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Endometrial CancerOB/GYN Hospital Fudan UniversityXin LU,MD,Ph.D.Endometriod cancer-ContentsIncidenceRisk factorsClassificationSymptomsPathologyFIGO StagingDiagnosisTreatmentWHO Cancer ReportGlobal cancer rates could increase by 50%to 15 million by 2020 Endometrial cancer is the 4th most common cancer in womenNew Diagnosed cases:142,000 Died cases each year:42,000 incidence 2-3%Average age:60sHistologic TypesEndometrial CancersEndometrioid(87%)Adenosquamous(4%)Papillary Serous (3%)Clear Cell (2%)Mucinous(1%)Other(3%)Endometrial Cancer:Type I/IIType IEstrogen RelatedYounger and heavier patientsLow gradeBackground of HyperplasiaPerimenopausalExogenous estrogenFamilial/genetic(15%)Lynch II syndrome/HNPCCFamilial trendType II(10%)AggressiveHigh gradeUnfavorable HistologyUnrelated to estrogen stimulationOccurs in older&thinner womenEndometrial Cancer:Risk FactorsRisk FactorsRelative Risk X Obesity 2-5 PCOS 5Estrogen use10-20Nulliparous3Infertility2-3Diabetes/Hypertension1.3-3Nulliparous3Early Menarche(12 y/o)1.5-2Atypical Hyperplasia OC0.3-0.5From:Williams Gynecology 2009Endometrium Carcinoma2009 ClassificationStage CharacteristicStage I*Tumor confined to the corpus uteri IA*No or less than half myometrial invasion IB*Invasion equal to or more than half of the myometriumStage II*Tumor invades cervical stroma,but does not extend beyond the uterus*Stage III*Local and/or regional spread of the tumor IIIA*Tumor invades the serosa of the corpus uteri and/or adnexae#IIIB*Vaginal and/or parametrial involvement#IIIC*Metastases to pelvic and/or para-aortic lymph nodes#.IIIC1*Positive pelvic nodes IIIC2*Positive paraaortic lymphnodes with or without positive pelvic lymph nodesStage IV*Tumor invades bladder and/or bowel mucosa,and/or distant metastases IVA*Tumor invasion of bladder and/or bowel mucosa IVB*Distant metastases,including intra-abdominal metastases and/or inguinal lymph nodes Stage I(73%)Confined to uterusStage II(11%)Cervix involvedStage III(13%)Uterine serosa,adnexae,positive cytology,vaginal metastases,pelvic/aortic node metastasesStage IV(3%)Bladder,bowel,inguinal node,distant metastasisEndometrial Cancer:FIGO Surgical StageEndometrial Cancer Prognosis:Survival by Stage:Stage%5yr survivalIA91IB88IC81IIA77IIB67IIIA60IIIB41IIIC32IVA20IVB5Survival by Grade:Grade%5yr survival192287374Overall 5Yr Survival 84%Stage and Grade are the most important prognostic factorsAltered oncogene/tumor suppressor gene expression is now being evaluated(molecular staging concept)Aggressive Histologic Subtypes(Clear-cell,Serous)Increasing age(over 65)Vascular invasionAneuploidyAltered oncogene/tumor suppressor gene expression(“molecular staging”concept-p53,PTEN,microsatellite instability,MDR-1,HER2/neu,ER/PR,Ki 67,PCNA,CD 31,EGF-R,MMR genes)Race?Endometrial Cancer:Poor Prognostic FactorsMolecular GeneticsPTEN mutations:32%Tumor suppressor gene(chrom 10)PhosphataseEarly event in carcinogenesisAssociated with:endometrioid histologyearly stagefavorable survival Molecular Geneticsp53 tumor suppressor geneCell cycle and apoptosis regulationMost commonly mutated gene in human cancersOverexpression(marker for mutation)Associated with poor prognosisearly stage:10%have p53 mutationadvanced stage:50%have p53 mutationnot found in hyperplasiaslate event in carcinogenesisGenetic Syndromes:HNPCCHereditary Non-Polyposis Colon CancerLynch II SyndromeAutosomal dominant inheritanceMMR(mismatch repair)mutationsGenetic instability leads to error-prone DNA replicationhMSH2(chrom 2)hMLH1(chrom 3)Early age of colon Ca:mean 45.2 yearsEndometrial Ca:second most common malignancy20%cumulative incidence by age 70Earlier age of onset than sporadic casesOther:ovary(3.5-8 fold),stomach,small bowel,pancreas,biliary tractDiagnosis of disease:Patient Awareness*More than 95%of patients with Endometrial Cancer report having symptomsPostmenapausal bleedingMenorrhagiaMetrorrhagiaBloody DischargeEndometrial biopsy is the main diagnostic tool performed either in the office or via D&C in ORUterine Cancer:Diagnosis/ScreeningPatient Symptoms/Awareness*Cytology Not a satisfactory screening testSonography Not Cost effectiveHysteroscopy Not Cost effectiveHistology Secondary to symptoms(not as a screening test)Endometrial Cancer:Transvaginal Ultrasound ScreeningEndometrial Cancer:Transvaginal Ultrasound ScreeningEndometrial Cancer:Transvaginal Ultrasound ScreeningNormal endometrial stripe:Postmenopausal4-8 mmPostmenopausal on HRT 4-10 mm U/S for Detection of any uterine pathologySensitivity:85-95%Specificity:60-80%PPV 2-10%NPV 99%Summary:Endometrial Cancer:Transvaginal Ultrasound ScreeningHysteroscopy Not satisfactory for screening testStudies of the efficacy of hysteroscopy as a diagnostic tool vary widelySensitivity reported ranging from 60-95%compared to D&C obtained at the same timeSpecificity 50-99%Hysteroscopy and Positive Cytology?Studies have been mixed:Some studies suggest an increase in positive peritoneal cytology seen at staging laparotomy in patients who have had hysteroscopyOther studies have failed to find a difference in positive cytology in patients diagnosed via hysteroscopy as compared to office biopsy or D&CHysteroscopy Not satisfactoryToo much cost and risk to be used as a screening test.Useful for evaluation of abnormal uterine bleeding where office biopsy is unrevealing.Use in conjunction with uterine curettageUseful to see and resect polyps and small submucous fibroidsUseful to perform directed biopsy of small lesions.Endometrial Cancer:Who Needs an Endometrial Biopsy?Postmenopausal bleedingPerimenopausal intermenstrual bleedingAbnormal bleeding with history of anovulationPostmenopausal women with endometrial cells on PapThickened endometrial stripe via sonographySampling of the EndometriumOffice biopsy procedures(Pipelle,Vabra aspirator,Karman cannula)will agree with a D&C performed in the OR 95%of the timeOffice biopsy has a 16%false negative rate when the lesion is in a polyp or the cancer covers less than 50%of the endometriumGuido et al.J Reprod Med.1995;40:553Patients with persistent PMB after negative office biopsy should have D&C(+/-hysteroscopy)D&C is the gold standard sampling method preoperative D&C will agree with diagnosis at hysterectomy 94%of the timeTreatment for Endometrial Hyperplasia without atypia:Progestin therapy continuous or cyclicalChildbearing age:Progestin dominant OCPs orDepo-Provera 150mg IM q3 months orProvera 10mg po 10 days/month andMay follow with ovulation induction after normal biopsy if pregnancy desiredPeri or Postmenopausal:Provera 20mg po 10 days/month orDepo-Provera 200mg IM q2 monthsRepeat biopsy in 3-4 monthsTreatment for Atypical Endometrial Hyperplasia:23%risk of progression to carcinoma(over 10 years)if untreated.Standard treatment when childbearing is complete is total hysterectomy(abdominal or vaginal)Frozen section to rule out carcinoma(up to 20%have coexisting endometrial cancer)Treatment for Atypical Endometrial Hyperplasia:Conservative medical therapy can be attempted in younger patients who request preservation of fertility.D&C prior to initiation of medical therapy to rule out carcinomaMegace 40-80mg/day,Norethindrone acetate 5mg/dayConservative therapy may also be attempted in young patients with early,well differentiated endometrial carcinomas.Megace 120-200mg/day,Norethindrone acetate 5-10mg/dayEndometroid carcinoma,GradingFIGO-Gr 1-50%solid tumorNUCLEAR GRADESize,shape,staining and chromatin,variability,prominent nucleoli.High nuclear grade adds one point to FIGO gradeCA125Chest X-rayMammogramsColon EvaluationOthers as indicatedUterine Cancer:Pre-op EvaluationUterine Cancer:Pre-op EvaluationTransvaginal U/S?CT Scan?MRI?Uterine Cancer:Pre-op EvaluationUterine Cancer:Surgical StagingPreoperative preparationAntimicrobial prophylaxisDVT prophylaxisSteep TrendelenburgLong instruments availableAvailability of frozen section to determine the extent of staging procedure.Capability of complete surgical stagingCapability of tumor reduction if indicatedEndometrial Cancer:Intra-operative Surgical PrincipalsEndometrial Cancer:Surgical ApproachTAH-BSO/washings only Endometrioid*Grades 1 and 50%myometrial invasion*or Grade 2 and no or minimal invasion and 50%myometrial invasionAny 2 cm tumor diameterAll Serous/clear cell subtype*Pre operative assessment of advanced disease(gross cervical or vaginal dz,etc)*TAH-BSO,washings,lymphadenectomy*omental/peritoneal biopsyEndometrial Cancer:Adjuvant TherapyBrachytherapyExternal beam radiotherapyHormonal therapyCytotoxic chemotherapyCombination therapyEndometrial Cancer:RecurrencePelvic examinationPap smearsCA125(high-risk)Chest X-ray(high-risk)Endometrial Cancer:Site of RecurrenceIn Radiated PatientsSite%Distant65Pelvic and distant15Pelvis only15Vagina5Endometrial Cancer:Follow-Up75-95%of recurrences are in first 36 months60%of patients have symptoms(pain,wgt loss,vaginal bleeding)Rare to cure distant recurrences50%vaginal recurrences cured