Endometrial cancer. Szabolcs Máté MD. I. St. Department of Obstetrics and Gyneacology.

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1 Endometrial cancer Szabolcs Máté MD. I. St. Department of Obstetrics and Gyneacology

2 Epidemiology Developing countries Cervical cancer is the most common gyn. malignant tumor Developed countries Cervical cancer screening Incidence is of cervical cancer is declining Life style risks for endometrial cancer Incidence is increasing of ENDOMETRIAL and OVARIAN cancer

3 Epidemiology Median age at diagnosis (USA) 62 years

4 Epidemiology - USA

5 Stage distribution

6 Staging- FIGO 2009

7 Clinical signs Abnormal vaginal bleeding, odorous discharge Is present in 75-90% The amount of bleeding is not in connection with the chance of malignancy Risk of malignancy in the background of an abnormal bleeding depends on: Age Risk factors

8 Risk factors Hyper oestrogen conditions Chronic anovulation Obesity Peripheral aromatase enzyme Androgen (suprarenal gland, ovaries) oestrone Oestrogen producing tumor (Granulosa cell tu.) Diabetes, hypertension Obesity Independent risk factors Imbalanced hormonal therapy Oestrogen replacement therapy gestagen opposition is compulsory in case of uterus Null parity

9 Protective factors Hormonal anti-contraceptives (OAC) Combined OAC Reduces risk at least by 50% Progesteron only pills (minipill, Levonorgestrel IUD, Depo products) Also effective Age at last pregnancy 32% less risk if the last delivery is between years versus under 25 years Physical activity RR ~0,75 Coffee Tea RR 0,87-0,64 RR 0.87 (95% CI, ) heavy coffee drinkers, RR 0.64 (95% CI, ) Green tea (RR 0.8, 95% CI ) Black tea (RR 0.8, 95% CI )

10 Classification Clinical behaviour Microscopic features Type I Type II Distribution 80% 10-20% Prognosis Good Bad Imbalanced oestrogen effect Growing tendency Slow Quick Precursor Yes Atypical hyperplasia/ Endometrial Intraepithelial Neoplasia No Endometrial Intraepithelial carcinoma Grade Low High Invasion Usually superficial Often deep Molecular alterations PTEN, KRAS mutations Microsatellite instability P53, other mutations

According to the proportion of glandular structure Normal

11 Type I endometrial carcinoma Histological types Endometrioid adenocarcinoma grade 1,2 Histological grading According to the proportion of glandular structure Normal endomertium Endometrioid adenocc grade 1 Endometrioid adenocc grade 3

12 Type II endometrial carcinoma Histological types Endometrioid adenocarcinoma Grade 3 Non-endometrioid Serous adenocaricinoma Clear cell adenocaricinoma Carcinosarcoma (Malignant Mixed Müllerian Tumor) Undifferenciated Mucinosus, Squamous, transitional cell, mesonephric

13 Endometrioid adenocarcinoma Most common type 75-80% Majority is well differenciated (glandular structures) Grade Proportion of glandular structure Nuclearis grade Genetic profile Microsatellite instability PTEN, K-ras, and beta-catenin gen mutation Typically Oestrogen and Progesteron receptor expression

14 Serous and clear cell adenocarcinoma Aggressive types Bad prognosis High grade Often diagnosed at advanced stage Myometrial and vascular invasion is more common Serous 1-5% Clear cell 5-10%

15 Pathogenesis 1994 WHO classification Hyperplasia simplex Hyperplasia complex Hyperplasia simplex atypica Hyperplasia complex atypica EIN 79% atypic hyperplasia 44% complex non-atypic hyperplasia 5% simplex hyperlpasia

16 Pathogenesis Endometrial Intraepithelial Neoplasia (EIN) Focal neoplastic lesion Genetic modifications PTEN mutation 44% PAX2 nuclear transcription factor inactivation 78% Kras mutation B cathenin mutation Endometrial Intapeithelial Carcinoma (EIC) Serous adenocarcinoma - premalignant form p53 mutation

17 Pathogenesis Clear cell carcinoma No known premalignant lesion No known epidemiologic risk factor Gene expression profile is unique NO oestrogen and progesteron receptor expression NO p53 mutation Hepatocyte nuclear factor-1β (HNF-1β) transcription factor - up regulation ARID1A tumor suppressor gene mutation

18 Genetic predisposition BRCA1, 2 mutations does NOT increase the risk for endometrial cancer! Lynch-syndrome Autosomal dominant Risk of general population 1/370 in the USA Cowden syndrome Rare Autosomal dominant PTEN gene mutation Endometrial cc.- Lifetime risk: 3-28% MMR (Mismatch Repair) genes germline mutation 90% MSH2, MLH1 7-10% MSH6 5% PMS2 1% EPCAM Recognise and repair the impair / nucleotides Dysfunction Microsatellite instability (MSI) Tumor suppressor gene inactivation Carcinogenesis

19 Lynch syndrome Early onset malignancies Different organs Large bowel, rectum Endometrium Ovaries Small bowels, stomach Bile duct, pancreas Ureters, pyelons Glioblastoma Sweat glands Endometrial ca. Lifetime risk (%) Mean age at diagnosis (years) LS / All cancers (%) ,3 Colorectal Ca % Ovarian ca

20 Lynch-syndrome prophylactic surgery 315 patients with Lynch syndrome 61 Hysterectomy 47 Hysterectomy+ salpingo-oophorectomy Control group Women with Lynch-syndrome NO operation Prophylactic surgery group Endometrium cc., ovarium cc., primer peritoneal cc. 0 (0%) Control group Endometrial cancer 69 (33%) Ovarian cancer 12 (5%)

21 Abnormal uterine bleeding Workup Physical examination Origin of bleeding Size and mobility of uterus Adnexal tumor (metastasis, synchronic tumor) Surgery planning (laparoscopy, laparotomy, transvaginal) Laboratory tests Exclude pregnancy Blood count Coagulogram (Oral anticoagulant therapy?) Transvaginal sonography Size of uterus Leiomyoma Endometrium thickness and structure Myometrium infiltration Cervical stroma invasion Ovaries (cyst, tumor?) Ascites?

22 Transvaginal sonography

23 Abnormal uterine bleeding Tissue sampling is needed < 45 years Long lasting irregular bleedings + Hyper-oestrogen / imbalanced oestrogen condition 45 years Obesity - menopause Chronic Cycles shorter anovulation than 21 (PCO days syndrome) Failure Heavy of medical bleeding treatment Genetic Menstruation predisposition longer (Lynch than syndrome) 7 days (Higher risk in case of amenorrhoeal periods) Endometrial cancer 19% years 6% Postmenopausal years Any type of bleeding Endometrial ca. in the background of bleeding 3-20% Endometrial hyperplasia 5-15%

Endometrial sampling Endometrial biopsy Pipelle No

sampling (D&C) Dilatation and Curettage Gold standard

endometrial biopsy Heavy bleeding (to stop bleeding)

24 Endometrial sampling Endometrial biopsy Pipelle No anaesthesia The least invasive Diagnosis- tissue sampling (D&C) Dilatation and Curettage Gold standard Anaesthesia, One day surgery Indicated 2x negative endometrial biopsy Heavy bleeding (to stop bleeding) Hysteroscopy, visual guided biopsy Not the first choice Gold standard

25 Screening General population Not indicated Early signs, good prognosis TVS not specific enough Tamoxifen therapy TVS Endometrial thickness measuring <6-8mm Genetic predisposition Lynch syndrome Cowden syndrome Screening regular endometrial sampling Prophylactic hysterectomy

26 Physical examination Preoperative evaluation Uterus size, mobility Adnexal tumor Staging Vaginal vault infiltration Digital imaging (Abdomino-pelvic CT, MRI) CT Lymph node metastasis Distant / Parenchymal metastasis, Ascites MRI Detailed examination of small pelvis Myometrial-, cervical infiltration TVS Myometrial-, cervical infiltration Adnexal region Ascites Tumor marker CA-125 elevates in case of dissemination Peritoneal, Lymph node General work-up Risk assessment anaesthesia perioperative complications

27 Therapy Surgery Hysterectomy Adnexectomy Lymphadenectomy Irradiation Pelvic Adjuvant Para-aortic Definitive Chemotherapy EBRT Brachy therapy HDR-AL Adriamycin Cisplatin Paclitaxel Carboplatin Adjuvant Palliative Hormonal therapy Receptor positive Gestagen Palliative

28 Hysterectomy + adnexectomy Total (cervix+corpus) Route Laparotomy Laparoscopy Advantage Less surgical stress Less bleeding Less wound healing complication Faster recovery Disadvantage Longer More difficult? Trendelenburg position More expensive equipment Vaginal Grade 1, Stage I/a, Descensus Bad general condition (Robotic)

Hot topics in surgery- Lymphadenectomy Small pelvic Para-aortic Questions: Total lymphadenectomy Indication Suspicious / positive node on imaging Intraoperative finding of enlarged node Risk based

29 Hot topics in surgery- Lymphadenectomy Small pelvic Para-aortic Questions: Total lymphadenectomy Indication Suspicious / positive node on imaging Intraoperative finding of enlarged node Risk based Grade1, St Ia 3-5% Grade3, St Ib 20% High risk for lymph node met. Serous, Clear cell, High-grade Myometrial infiltration >50% St II (cervix stroma infiltration) Large tumor >2cm Selective lymphadenectomy (Removal of enlarged nodes) Sampling (random removal) Para-arotic region (up to the left renal vein) Higher operative load Higher postop risk Commonly - Limited surgical stress tolerability Obesity, Age, Co-morbidity

30 Kismedencei lymphadenectomia

31 Para-aortikus lymphadenectomia

32 Hot topics in surgery Cervical stromal infiltration (Stage II) Formerly Radical hysterectomy Up to date Simple hysterectomy Cytoreduction In case of peritoneal dissemination operate as ovarian cancer maximal debulking Survival benefit Peritoneal fluid Formerly it was a part of staging Assessment of myometrial infiltration intraop. Macroscopic sensitivity 75%, specificity 92% Frozen section Indication for lymphadenectomy Now it isn't Omentectomy Serous adenocarcinoma

Adjuvant treatment Depends on Residual tumor Risk of recurrance Low risk Medium risk Higher chance for local, but low for distant recurrence High risk High risk for recurrence and for cancer related

33 Adjuvant treatment Depends on Residual tumor Risk of recurrance Low risk Medium risk Higher chance for local, but low for distant recurrence High risk High risk for recurrence and for cancer related death Risk groups Histology Stage LVSI (Lymphovascular space invasion) NO benefit of adjuvant treatment Endometrioid Grade 1 or 2 Stage Ia Can be beneficial Adjuvant irradiation EBRT / HDR-AL Deep myometrial invasion Cervical stromal invasion Adjuvant chemotherapy / Chemo-radion therapy is needed A cervical stromal infiltration Stage III, IV Serous, Clear cell histological subtype Grade 3, LVSI +

34 Prognosis Stage Histological Type and grade

35 Thank you for your attention!

Index. B Bilateral salpingo-oophorectomy (BSO), 69

Index. B Bilateral salpingo-oophorectomy (BSO), 69 A Advanced stage endometrial cancer diagnosis, 92 lymph node metastasis, 92 multivariate analysis, 92 myometrial invasion, 92 prognostic factors FIGO stage, 94 histological grade, 94, 95 histologic cell