Uterine Cancer

Pedro T. Ramirez, M.D.

Associate Professor Director of Minimally Invasive Research & Education Department of Gynecologic Oncology

Uterine Cancer
Fourth most common cancer in women in the U.S. behind breast, lung, and colon cancer Most common gynecologic malignancy Eighth leading cause of female mortality from cancer 97% arise from the endometrium (endometrial carcinoma) 3% arise from the mesenchymal components (sarcoma)

Epidemiology
Median age of diagnosis: 60 years
Most common in women > age 50 years

Incidence is highly dependent on age 75% of uterine cancers occur in postmenopausal women There are two major pathogenic types of endometrial cancer
Type I Type II

Type I Endometrial Carcinoma

Younger/peri-menopausal women Obese Associated with estrogen excess Well differentiated endometrioid Superficial myometrial invasion Infrequent lymph node metastases Associated with hyperplasia Genetic mutations in K-ras, PTEN, MLH1 Better prognosis

Type II Endometrial Carcinoma

Older/post-menopausal women Thin Poorly differentiated carcinoma Papillary Serous Clear Cell Deep myometrial invasion Frequent lymph node metastases Associated with atrophy Genetic mutations in p53, Erb-B2 Not associated with typical risk factors

RISK FACTORS
Exposure to estrogen is a key risk factor
Risk is increased with dose and time exposed Endogenous estrogen
Morbid obesity Polycystic ovary syndrome Oligomenorrhea

Exogenous estrogen
Hormone replacement without progestin Tamoxifen (estrogen agonist in the endometrium)

Risk Factors
OBESITY
21-50lb overweight 3x incidence >50lb weight - 10x incidence

Nulliparity incidence increased 2x Late Menopause - incidence increased 2.5x Diabetes, hypertension, hypothyroidism are associated with endometrial cancer

Familial Syndromes
Lynch Syndrome/HNPCC (Hereditary Nonpolyposis Colorectal Cancer)
Caused by inherited germline mutation in DNA-mismatch repair genes (MLH1, MSH2, MSH6, PMS2)

Cowden Syndrome
PTEN mutation

Endometrial Cancer Screening

ACS (2001)
No routine screening Inform patients at average/increased risk about the signs and symptoms Screen based on presence of symptoms Lynch Syndrome screen annually with endometrial biopsy at age 35yrs

Signs and Symptoms

Bleeding
Present in 90% of all cases 15% of patients with postmenopausal bleeding will have endometrial cancer

Other Signs/Symptoms
Vaginal Discharge(80-90%) Pelvic Pain, Pressure Referred Leg Pain Change in Bowel Habits Pyometria/Hematometria

Diagnosis
Pap Smear
Only 30-50% patients with cancer will have an abnormal result AGUS predictive of carcinoma

Endometrial Biopsy
False negative rate of 5-10%

Transvaginal Ultrasound
Not for routine screening or diagnosis Suspicious findings include endometrial stripe >5mm, polypoid mass, or fluid collection in uterus

Diagnosis: Gold Standard

Fractional Dilation and Curettage
Use in cases of cervical stenosis, patient intolerance to exam, recurrent bleeding after negative biopsy, or bleeding unexplained by endometrial biopsy result Sample endocervix and endometrium False neg 2-6%

May add hysteroscopy to identify nonmalignant causes of bleeding

Endometrial Hyperplasia
Simple

Complex

Hyperplasia: Progression to Cancer

NO ATYPIA
Simple 1.3%
Complex 3%

ATYPIA
Simple 8%
Complex 29%

Significant percentage (43%) of complex hyperplasia with atypia will have coexisting adenocarcinoma

Management: Hyperplasia
NO ATYPIA
No Treatment (only for simple) Continuous Progestins Re-examination if bleeding
PROGESTIN OPTIONS
Medroxyprogesterone 10mg/d (10-30mg/d) Norethindrone 2.5mg/d (2.5-10mg/d) Megestrol 160mg/d* Oral contraceptive pills Levonorgestrel-eluting Intrauterine Device

Management: Hyperplasia
ATYPIA
Hysterectomy If poor surgical candidate/ desires fertility sparing
Continuous high dose progestin
Megestrol acetate 160mg/day divided doses

Levonorgestrel intrauterine device Re-exam every 3 months Response to hormones 50-75%

Endometrial Carcinoma
HISTOLOGY
Endometrioid 80% Papillary Serous 5-7% Mucinous 5% Clear cell 3% Villoglandular 2% Secretory 1% Pure Squamous Rare

Important Histology Points

Papillary serous carcinomas are aggressive
Even when mixed with other types, if there is > 25% serous they will retain aggressive behavior

Clear cell carcinomas act similar to high grade endometrioid type carcinoma Mucinous carcinomas act similar to well differentiated endometrioid type carcinoma Squamous carcinomas have a poor prognosis

Endometrial Cancer Grade

The grade is based on the percentage of the solid component.
Well Differentiated (Grade 1): <5% Moderately Differentiated (Grade 2): 5-50% Poorly Differentiated (Grade 3): > 50%

Synchronous Endometrial and Ovarian Cancer

Incidence of 1.4 - 3.8% Both tumors are typically well differentiated cancers Good prognosis because ovarian tumor found at earlier stage 30% of patients with endometrioid ovarian cancer will have associated endometrial cancer 15-20% of patients with granulosa cell tumors will have associated endometrial cancer

Pretreatment Evaluation
History & Physical Laboratory
CBC, Chem, Liver Ca-125 useful in advanced disease

Radiology
Chest X-Ray MRI/ Ultrasound do not reliably assess depth of invasion All other studies are ordered as needed based on symptoms

Endometrial Cancer Treatment

Surgery is the mainstay of treatment followed by adjuvant radiation and/or chemotherapy based on stage of disease. Primary radiotherapy or hormonal therapy may be employed in patients who have contraindications to surgery.

Primary Radiation Therapy

3-5% of patients who cannot tolerate surgery
Elderly, obese, multiple medical co-morbidities

Excellent survival and local control rates 5 year disease-specific survival is 87%

Hormone Therapy
Appropriate in patients that desire fertility preservation
Young patient Well differentiated cancer

Approximately 75% response rate

25% recurrence at a median of 19 months

High dose progestins ONLY-G1 tumors!!

Surgical Treatment
Exploration Simple hysterectomy
Radical if suspected cervical involvement

Bilateral salpingooophorectomy Pelvic washings Lymphadenectomy

Pelvic Para-aortic

+/- Omentectomy

Risk of Lymph Node Metastasis

Grade
Grade 1 = 3% Grade 2 = 9% Grade 3 = 18%

Myometrial Invasion
None/Superficial = <5% > myometrium = 20%

Cervical Involvement
15%

Routine Lymphadenectomy
No clear evidence of impact of routine lymphadenectomy on survival
Retrospective studies have shown a survival benefit from lymphadenectomy, however, recent randomized control trials fail to show this benefit.

Benefit may be directly related to appropriate surgical staging and treatment planning

Laparoscopic Staging
GOG LAP2

Randomized trial of laparoscopy versus laparatomy for endometrial cancer staging 2,616 Stage I/IIa patients enrolled Data suggest that laparoscopic surgical staging is feasible for most patients
23% conversion to laparotomy Equivalent complications Shorter length of stay and longer operative times in laparoscopic group

Long-term results of progression-free and overall survival are not yet available

Laparotomy vs. Laparoscopy?

Laparotomy vs. Laparoscopy?

Survival by Surgical Stage

Stage I Stage II Stage III Stage IV
3-Year 93% 84% 70% 30% 5-Year 90% 78% 62% 21%

Prognostic Factors
Stage is the most significant predictor of survival Lymph node metastasis is the most important prognostic factor in clinically early endometrial cancer (6-fold higher recurrence rate) Prognostic Factor Reduction in 5-yr survival
Lymph node metastasis Histology Type Papillary serous/Clear cell High grade endometrioid Deep myometrial invasion Tumor Size Entire uterine cavity >2cm Lymphovascular space invasion Adnexal involvement alone 40% 40-60% 25% 30% 30% 10% 20% 5%

Adjuvant Therapy
Observation Vaginal vault radiation External pelvic radiation Extended-field (pelvic/para-aortic) radiation Hormonal therapy Chemotherapy

Low Risk Endometrial Cancer

Stage IA (grade 1 or 2) Excellent prognosis No further treatment

Adjuvant Radiation Therapy

Reduces risk of recurrence NO impact on overall survival

Vaginal brachytherapy -Intermediate risk tumors (Stage IA, grade 2/3 or Stage IB, grade 1/2) External beam radiation therapy -High risk tumors (Positive lymph nodes, cervical involvement)

Follow Up
First 2 year Q3- 4months Every 6 months until 5 years NED Each visit
Pelvic Exam PAP annually CXR annually

Recurrence
50% recurrences occur within 2 years of treatment

Most common site of recurrence is vaginal or pelvic

Most common sites of extra-pelvic metastasis: lung Isolated vaginal recurrence has the best prognosis Estrogen/progesterone receptor: hormonal therapy Chemotherapy options metastatic disease

Uterine Sarcoma
3% of all uterine cancers 15% of all deaths from uterine cancer Types
Carcinosarcoma Leiomyosarcoma Endometrial Stromal Tumors

Carcinosarcoma
Post-menopausal- median age of 62 years Associated with diabetes, hypertension, and obesity Increased in African-American women 7-37% of patients have prior pelvic irradiation

Carcinosarcoma Survival
Poor prognosis: 2-year survival Stage I disease-50% Stage II disease-10%

Extrauterine 40-60% at diagnosis

Leiomyosarcoma
Leiomyosarcoma:
1. Mitotic count: > 10 mitosis per HPF 2. Cellular atypia 3. Coagulative necrosis

Median age 52 years Premenopausal have a better prognosis

Leiomyomata: sarcomatous rate of 0.13%

Survival rates range from 20 63%

Sarcoma Treatment: Surgery

Stage I/II sarcomas should be treated with hysterectomy Lymphadenectomy is indicated in all sarcomas except leiomyosarcoma

Bilateral salpingo-ophorectomy NOT necessary in premenopausal women

Sarcoma Treatment: Radiation

Radiation therapy results in lower pelvic recurrence rates but NO change in overall survival rate The use of radiation in leiomyosarcoma does not impact recurrence, progression-free, or overall survival

Sarcoma Treatment: Recurrence

Isolated lesions -surgical excision Recurrent carcinosarcoma -paclitaxel, platinum or ifosfamide Recurrent leiomyosarcoma -doxorubicin, ifosfamide, docetaxel and gemcitabine

MD Anderson Cancer Center