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Cancers of the Uterine Corpus

Cancers of the Uterine Corpus. SUNY Downstate Medical Center Division of Gynecologic Oncology Mark Borowsky, MD. American Cancer Society Female Cancers: 2000 Statistics. Cancers of the uterine corpus are the 4 th most common cancer in American women Lifetime incidence ~2-3%. Lifetime risk.

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Cancers of the Uterine Corpus

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  1. Cancers of the Uterine Corpus SUNY Downstate Medical Center Division of Gynecologic Oncology Mark Borowsky, MD

  2. American Cancer SocietyFemale Cancers: 2000 Statistics • Cancers of the uterine corpus are the 4th most common cancer in American women • Lifetime incidence ~2-3%

  3. Lifetime risk

  4. American Cancer SocietyFemale Cancers: 2000 Statistics • Median Age 61 • 25% diagnosed before the menopause • 5% diagnosed before age 40

  5. American Cancer SocietyFemale Cancers: 2000 Statistics • 6,500 Deaths per year • 8th cause of female cancer death • 2% of all female cancer death • Uterine corpus cancer cases and deaths have increased 25% and 12% respectively from 1994 to 2004

  6. Cancers of the Uterine Corpus:Histologic Types • Carcinoma (94%) • Endometrioid (87%) • Adenosquamous (4%) • Papillary Serous* (3%) • Clear Cell* (2%) • Mucinous (1%) • Other (3%) • Sarcoma (6%) • Carcinosarcoma* (60%) • Leiomyosarcoma* (30%) • Endometrial Stromal Sarcoma (10%) • Adenosarcoma (<1%) *poor prognosis histology

  7. Endometrial Cancer:Type I/II Concept • Type I • Estrogen Related • Younger and heavier patients • Low grade • Background of Hyperplasia • Perimenopausal • Exogenous estrogen • Type II (~10% of total cases) • Aggressive • High grade • Unfavorable Histology • Unrelated to estrogen stimulation • Occurs in older & thinner women • Familial/genetic (~15% of total cases) • Lynch II syndrome/HNPCC • Familial trend

  8. Endometrial Cancer: Type I Risk Factors

  9. Uterine Cancer: Surgical Staging • Replaced Clinical Staging 1989 • Conceptual rationale • Better defines extent of disease (metastases, depth of invasion, cervix involvement, etc.) • Minimizes over/under treatment • Minimally increases perioperative morbidity/mortality • Decreases overall Rx risks and costs • Better allows comparison of therapeutic results

  10. Uterine Cancer: Surgical Staging • Clinical Stage I will be upstaged 30% of the time at laparotomy • 5% for positive adnexa (Surgical Stage IIIa) • 6% for positive para-aortic lymph nodes (Surgical Stage IIIc) • 9% for positive pelvic nodes (Surgical Stage IIIc) • 12% for positive cytology on pelvic washings (Surgical Stage IIIa) • 6% other {eg. cervical (St II) or abdominal disease (St IV)} • Clinical Stage II or III will be upstaged 60% of the time at laparotomy

  11. Endometrial Cancer: Clinical vs. Surgical Staging Lanciano et al: Radiother Oncol 28:189,1993

  12. Endometrial Cancer: FIGO Surgical Stage

  13. Endometrial Cancer Prognosis: • Overall 5Yr Survival 84% • Stage and Grade are the most important prognostic factors • Altered oncogene/tumor suppressor gene expression is now being evaluated (molecular staging concept)

  14. Endometrial Cancer: Poor Prognostic Factors • Aggressive Histologic Subtypes (Clear-cell, Serous) • Increasing age (over 65) • Vascular invasion • Aneuploidy • Altered 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?

  15. Molecular Genetics • PTEN mutations: 32% • Tumor suppressor gene (chrom 10) • Phosphatase • Early event in carcinogenesis • Associated with: • endometrioid histology • early stage • favorable survival

  16. Molecular Genetics • p53 tumor suppressor gene • Cell cycle and apoptosis regulation • Most commonly mutated gene in human cancers • Overexpression (marker for mutation) • Associated with poor prognosis • early stage: 10% have p53 mutation • advanced stage: 50% have p53 mutation • not found in hyperplasias • late event in carcinogenesis

  17. Genetic Syndromes: HNPCCHereditary Non-Polyposis Colon Cancer Lynch II Syndrome • Autosomal dominant inheritance • MMR (mismatch repair) mutations • Genetic instability leads to error-prone DNA replication • hMSH2 (chrom 2) • hMLH1 (chrom 3) • Early age of colon Ca: mean 45.2 years • Endometrial Ca: second most common malignancy • 20% cumulative incidence by age 70 • Earlier age of onset than sporadic cases • Other: ovary (3.5-8 fold), stomach, small bowel, pancreas, biliary tract

  18. Five Year Survival by Race:

  19. Five Year Survival by Race: Matthews RP, Hutchinson-Colas J, Maiman M, et al.: Papillary Serous and Clear Cell Type Lead to Poor Prognosis of Endometrial Carcinoma in Black Women. Gynecol Oncol. 65: 206-212, 1997. • Retrospective review 401 patients (60% black) • 5 yr Survival • Black women: 56% Other races: 71% • Black women were more likely to have clear cell or UPSC histology. • After controlling for stage only clear cell and UPSC histology independently predicted poor outcome. • Race not predictive of survival when stage and histology controlled for.

  20. Diagnosis of disease: Patient Awareness* • More than 95% of patients with Endometrial Cancer report having symptoms • Postmenapausal bleeding • Menorrhagia • Metrorrhagia • Bloody Discharge • Endometrial biopsy is the main diagnostic tool • performed either in the office or via D&C in OR

  21. Post menopausal bleeding

  22. Postmenopausal Bleeding

  23. Uterine Cancer:Diagnosis/Screening • Patient Symptoms/Awareness* • Cytology – Not a satisfactory screening test • Sonography – Not Cost effective • Hysteroscopy – Not Cost effective • Histology – Secondary to symptoms (not as a screening test)

  24. Cytology – Not sensitive, nor specific • Less than 50% of patients with endometrial Ca have endometrial cells on Pap smear • Endometrial cells and/or AGCUS on a pap are frequently a sign of endometrial pathology and deserve further investigation

  25. Endometrial Cancer:Transvaginal Ultrasound Screening

  26. Endometrial Cancer:Transvaginal Ultrasound Screening Fleischer AC, Wheeler JE, Lindsay I, et al.: An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. American Journal of Obstetrics and Gynecology 184(2): 70-75, 2001. • Study of 1,926 asymptomatic postmenopausal women on idoxifene for transvaginal u/s screening • All patients agree to biopsy after u/s (1,792 biopsies) • Using 6 mm cutoff for “Abnormal” the sensitivity of the test was 33% (missed 67% of atypical hyperplasia and cancer) • 45% of women were > or = 6mm • PPV was only 2% • NPV>99%

  27. Endometrial Cancer:Transvaginal Ultrasound Screening Langer RD, Pierce JJ, O'Hanlan KA, et al.: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. New England Journal of Medicine 337(25): 1792-1798, 1997. • 448 Women, all asymptomatic and all on HRT • All agree to TV u/s and biopsy • Threshold of 5mm used • 4% incidence of cancer • Test Sensitivity was 90% at threshold of 5mm • But >50% of women had endometrial thickness of 5mm or more

  28. Endometrial Cancer:Transvaginal Ultrasound Screening

  29. Endometrial Cancer:Transvaginal Ultrasound Screening Rebecca Smith-Bindman, MD; Karla Kerlikowske, MD; Vickie A. Feldstein, MD, etal: Endovaginal Ultrasound to Exclude Endometrial Cancer and Other Endometrial Abnormalities. JAMA. 1998;280:1510-1517 • Meta-analysis 35 studies, 5,892 women • All with PMB, HRT use varied • 5mm threshold used • Sensitivity 92% • Specificity 92% for non HRT users • Specificity 77% for HRT users

  30. Endometrial Cancer:Transvaginal Ultrasound Screening

  31. Endometrial Cancer:Transvaginal Ultrasound Screening

  32. Summary: Endometrial Cancer:Transvaginal Ultrasound Screening • Normal endometrial stripe: • Postmenopausal 4- 8 mm • Postmenopausal on HRT 4- 10 mm • U/S for Detection of any uterine pathology • Sensitivity: 85-95% • Specificity: 60-80% • PPV 2-10% • NPV 99%

  33. Hysteroscopy – Not satisfactory for screening test • Studies of the efficacy of hysteroscopy as a diagnostic tool vary widely • Sensitivity reported ranging from 60-95% compared to D&C obtained at the same time • Specificity 50-99%

  34. Normal Endometrium

  35. Endometrial Polyp

  36. Polyp and Atypical Hyperplasia

  37. Focal Simple Hyperplasia

  38. Grade 3 Endometrial cancer

  39. 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 hysteroscopy • Other studies have failed to find a difference in positive cytology in patients diagnosed via hysteroscopy as compared to office biopsy or D&C

  40. Positive Studies: Bradley WH, Boente MP, Brooker, D, et al.: Hysteroscopy and Cytology in Endometrial Cancer. Obstet Gynecol 2004;104:1030-3 Zerbe M, Zhang J, Bristow RE, et al.: Retrograde seeding of malignant cells during hysteroscopy in presumed early endometrial cancer. Gynecol Oncol 2000;79:55-8 Obermair A, Geramou M, Gucer F, et al.: Does hysteroscopy facilitate tumor cell dissemination. Cancer 2000;88:139-43 Increase in positive cytology from ~2-3% to ~10% (RR 3-4)

  41. Negative Studies: Gu M, Shi W, Huang J, et al.: Association between initial diagnostic procedure and hysteroscopy and abnormal peritoneal wahisngs in patients with endometrial carcinoma. Cancer 2000;90:3:143-7 Selvaggi L Cormio G, Ceci O, et al.: Hysteroscopy does not increase the risk of microscopic extrauterine spread in endometrial carcinoma. Int J Gynecol Cancer 2003;13:223-7

  42. Hysteroscopy – Not satisfactory • Too 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 curettage • Useful to see and resect polyps and small submucous fibroids • Useful to perform directed biopsy of small lesions.

  43. Endometrial Cancer:Who Needs an Endometrial Biopsy? • Postmenopausal bleeding • Perimenopausal intermenstrual bleeding • Abnormal bleeding with history of anovulation • Postmenopausal women with endometrial cells on Pap • Thickened endometrial stripe via sonography

  44. Sampling of the Endometrium • Office biopsy procedures (Pipelle, Vabra aspirator, Karman cannula) will agree with a D&C performed in the OR ~95% of the time • Office biopsy has a 16% false negative rate when the lesion is in a polyp or the cancer covers less than 50% of the endometrium • Guido et al. J Reprod Med. 1995;40:553 • Patients 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 time

  45. Endometrial cyclic changesProliferative phase

  46. Endometrial cyclic changesProliferative phase

  47. Endometrial cyclic changesEarly secretory

  48. Endometrial cyclic changesmid-secretory

  49. Endometrium: Post-menopausal atrophy

  50. Endometrial Simple Hyperlasia

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