Endometrial cancer

Szabolcs Máté MD.

I. St. Department of Obstetrics and Gyneacology

dr.mate.szabolcs@gmail.com

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

Epidemiology

Median age at diagnosis (USA)

62 years

Epidemiology - USA

Stage distribution

Staging- FIGO 2009

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

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

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 35-39 years versus under 25 years

Physical activity

RR ~0,75

Coffee

RR 0,87-0,64

RR 0.87 (95% CI, 0.78-0.97) heavy coffee drinkers, RR 0.64 (95% CI, 0.48-0.86)

Tea

Green tea (RR 0.8, 95% CI 0.7-0.9)

Black tea (RR 0.8, 95% CI 0.5-1.3)

Classification

• Clinical behaviour

• Microscopic features

Type I Type II

Distribution 80% 10-20%

Prognosis Good Bad

Imbalanced oestrogen effect

Yes No

Growing tendency Slow Quick

Precursor Atypical hyperplasia/

Endometrial Intraepithelial Neoplasia

Endometrial Intraepithelialcarcinoma

Grade Low High

Invasion Usually superficial Often deep

Molecular alterations PTEN, KRAS mutations Microsatellite instability

P53, other mutations

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

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

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

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%

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

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

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

Genetic predisposition

BRCA1, 2 mutations does NOT increase the risk

for endometrial cancer!

Cowden syndrome

Rare

Autosomal dominant

PTEN gene mutation

Endometrial cc.- Lifetime risk: 3-28%

Lynch-syndrome

Autosomal dominant

Risk of general population 1/370 in the USA

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

Lynch syndrome

Early onset malignancies

Different organs

Large bowel, rectum

Endometrium

Ovaries

Small bowels, stomach

Bile duct, pancreas

Ureters, pyelons

Glioblastoma

Sweat glands

Lifetime risk (%)

Mean age at diagnosis

(years)

LS / All cancers

(%)

Endometrial ca.

40-60 48–62 2,3

ColorectalCa

40-60 45 2-5%

Ovarian ca. 10-12 42.5

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%)

Abnormal uterine bleeding

Workup

Physical examination

Origin of bleeding

Size and mobility of uterus

Adnexal tumor(metastasis, synchronic tumor)

Surgery planning (laparoscopy, laparotomy, trans-vaginal)

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?

Transvaginal sonography

< 45 years

• Long lasting irregular bleedings +

• Hyper-oestrogen / imbalanced oestrogen condition

• Obesity

• Chronic anovulation (PCO syndrome)

• Failure of medical treatment

• Genetic predisposition (Lynch syndrome)

Abnormal uterine bleeding

Tissue sampling is needed

45 years - menopause

• Cycles shorter than 21 days

• Heavy bleeding

• Menstruation longer than 7 days

• (Higher risk in case of amenorrhoeal periods)

Endometrial cancer

19% 45-54 years

6% 35-44 yearsPostmenopausal

• Any type of bleeding

• Endometrial ca. in the background of bleeding 3-20%

• Endometrial hyperplasia 5-15%

Diagnosis- tissue samplingEndometrial sampling

• Endometrial biopsy

• Pipelle

• No anaesthesia

• The least invasive

(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

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

Preoperative evaluation

Physical examination

Uterus size, mobility

Adnexal tumor

Vaginal vault infiltration

Staging

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

Therapy

Irradiation

Adjuvant

Definitive

EBRT

Brachy therapy

HDR-AL

Surgery

Hysterectomy

Adnexectomy

Lymphadenectomy

Pelvic

Para-aortic Chemotherapy

Adriamycin Cisplatin

Paclitaxel Carboplatin

Adjuvant

Palliative

Hormonal therapy

Receptor positive

Gestagen

Palliative

Hysterectomy + adnexectomy

Total (cervix+corpus)

Route

Laparotomy

Laparoscopy

Vaginal

Grade 1, Stage I/a,

Descensus

Bad general condition

(Robotic)

Advantage Disadvantage

Less surgical stress Longer

Less bleeding More difficult?

Less wound healing complication Trendelenburg position

Faster recovery More expensive equipment

Hot topics in surgery- Lymphadenectomy

Small pelvic

Para-aortic

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

Questions:

Total lymphadenectomy

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

Kismedencei lymphadenectomia

Para-aortikus lymphadenectomia

Hot topics in surgery

Cervical stromal infiltration (Stage II)

Formerly

Radical hysterectomy

Up to date

Simple hysterectomy

Assessment of myometrial infiltration – intraop.

Macroscopic

sensitivity 75%, specificity 92%

Frozen section

Indication for lymphadenectomy

Omentectomy

Serous adenocarcinoma

Peritoneal fluid

Formerly it was a part of staging

Now it isn't

Cytoreduction

In case of peritoneal dissemination operate as ovarian cancermaximal debulking

Survival benefit

Adjuvant treatment

Low risk

NO benefit of adjuvant treatment

Endometrioid

Grade 1 or 2

Stage Ia

Medium risk

Higher chance for local, but low for distant

recurrence

Can be beneficial

Adjuvant irradiation

EBRT / HDR-AL

Deep myometrial

invasion

Cervical stromal

invasion

Grade 3, LVSI +

High risk

High risk for recurrence and for cancer related death

Adjuvant chemotherapy / Chemo-radion therapy is needed

A cervical stromal

infiltration

Stage III, IV

Serous, Clear cell

histological subtype

Depends on

Residual tumor

Risk of recurrance

Risk groups

Histology

Stage

LVSI

(Lymphovascular

space invasion)

Prognosis

Stage Histological Type and grade

Thank you for your attention!