Endometrial Cancer Tseng Jen-Yu 02/05/2007 Tseng Jen-Yu 02/05/2007

Overview Origin => Uterine endometrial lining Most common gynecologic malignancy 35,000 cases diagnosed each year Resulting in 4000 ~ 5000 deaths Normally occurs in postmenopausal Average age at diagnosis => 60 y/o < 5% under age of 40 Lifetime risk: 1.1% Lifetime risk of dying: 0.4% Origin => Uterine endometrial lining Most common gynecologic malignancy 35,000 cases diagnosed each year Resulting in 4000 ~ 5000 deaths Normally occurs in postmenopausal Average age at diagnosis => 60 y/o < 5% under age of 40 Lifetime risk: 1.1% Lifetime risk of dying: 0.4%

Estrogen dependent disease Prolonged exposure without the balancing effects of progesterone Premalignant potential Endometrial hyperplasia Simple => 1% Complex => 3% Simple with atypia => 8% Complex with atypia => 29% Estrogen dependent disease Prolonged exposure without the balancing effects of progesterone Premalignant potential Endometrial hyperplasia Simple => 1% Complex => 3% Simple with atypia => 8% Complex with atypia => 29%

Incidence and Prevalence Most common gynecologic cancer 4th most common in women (US) 2nd most common in women (UK) 5th most common in women (worldwide) Western developed > Southeast asia 35,000 new cases annually 5,000 death annually Increase in the 1970’s Increased use of menopausal estrogen therapy Most common gynecologic cancer 4th most common in women (US) 2nd most common in women (UK) 5th most common in women (worldwide) Western developed > Southeast asia 35,000 new cases annually 5,000 death annually Increase in the 1970’s Increased use of menopausal estrogen therapy

Types 90% endometrial adenocarcinoma Arise from the epithelium Tumor grading Grade 1 Well differentiated Grade 2 Moderately differentiated with solid component Grade 3 Poorly differentiated with solid sheets of tumor 90% endometrial adenocarcinoma Arise from the epithelium Tumor grading Grade 1 Well differentiated Grade 2 Moderately differentiated with solid component Grade 3 Poorly differentiated with solid sheets of tumor

10% rare cell types Papillary serous carcinoma Clear cell carcinoma Papillary endometrial carcinoma Mucinous carcinoma Rarer cancers Onset at later age Greater risk for metastases Poorer prognosis 50% of treatment failure 10% rare cell types Papillary serous carcinoma Clear cell carcinoma Papillary endometrial carcinoma Mucinous carcinoma Rarer cancers Onset at later age Greater risk for metastases Poorer prognosis 50% of treatment failure

Risk Factors Obesity Excess weight have 2 ~ 5 x greater risk Fat cells (adipocytes) produce estrogen Diabetes Mellitus and Hypertension DM women have 2 x greater risk Nulliparity Progesterone counterbalances estrogen Pregnancy lowers risk Obesity Excess weight have 2 ~ 5 x greater risk Fat cells (adipocytes) produce estrogen Diabetes Mellitus and Hypertension DM women have 2 x greater risk Nulliparity Progesterone counterbalances estrogen Pregnancy lowers risk

Early Menarche and Late Menopause Associated with more estrogen exposure Estrogen Replacement Therapy Place women at high risk Risk reduced when + progesterone Tamoxifen Anti-estrogenic drug for breast cancer Side effect Induces non-cancerous uterine tumors Some may develop into endometrial cancer Long term use => endometrial cancer Only 1 in 500 develop endometrial cancer Early Menarche and Late Menopause Associated with more estrogen exposure Estrogen Replacement Therapy Place women at high risk Risk reduced when + progesterone Tamoxifen Anti-estrogenic drug for breast cancer Side effect Induces non-cancerous uterine tumors Some may develop into endometrial cancer Long term use => endometrial cancer Only 1 in 500 develop endometrial cancer

Genetic Predisposition Risk may approach 50% in some families Previous Cancer History of breast / colon / ovarian cancer are at increased risk Time interval can be as long as 10 years Diet Association is still unclear Diet rich in animal fat and protein => risk ^ Diet rich in vegetable, fruits, grain=> risk v Genetic Predisposition Risk may approach 50% in some families Previous Cancer History of breast / colon / ovarian cancer are at increased risk Time interval can be as long as 10 years Diet Association is still unclear Diet rich in animal fat and protein => risk ^ Diet rich in vegetable, fruits, grain=> risk v

Reduced Risk Oral Contraceptives Combined OC => 50% reduced rate Actual reduction number small because uncommon in women of child bearing age Long term offers protection Reduced risk presumably => progesterone Tobacco Smoking Some evidence that it reduces the rate Smokers have lower levels of estrogen and lower rate of obesity Oral Contraceptives Combined OC => 50% reduced rate Actual reduction number small because uncommon in women of child bearing age Long term offers protection Reduced risk presumably => progesterone Tobacco Smoking Some evidence that it reduces the rate Smokers have lower levels of estrogen and lower rate of obesity

Prevention and Survival Early detection is best prevention Treating precancerous hyperplasia Hormones (progestin) D&C Hysterectomy 10 ~ 30% untreated develop into cancer Average 5 year survival Stage I => 72 ~ 90% Stage II=> 56 ~ 60% Stage III => 32 ~ 40% Stage IV => 5 ~ 11% Early detection is best prevention Treating precancerous hyperplasia Hormones (progestin) D&C Hysterectomy 10 ~ 30% untreated develop into cancer Average 5 year survival Stage I => 72 ~ 90% Stage II=> 56 ~ 60% Stage III => 32 ~ 40% Stage IV => 5 ~ 11%

Signs Postmenopausal vaginal bleeding Abnormal uterine bleeding Bleeding in between periods Heavier / longer lasting menstrual bleeding Abnormal vaginal discharge / Pyometra Pelvic or back pain Pain on urination Pain on sexual intercourse Blood in stool or urine Postmenopausal vaginal bleeding Abnormal uterine bleeding Bleeding in between periods Heavier / longer lasting menstrual bleeding Abnormal vaginal discharge / Pyometra Pelvic or back pain Pain on urination Pain on sexual intercourse Blood in stool or urine

Diagnosis Endometrial sampling Dilation and curettage / Endometrial aspiration Image TVS / CT scan / MRI Standard Hysteroscopy + targeted biopsy Tumor marker Ca 125 / 199 Cystoscope / Proctoscope Endometrial sampling Dilation and curettage / Endometrial aspiration Image TVS / CT scan / MRI Standard Hysteroscopy + targeted biopsy Tumor marker Ca 125 / 199 Cystoscope / Proctoscope

Staging Stage I Tumor confined to uterine body Stage Ia Tumor limited to endometrium Stage Ib Tumor invades less than ½ of myometrium Stage Ic Tumor invades more than ½ of myometrium Stage II Tumor extends to the cervix Stage IIa Cervical extension limited to endocervical glands Stage IIb Tumor invades cervical stroma Stage I Tumor confined to uterine body Stage Ia Tumor limited to endometrium Stage Ib Tumor invades less than ½ of myometrium Stage Ic Tumor invades more than ½ of myometrium Stage II Tumor extends to the cervix Stage IIa Cervical extension limited to endocervical glands Stage IIb Tumor invades cervical stroma

Stage III Regional tumor spread Stage IIIa Tumor invades serosa / adnexa / peritoneum / ascites (+) Stage IIIb Vaginal involvement / metastases present Stage IIIc Tumor spread to pelvic LN Stage IV Bulky pelvic disease or distant spread Stage IVa Tumor has spread to bladder or rectum Stage IVb Distant metastases present / inguinal LN Stage III Regional tumor spread Stage IIIa Tumor invades serosa / adnexa / peritoneum / ascites (+) Stage IIIb Vaginal involvement / metastases present Stage IIIc Tumor spread to pelvic LN Stage IV Bulky pelvic disease or distant spread Stage IVa Tumor has spread to bladder or rectum Stage IVb Distant metastases present / inguinal LN

Spread Direct spread Through endometrial cavity to the cervix Through fallopian tubes to ovary / peritoneum Invade myometrium reaching serosa Rare: invasion to pubic bone Lymphatic spread Pelvic and para-aortic LN Inguinal LN ( rare ) Hematogenous spread Rare but may spread to lungs Direct spread Through endometrial cavity to the cervix Through fallopian tubes to ovary / peritoneum Invade myometrium reaching serosa Rare: invasion to pubic bone Lymphatic spread Pelvic and para-aortic LN Inguinal LN ( rare ) Hematogenous spread Rare but may spread to lungs

Treatment Surgery Early stage ( I and II ) Typical surgery is ATH + BSO + BPLND VTH + BSO + laparoscopic BPLND LAVH + BPLND Advanced stage Debulking surgery Radiotherapy +/- hormone / chemotherapy Surgery Early stage ( I and II ) Typical surgery is ATH + BSO + BPLND VTH + BSO + laparoscopic BPLND LAVH + BPLND Advanced stage Debulking surgery Radiotherapy +/- hormone / chemotherapy

Radiation External beam pelvic radiation Reserve use of radiotherapy until post-ATH Adjuvant radiation therapy is controversial Regional pelvic radiation proven to decrease pelvic recurrence Not necessarily improve survival rate Most beneficial for patients with tumor confined to the pelvis Patients with increased likelihood of recurrence ( Stage Ic to IIIc) Brachytherapy Prevent vaginal cuff recurrence Radiation External beam pelvic radiation Reserve use of radiotherapy until post-ATH Adjuvant radiation therapy is controversial Regional pelvic radiation proven to decrease pelvic recurrence Not necessarily improve survival rate Most beneficial for patients with tumor confined to the pelvis Patients with increased likelihood of recurrence ( Stage Ic to IIIc) Brachytherapy Prevent vaginal cuff recurrence

Hormonal therapy Progesterone => for metastatic cancer Less than 20% response rate Chemotherapy No clear results on effectiveness Potentially most useful in metastatic cancer Not as important as surgery and radiation Only used in advanced or recurrent tumor after definitive treatment with surgery and radiation Hormonal therapy Progesterone => for metastatic cancer Less than 20% response rate Chemotherapy No clear results on effectiveness Potentially most useful in metastatic cancer Not as important as surgery and radiation Only used in advanced or recurrent tumor after definitive treatment with surgery and radiation

Recurrence Likely in women with advanced disease Within 3 years of original diagnosis Hormone therapy can be considered Use of chemotherapy is being evaluated External beam pelvic radiation or brachytherapy Likely in women with advanced disease Within 3 years of original diagnosis Hormone therapy can be considered Use of chemotherapy is being evaluated External beam pelvic radiation or brachytherapy

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