirolinus inhibits mTOR and has a 26% response rate and 63% disease stabilisation rate Trials on Bevacizumab (Avastin), recombinant monocloncal antibody against vascular endothelial growth factor (VEGF) Epidermal growth factor (EGFR) inhibitors (erlotinib, tyrosine kinase inhibitor TKI) not helpful so far but some tumours have high EGFR levels

Endometrial polyps: a study Endometrial polyps: a study Human Reproduction,Vol.32,No.2pp. 340 345,2017 The natural history of endometrial polyps M.Wong, B.Crnobrnja, V.Liberale, K.Dharmarajah, M.Widschwendter,and D.Jurkovic at UCL, Slovenia and Italy 1997-2005 case note review of women(112) treated expectantly 6 months with endometrial cancer all adults. All had 2 x USS and growth rate of polyps ascertained exclusion: anyone on hormones or hormone modulators Results: mean 22.5months range 6-136months 11/75 =15% women with no abnormal bleeding developed abnormal bleeding Growth rate did not associate with abnormal bleeding 7/11= 6.3% had complete spontaneous polyp regression Those that had surgery (9%) were confirmed as benign Findings: women should be told that the growth pattern of a polyp cannot be accurately predicated

Endometrial hyperplasia Endometrial hyperplasia Management of Endometrial Hyperplasia Management of Endometrial Hyperplasia Green- -top Guideline No. 67 RCOG/BSGE Joint Guideline | February 2016 top Guideline No. 67 RCOG/BSGE Joint Guideline | February 2016 Green Presents as abnormal bleeding, HMB, irregular bleeding, IMB,PMB, unscheduled bleeding on HRT Risks: obesity, PCO syndrome, oestrogen secreting tumours, drug induced oestrogen stimulation, possible immunosuppression If endometrial thickness is<3-4mm then risk of endometrial cancer is <1% 2014 World Health Organization (WHO) classification separates endometrial hyperplasia into 1. hyperplasia without atypia; endometrial cancer is < 5% over 20 years and majority of cases regress spontaneously during follow-up 2. atypical hyperplasia

hyperplasia without atypia hyperplasia without atypia endometrial cancer risk is < 5% over 20 years and most regress spontaneously during follow-up. Followed up in gynae. OPC 6 monthly, before if abnormal bleeding Lose weight if obese, review (stop HRT) Both continuous oral and local intrauterine (levonorgestrel-releasing intrauterine system [LNG-IUS]) progestogens are effective in achieving regression. The LNG-IUS is first-line medical treatment as compared with oral progestogens it has a higher regression rate, more favourable bleeding profile and fewer adverse effects. Try to keep in for 5 years as reduces relapse rates Continuous progestogens should be used (medroxyprogesterone 10 20 mg/day or norethisterone 10 15 mg/day) for women who decline the LNG-IUS. Endometrial ablation not recommended Can have hysterectomy (BSO in postmenopausal women) but not first line

Hyperplasia with atypia Hyperplasia with atypia Treatment is hysterectomy, laparoscopic if possible and possibly with BSO( individualise in pre-menopausal women) If patients want fertility and refuse surgery then LNG-IUS or second line progesterone continuously with monitoring should be started and 3 monthly surveillance

HRT and hyperplasia HRT and hyperplasia Do not use unopposed oestrogen in women with a uterus] Report unscheduled bleeding on HRT (3 months as in FSRH hormonal contraception advice?) If hyperplasia occurs on sequential HRT change to continuous progesterone as LNG-IUS or with continuous combined HRT preparation (Kliovance) under specialist advice

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