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Is This Ovary Malignant? Separating the Olives from the Pits

Is This Ovary Malignant? Separating the Olives from the Pits. Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology University of Kentucky Markey Cancer Center. Siena, Italy. Settled 900-400 BC Walled city by 12 th century 1 st Palio race in 1656. Il Palio di Siena.

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Is This Ovary Malignant? Separating the Olives from the Pits

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  1. Is This Ovary Malignant?Separating the Olives from the Pits Frederick R. Ueland, M.D. Associate Professor Gynecologic Oncology University of Kentucky Markey Cancer Center

  2. Siena, Italy Settled 900-400 BC Walled city by 12th century 1stPalio race in 1656

  3. Il Paliodi Siena

  4. Outline • The challenge of ovarian tumors • Value of specialists in ovarian cancer • Essentials in preoperative evaluation • Examination • Imaging • Biomarkers • Algorithms • ACOG • RMI • Summary

  5. Challenge of Ovarian Tumors • There are 155 million women in United States • ~125 million women 13 years of age or older • 90 million are between 13 and 50 years of age • 30 million are over age 50 • How common are ovarian tumors? • Premenopausal • 14% annual incidence (13 million), 30% prevalence (27 million) • Postmenopausal • 5% annual incidence (1.5 million), 16% prevalence (5 million) • Resolution: 70% of unilocular, 55% of complex tumors • Millions of ovarian tumors, 22,000 cancers annually • Which tumors need removal and by whom? United States Census Bureau, 2008; Data from University of Kentucky Ovarian Cancer Screening Program, 2009 (N=27,000)

  6. Ovarian Tumors Premenopausal Postmenopausal • Many tumors, few cancers • Low prevalence • 15% of ovarian neoplasms are malignant • Germ cell tumors • Borderline tumors • Epithelial cancers • Benign ovarian tumors • 70% functional cysts • 20% neoplastic • 10% endometriomas • Other • Inflammatory • Few tumors, many cancers • High prevalence • 50% of ovarian neoplasms are malignant • Epithelial ovarian cancer • Metastatic cancer • Granulosa cell tumors • Benign ovarian tumors • Cystadenoma • Fibroma • Thecoma

  7. Cancer Mortality1930-2003 Colon & rectum Uterus Stomach Ovary Rate Per 100,000 Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006

  8. NIH Consensus Statement1994 “Women with ovarian masses identified preoperatively as having a significant risk of cancer should be given the option of surgery performed by a gynecologic oncologist”

  9. Value of Specialists • Meta-analysis of 18 studies concluded marked benefit with gynecologic oncologist (Giede 2005) • Complete surgical staging with early disease • Optimal cytoreductive surgery with advanced disease • Improved median and overall survival • Involvement of GO supported by: • NCCN guidelines • SGO, ACOG • SOGC clinical practice guidelines • NIH • London Medical Advisory statement

  10. Preoperative Evaluation • Physical examination • Pelvic, abdominal, and lymph node survey • Imaging study • Transvaginal ultrasonography • CT scan • Biomarkers • CA125 • Not FDA-cleared as a diagnostic test • Low sensitivity and specificity

  11. Pelvic ExaminationDetecting ovarian tumors Ovarian palpation is difficult in older women, obese women, and when the uterus is large Ueland et al. Gyn Oncol, 2005

  12. UltrasoundOvarian tumors • Unilateral • Simple, unilocular • Septated (MI < 5) • No ascites • Resolution • Bilateral • Complex (MI ≥ 5) • Solid wall abnormalities • Internal papillations • Ascites • Persistence or growth Benign Malignant

  13. When Cysts are NOT Malignant • Unilocular cysts • Septated ovarian cysts Modesitt et al. Risk of malignancy in unilocular ovarian cystic tumors. Gynecol Oncol 102:594-599, 2003 Saunders B. et al. Risk of Sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol 118: 278-282, 2010.

  14. UltrasoundKentucky Morphology Index Ascites Ueland et al. Gynecol Oncol, 2003

  15. Kentucky Morphology Index Sensitivity 0.98 Specificity 0.81 PPV 0.41 NPV 0.99 83 92 77 38 32 20 Ueland et al. Gynecol Oncol, 2003

  16. Ovarian Tumor Ultrasound Definition of (+) US varied with each author

  17. Ovarian Biomarkers • CA125 • HE4 • CEA • CA19-9 • LDH • β-hCG • AFP • OVA1

  18. CA125 • Antigen derived from: • Coelomic epithelium (pericardium, pleura, peritoneum) • Mullerian epithelium (tubal, endometrial, endocervical) • Two different assays • Assay I < 35 U/ml; Assay II < 20 U/ml • Expressed by 80% non-mucinous EOC • Low sensitivity (false negatives) • 50% sensitivity in early stage ovarian cancers • 20-25% false negatives in advanced stage cancers • Mucinous, clear cell cancers, mixed mullerian tumors • FDA-cleared to monitor cancer treatment • Neither a screening nor a diagnostic test

  19. CA125Non-specific • Benign ovarian cysts • Uterine leiomyomata • Pelvic inflammatory disease • Endometriosis • Adenomyosis • Pregnancy • Menstruation • Ascites • Heart failure • Liver failure • Renal failure • Peritoneal tuberculosis • Diverticulitis • Pancreatitis • Recent abdominal or thoracic surgery • Other malignancies

  20. HE4 • Antigen derived from: • Human epididymis protein • Product of the WFDC2 (HE4) gene that is over-expressed in patients with ovarian carcinoma1 • FDA-cleared to monitor cancer treatment with other clinical methods • HE4 not for monitoring mucinous or germ cell ovarian cancers 2 • Neither a screening nor a diagnostic test • Quest Diagnostics Website www.questdiagnostics.com • He4 Product Insert, Fujirebio Diagnostics, Inc.

  21. Risk of Malignancy Algorithm • CA125 and HE4 • Accrual from tertiary centers Prevalence= 34% Moore R, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 2009;112:40-46.

  22. Other Ovarian Biomarkers • CEA • Mucinous neoplasms • CA19-9 • Gastrointestinal (pancreatic) • LDH* • Dysgerminoma • β-hCG* • Pregnancy • Trophoblastic disease • Choriocarcinoma • AFP* • Hepatic neoplasms • Endodermal sinus tumors *Most beneficial in young women with solid tumors

  23. FDA NEWS RELEASE For Immediate Release: Sept. 11, 2009 Media Inquiries: Peper Long, 301-796-4671, mary.long@fda.hhs.govConsumer Inquiries: 888-INFO-FDA FDA Clears a Test for Ovarian CancerTest can help identify potential malignancies, guide surgical decisions The U.S. Food and Drug Administration today cleared a test that can help detect ovarian cancer in a pelvic mass that is already known to require surgery. The test, called OVA1, helps patients and health care professionals decide what type of surgery should be done and by whom.

  24. OVA1 • Panel: CA125-II, transthyretin, apolipoprotein A1, beta 2 microglobulin, transferrin • Sensitivity • EOC 99%, nonEOC 78%, borderline 75%, metastases 94% • Stage I 90%, stage II-IV 100% Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  25. ACOG Referral Guidelines Premenopausal Women Postmenopausal Women • CA125 >200 U/mL • Ascites • Evidence of abdominal or distant metastases • Family history one or more first-degree relatives with ovarian or breast cancer • CA125 >35 U/mL • Nodular or fixed mass • Ascites • Evidence of abdominal or distant metastases • Family history one or more first-degree relatives with ovarian or breast cancer ACOG Committee Opinion: number 280, December 2002. Obstet Gynecol 2002;100:1413-6

  26. ACOG Validation • Im, 2005 • Chart review 1035 patients, 7 tertiary centers • 95%- imaging, 68%- CA125, 24%- both • “SGO and ACOG referral guidelines effectively separate women with pelvic masses into two risk categories for malignancy” • Dearking, 2007 • Prospective, single-institutional trial, 837 patients • Guidelines performed well in predicting advanced-stage disease, but “poorly” in early-stage disease, and premenopausal women • “Need a more sensitive biomarker” • Recommended modifications: • CA-125 >67 U/mL (pre); exclude FH of breast, ovarian cancer

  27. OVA1 Trial • 27 sites throughout United States • 516 patients,161 malignancies • 52% from primary care providers • Preoperative evaluation • Physician assessment • Imaging, serum • Biomarker assays- Quest laboratories • Johns Hopkins Biomarker Discovery Center • Specialty Laboratories • Independent data analysis • Applied Clinical Intelligence Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  28. ACOG Performance Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  29. ACOG PerformancePremenopausal women Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  30. ACOG Revisited OVA1 replacing CA125 Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  31. ACOG PerformanceUnivariate comparison Presented at SGO Annual Meeting, San Francisco, CA March, 2010

  32. ACOG Simplified* • OVA1 (+) • Nodular or fixed mass • Ascites • Metastases *presence of any criterion warrants referral to a gynecologic oncologist Sensitivity 93% Specificity 40% PPV 41% NPV 93%.

  33. Risk of Malignancy IndexU x M x CA125 *<7 cm or ≥7 cm

  34. Risk of Malignancy IndexCutoff = 200 Manjunath et al. Gynecol Oncol 81:225-229, 2001.

  35. Ultrasound with Biomarker *US= solid, papillary projections, ascites only Data from OVA1 trial presented at SGO, 2010

  36. Correlation of OVA1 and Cancer

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