Uterine CancerUterine Cancer

Pedro T. Ramirez, M.D.Associate Professor

Director of Minimally Invasive Research & Education

Department of Gynecologic Oncology

Uterine CancerUterine Cancer

• Fourth most common cancer in women in Fourth most common cancer in women in the U.S. behind breast, lung, and colon the U.S. behind breast, lung, and colon cancer cancer

• Most common gynecologic malignancyMost common gynecologic malignancy• Eighth leading cause of female mortality Eighth leading cause of female mortality

from cancerfrom cancer• 97% arise from the endometrium 97% arise from the endometrium

(endometrial carcinoma)(endometrial carcinoma)• 3% arise from the mesenchymal 3% arise from the mesenchymal

components (sarcoma)components (sarcoma)

EpidemiologyEpidemiology

• Median age of diagnosis: 60 yearsMedian age of diagnosis: 60 years– Most common in women > age 50 yearsMost common in women > age 50 years

• Incidence is highly dependent on ageIncidence is highly dependent on age• 75% of uterine cancers occur in post-75% of uterine cancers occur in post-

menopausal womenmenopausal women• There are two major pathogenic types of There are two major pathogenic types of

endometrial cancer endometrial cancer – Type IType I– Type IIType II

Type I Endometrial CarcinomaType I Endometrial Carcinoma

• Younger/peri-menopausal womenYounger/peri-menopausal women• ObeseObese• Associated with estrogen excessAssociated with estrogen excess• Well differentiated endometrioidWell differentiated endometrioid• Superficial myometrial invasionSuperficial myometrial invasion• Infrequent lymph node metastasesInfrequent lymph node metastases• Associated with hyperplasiaAssociated with hyperplasia• Genetic mutations in K-ras, PTEN, MLH1Genetic mutations in K-ras, PTEN, MLH1• Better prognosisBetter prognosis

Type II Endometrial CarcinomaType II Endometrial Carcinoma

• Older/post-menopausal womenOlder/post-menopausal women• ThinThin• Poorly differentiated carcinomaPoorly differentiated carcinoma

– Papillary SerousPapillary Serous– Clear CellClear Cell

• Deep myometrial invasionDeep myometrial invasion• Frequent lymph node metastasesFrequent lymph node metastases• Associated with atrophyAssociated with atrophy• Genetic mutations in p53, Erb-B2Genetic mutations in p53, Erb-B2• Not associated with typical risk factorsNot associated with typical risk factors

RISK FACTORSRISK FACTORS

• Exposure to estrogen is a key risk factorExposure to estrogen is a key risk factor• Risk is increased with dose and time Risk is increased with dose and time

exposedexposed

• Endogenous estrogenEndogenous estrogen– Morbid obesityMorbid obesity

– Polycystic ovary syndromePolycystic ovary syndrome

– OligomenorrheaOligomenorrhea

• Exogenous estrogenExogenous estrogen– Hormone replacement without progestinHormone replacement without progestin

– Tamoxifen (estrogen agonist in the endometrium)Tamoxifen (estrogen agonist in the endometrium)

Risk FactorsRisk Factors

• OBESITY OBESITY – 21-50lb overweight – 3x incidence21-50lb overweight – 3x incidence– >50lb weight - 10x incidence>50lb weight - 10x incidence

• Nulliparity – incidence increased 2xNulliparity – incidence increased 2x• Late Menopause - incidence increased 2.5xLate Menopause - incidence increased 2.5x• Diabetes, hypertension, hypothyroidism are Diabetes, hypertension, hypothyroidism are

associated with endometrial cancerassociated with endometrial cancer

Familial SyndromesFamilial Syndromes

• Lynch Syndrome/HNPCC (Hereditary Lynch Syndrome/HNPCC (Hereditary Nonpolyposis Colorectal Cancer)Nonpolyposis Colorectal Cancer)– Caused by inherited germline mutation in Caused by inherited germline mutation in

DNA-mismatch repair genes (MLH1, MSH2, DNA-mismatch repair genes (MLH1, MSH2, MSH6, PMS2)MSH6, PMS2)

• Cowden SyndromeCowden Syndrome– PTENPTEN mutation mutation

Endometrial Cancer ScreeningEndometrial Cancer Screening

• ACS (2001)ACS (2001)– No routine screening No routine screening – Inform patients at average/increased Inform patients at average/increased

risk about the signs and symptomsrisk about the signs and symptoms– Screen based on presence of Screen based on presence of

symptomssymptoms– Lynch Syndrome – screen annually Lynch Syndrome – screen annually

with endometrial biopsy at age 35yrswith endometrial biopsy at age 35yrs

Signs and SymptomsSigns and Symptoms

• BleedingBleeding– Present in 90% of all casesPresent in 90% of all cases– 15% of patients with postmenopausal bleeding 15% of patients with postmenopausal bleeding

will have endometrial cancerwill have endometrial cancer

• Other Signs/SymptomsOther Signs/Symptoms– Vaginal Discharge(80-90%)Vaginal Discharge(80-90%)– Pelvic Pain, PressurePelvic Pain, Pressure– Referred Leg PainReferred Leg Pain– Change in Bowel HabitsChange in Bowel Habits– Pyometria/HematometriaPyometria/Hematometria

DiagnosisDiagnosis

• Pap SmearPap Smear– Only 30-50% patients with cancer will have an Only 30-50% patients with cancer will have an

abnormal resultabnormal result– AGUS predictive of carcinomaAGUS predictive of carcinoma

• Endometrial BiopsyEndometrial Biopsy– False negative rate of 5-10%False negative rate of 5-10%

• Transvaginal UltrasoundTransvaginal Ultrasound– Not for routine screening or diagnosisNot for routine screening or diagnosis– Suspicious findings include endometrial stripe Suspicious findings include endometrial stripe

>5mm, polypoid mass, or fluid collection in uterus>5mm, polypoid mass, or fluid collection in uterus

Diagnosis: Gold StandardDiagnosis: Gold Standard

• Fractional Dilation and CurettageFractional Dilation and Curettage– Use in cases of cervical stenosis, patient Use in cases of cervical stenosis, patient

intolerance to exam, recurrent bleeding after intolerance to exam, recurrent bleeding after negative biopsy, or bleeding unexplained by negative biopsy, or bleeding unexplained by endometrial biopsy resultendometrial biopsy result

– Sample endocervix and endometriumSample endocervix and endometrium

– False neg – 2-6%False neg – 2-6%

• May add hysteroscopy to identify non-May add hysteroscopy to identify non-malignant causes of bleedingmalignant causes of bleeding

Endometrial HyperplasiaEndometrial Hyperplasia• SimpleSimple

• ComplexComplex

Hyperplasia: Progression to CancerHyperplasia: Progression to Cancer

• NO ATYPIANO ATYPIA

Simple – 1.3%Simple – 1.3%

Complex – 3%Complex – 3%

• ATYPIAATYPIA

Simple – 8%Simple – 8%

Complex – 29%Complex – 29%

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

coexisting adenocarcinomacoexisting adenocarcinoma

Management: HyperplasiaManagement: Hyperplasia NO ATYPIANO ATYPIA

– No Treatment (only for simple)No Treatment (only for simple)– Continuous ProgestinsContinuous Progestins– Re-examination if bleedingRe-examination if bleeding

PROGESTIN OPTIONSPROGESTIN OPTIONSMedroxyprogesterone 10mg/d (10-30mg/d)Medroxyprogesterone 10mg/d (10-30mg/d)Norethindrone 2.5mg/d (2.5-10mg/d)Norethindrone 2.5mg/d (2.5-10mg/d)Megestrol 160mg/d*Megestrol 160mg/d*Oral contraceptive pillsOral contraceptive pillsLevonorgestrel-eluting Intrauterine DeviceLevonorgestrel-eluting Intrauterine Device

Management: HyperplasiaManagement: HyperplasiaATYPIAATYPIA

• HysterectomyHysterectomy• If poor surgical candidate/ desires If poor surgical candidate/ desires

fertility sparingfertility sparing– Continuous high dose progestinContinuous high dose progestin

• Megestrol acetate 160mg/day divided dosesMegestrol acetate 160mg/day divided doses

– Levonorgestrel intrauterine deviceLevonorgestrel intrauterine device– Re-exam every 3 monthsRe-exam every 3 months

– Response to hormones 50-75%Response to hormones 50-75%

Endometrial CarcinomaEndometrial Carcinoma

• HISTOLOGYHISTOLOGY– Endometrioid – 80%Endometrioid – 80%– Papillary Serous 5-7%Papillary Serous 5-7%– Mucinous – 5%Mucinous – 5%– Clear cell – 3%Clear cell – 3%– Villoglandular – 2%Villoglandular – 2%– Secretory – 1%Secretory – 1%– Pure Squamous – RarePure Squamous – Rare

Important Histology PointsImportant Histology Points

• Papillary serous carcinomas Papillary serous carcinomas are aggressiveare aggressive– Even when mixed with other types, if there is > Even when mixed with other types, if there is >

25% serous they will retain aggressive behavior25% serous they will retain aggressive behavior

• Clear cell carcinomas Clear cell carcinomas act similar to high act similar to high grade endometrioid type carcinomagrade endometrioid type carcinoma

• Mucinous carcinomas Mucinous carcinomas act similar to well act similar to well differentiated endometrioid type carcinomadifferentiated endometrioid type carcinoma

• Squamous carcinomas Squamous carcinomas have a poor have a poor prognosisprognosis

Endometrial Cancer GradeEndometrial Cancer Grade

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

Synchronous Endometrial and Synchronous Endometrial and Ovarian CancerOvarian Cancer

• Incidence of 1.4 - 3.8%Incidence of 1.4 - 3.8%• Both tumors are typically well differentiated Both tumors are typically well differentiated

cancerscancers• Good prognosis because ovarian tumor Good prognosis because ovarian tumor

found at earlier stagefound at earlier stage• 30% of patients with endometrioid ovarian 30% of patients with endometrioid ovarian

cancer will have associated endometrial cancer will have associated endometrial cancercancer

• 15-20% of patients with granulosa cell 15-20% of patients with granulosa cell tumors will have associated endometrial tumors will have associated endometrial cancercancer

Pretreatment EvaluationPretreatment Evaluation

• History & PhysicalHistory & Physical

• LaboratoryLaboratory– CBC, Chem, LiverCBC, Chem, Liver– Ca-125 – useful in Ca-125 – useful in

advanced diseaseadvanced disease

• RadiologyRadiology– Chest X-RayChest X-Ray– MRI/ Ultrasound – do not MRI/ Ultrasound – do not

reliably assess depth of reliably assess depth of invasioninvasion

– All other studies are All other studies are ordered as needed based ordered as needed based on symptomson symptoms

Endometrial Cancer TreatmentEndometrial Cancer Treatment

• Surgery is the mainstay of Surgery is the mainstay of treatment followed by treatment followed by adjuvant radiation and/or adjuvant radiation and/or chemotherapy based on chemotherapy based on stage of disease.stage of disease.

• Primary radiotherapy or Primary radiotherapy or hormonal therapy may be hormonal therapy may be employed in patients who employed in patients who have contraindications to have contraindications to surgery.surgery.

Primary Radiation TherapyPrimary Radiation Therapy

• 3-5% of patients who 3-5% of patients who cannot tolerate surgerycannot tolerate surgery– Elderly, obese, multiple Elderly, obese, multiple

medical co-morbiditiesmedical co-morbidities

• Excellent survival and Excellent survival and local control rateslocal control rates

• 5 year disease-specific 5 year disease-specific survival is 87%survival is 87%

Hormone TherapyHormone Therapy

• Appropriate in patients that desire fertility Appropriate in patients that desire fertility preservation preservation – Young patientYoung patient– Well differentiated cancerWell differentiated cancer

• Approximately 75% response rateApproximately 75% response rate– 25% recurrence at a median of 19 months25% recurrence at a median of 19 months

• High dose progestinsHigh dose progestins• ONLY-G1 tumors!!ONLY-G1 tumors!!

Surgical TreatmentSurgical Treatment

• ExplorationExploration• Simple hysterectomySimple hysterectomy

– Radical if suspected Radical if suspected cervical involvementcervical involvement

• Bilateral salpingo-Bilateral salpingo-oophorectomyoophorectomy

• Pelvic washingsPelvic washings• LymphadenectomyLymphadenectomy

– PelvicPelvic– Para-aorticPara-aortic

• +/- Omentectomy+/- Omentectomy

Risk of Lymph Node MetastasisRisk of Lymph Node Metastasis

• GradeGrade– Grade 1 = 3%Grade 1 = 3%– Grade 2 = 9%Grade 2 = 9%– Grade 3 = 18%Grade 3 = 18%

• Myometrial InvasionMyometrial Invasion– None/Superficial = <5%None/Superficial = <5%– > ½ myometrium = 20%> ½ myometrium = 20%

• Cervical InvolvementCervical Involvement– 15%15%

Routine LymphadenectomyRoutine Lymphadenectomy

• No clear evidence of impact of routine No clear evidence of impact of routine lymphadenectomy on survivallymphadenectomy on survival– Retrospective studies have shown a survival Retrospective studies have shown a survival

benefit from lymphadenectomy, however, recent benefit from lymphadenectomy, however, recent randomized control trials fail to show this benefit.randomized control trials fail to show this benefit.

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

Laparoscopic StagingLaparoscopic Staging

• GOG LAP–2GOG LAP–2– Randomized trial of laparoscopy versus Randomized trial of laparoscopy versus

laparatomy for endometrial cancer staging laparatomy for endometrial cancer staging – 2,616 Stage I/IIa patients enrolled2,616 Stage I/IIa patients enrolled– Data suggest that laparoscopic surgical Data suggest that laparoscopic surgical

staging is feasible for most patientsstaging is feasible for most patients• 23% conversion to laparotomy23% conversion to laparotomy• Equivalent complicationsEquivalent complications• Shorter length of stay and longer operative Shorter length of stay and longer operative

times in laparoscopic grouptimes in laparoscopic group– Long-term results of progression-free and Long-term results of progression-free and

overall survival are not yet availableoverall survival are not yet available

Laparotomy vs. Laparoscopy?

Laparotomy vs. Laparoscopy?

Survival by Surgical StageSurvival by Surgical Stage

3-Year3-Year 5-Year5-Year• Stage IStage I 93%93% 90%90%• Stage IIStage II 84%84% 78%78%• Stage IIIStage III 70%70% 62%62%• Stage IVStage IV 30%30% 21%21%

Prognostic FactorsPrognostic Factors

• Stage is the most significant predictor of survivalStage is the most significant predictor of survival• Lymph node metastasis is the most important Lymph node metastasis is the most important

prognostic factor in clinically early endometrial cancer prognostic factor in clinically early endometrial cancer (6-fold higher recurrence rate)(6-fold higher recurrence rate)

Prognostic FactorPrognostic Factor Reduction in 5-yr survivalReduction in 5-yr survival• Lymph node metastasisLymph node metastasis 40%40%• Histology TypeHistology Type

– Papillary serous/Clear cellPapillary serous/Clear cell 40-60%40-60%– High grade endometrioidHigh grade endometrioid 25%25%

• Deep myometrial invasion Deep myometrial invasion 30% 30% • Tumor SizeTumor Size

– Entire uterine cavityEntire uterine cavity 30%30%– >2cm>2cm 10%10%

• Lymphovascular space invasionLymphovascular space invasion 20%20%• Adnexal involvement aloneAdnexal involvement alone 5%5%

Adjuvant TherapyAdjuvant Therapy

• ObservationObservation

• Vaginal vault radiationVaginal vault radiation

• External pelvic radiationExternal pelvic radiation

• Extended-field (pelvic/para-aortic) Extended-field (pelvic/para-aortic) radiationradiation

• Hormonal therapyHormonal therapy

• ChemotherapyChemotherapy

Low Risk Endometrial CancerLow Risk Endometrial Cancer

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

Adjuvant Radiation TherapyAdjuvant Radiation Therapy

• Reduces risk of recurrence Reduces risk of recurrence

• NO impact on overall survivalNO impact on overall survival

• Vaginal brachytherapy Vaginal brachytherapy -Intermediate risk tumors -Intermediate risk tumors (Stage IA, grade 2/3 or Stage IB, grade 1/2) (Stage IA, grade 2/3 or Stage IB, grade 1/2)

• External beam radiation therapy External beam radiation therapy -High risk tumors-High risk tumors (Positive lymph nodes, cervical involvement) (Positive lymph nodes, cervical involvement)

Follow UpFollow Up

• First 2 year – Q3- 4monthsFirst 2 year – Q3- 4months

• Every 6 months until 5 years NEDEvery 6 months until 5 years NED

• Each visitEach visit– Pelvic ExamPelvic Exam– PAP annuallyPAP annually– CXR annuallyCXR annually

RecurrenceRecurrence• 50% recurrences occur within 2 years of treatment50% recurrences occur within 2 years of treatment

• Most common site of recurrence is vaginal or pelvicMost common site of recurrence is vaginal or pelvic

• Most common sites of extra-pelvic metastasis: lungMost common sites of extra-pelvic metastasis: lung

• Isolated vaginal recurrence has the best prognosisIsolated vaginal recurrence has the best prognosis

• Estrogen/progesterone receptor: hormonal therapyEstrogen/progesterone receptor: hormonal therapy

• Chemotherapy options metastatic diseaseChemotherapy options metastatic disease

Uterine SarcomaUterine Sarcoma

• 3% of all uterine cancers3% of all uterine cancers

• 15% of all deaths from uterine cancer15% of all deaths from uterine cancer

• TypesTypes– CarcinosarcomaCarcinosarcoma– LeiomyosarcomaLeiomyosarcoma– Endometrial Stromal TumorsEndometrial Stromal Tumors

CarcinosarcomaCarcinosarcoma

• Post-menopausal- median age of 62 yearsPost-menopausal- median age of 62 years

• Associated with diabetes, hypertension, and Associated with diabetes, hypertension, and obesityobesity

• Increased in African-American womenIncreased in African-American women

• 7-37% of patients have prior pelvic irradiation7-37% of patients have prior pelvic irradiation

Carcinosarcoma SurvivalCarcinosarcoma Survival

• Poor prognosis: Poor prognosis:

2-year survival2-year survivalStage I disease-50%Stage I disease-50%Stage II disease-10%Stage II disease-10%

• Extrauterine 40-60% at diagnosisExtrauterine 40-60% at diagnosis

LeiomyosarcomaLeiomyosarcoma• Leiomyosarcoma:Leiomyosarcoma:

1.1. Mitotic count: > 10 mitosis per HPFMitotic count: > 10 mitosis per HPF2.2. Cellular atypiaCellular atypia3.3. Coagulative necrosisCoagulative necrosis

• Median age 52 years Median age 52 years

• Premenopausal have a better prognosisPremenopausal have a better prognosis

• Leiomyomata: sarcomatous rate of 0.13%Leiomyomata: sarcomatous rate of 0.13%

• Survival rates range from 20 – 63%Survival rates range from 20 – 63%

Sarcoma Treatment: SurgerySarcoma Treatment: Surgery

• Stage I/II sarcomas should be treated Stage I/II sarcomas should be treated with hysterectomy with hysterectomy

• Lymphadenectomy is indicated in all Lymphadenectomy is indicated in all sarcomas sarcomas except leiomyosarcomaexcept leiomyosarcoma

• Bilateral salpingo-ophorectomy Bilateral salpingo-ophorectomy

NOT necessary in premenopausal NOT necessary in premenopausal women women

Sarcoma Treatment: RadiationSarcoma Treatment: Radiation

• Radiation therapy results in lower Radiation therapy results in lower pelvic recurrence rates but NO change pelvic recurrence rates but NO change in overall survival ratein overall survival rate

• The use of radiation in leiomyosarcoma The use of radiation in leiomyosarcoma does not impact recurrence, does not impact recurrence, progression-free, or overall survivalprogression-free, or overall survival

Sarcoma Treatment: RecurrenceSarcoma Treatment: Recurrence

• Isolated lesionsIsolated lesions-surgical excision-surgical excision

• Recurrent carcinosarcoma Recurrent carcinosarcoma -paclitaxel, platinum or ifosfamide-paclitaxel, platinum or ifosfamide

• Recurrent leiomyosarcomaRecurrent leiomyosarcoma-doxorubicin, ifosfamide, docetaxel and -doxorubicin, ifosfamide, docetaxel and gemcitabinegemcitabine

MD Anderson Cancer Center