Adnexal Masses in Menopausal Women

Adnexal Masses in Menopausal Women Surgery or Surveillance? Disclosure Frederick R. Ueland, MD Professor and Director Division of Gynecologic Oncology University of Kentucky I have no financial disclosures Ovarian Tumor Overview Wind River Range, WY July, 2017 Past 1980 s palpable ovary syndrome 2000 s observation of unilocular cysts 2010 s observation of septate cysts Present 10% require surgery for adnexal mass in their lifetime 1 13%-21% are malignant 2 1) Moore, McMeekin, Brown et al. Gynecol Oncol, 2009 2) Jordan. Current Biomarker Findings, 2013 1

Ovarian Tumor Overview The Specifics Premenopausal Many tumors, few cancers 15% are malignant - Germ cell tumors - LMP tumors - Epithelial cancers Benign tumors - 70% functional cysts - 20% neoplastic - 10% endometriomas Other - Inflammatory Menopausal Few tumors, many cancers 50% are malignant - Epithelial ovarian cancer - Metastatic cancer - Granulosa cell tumors Benign tumors - Cystadenoma - Fibroma - Thecoma 39,337 ultrasounds performed 30% high risk (9%) solid cyst+solid unilocular 70% 30% septate Normal Abnormal 70% low risk (21%) Pavlik E, Ueland F, Miller R, et al. Obstet Gynecol, 2013 Menopausal Women Incidence Number of new ovarian cysts identified 8.2% 1 3.3 million women 2 Prevalence Proportion who have cysts at any given time 17% 1 6.8 million women 2 Most are low risk for malignancy Ultrasound Lessons Learned Reducing Subjectivity IOTA: Simple Rules, ADNEX Model Kentucky Morphology Index 1) Pavlik E, Ueland F, Miller, R. et al. Obstet Gynecol, 2013 2) United States Census Bureau, 2010 2

Lessons Learned Limiting Subjectivity Tumor morphology helps stratify cancer risk Screening trial Surgeries per cancer - UKCTOCS 35.2 - PLCO 19.5 - Kentucky first decade (1990 S) 12.5 second decade (2000 S) 5.2 third decade (2010 S) 4.0 First International Consensus Report 1 International Ovarian Tumor Analysis (IOTA) o Simple Rules 2 o ADNEX 3 Kentucky Morphology index 4 Serial sonography 5 9 1) J Ultrasound Med, 2017; 2) Ultrasound Obstet Gynecol, 2008; 3) Br Med J, 2014; 4) Gynecol Oncol, 2003; 5) Gynecol Oncol, 2014 IOTA Simple Rules M1 Irregular solid M2 Presence of ascites M3 At least 4 papillary projections M4 Irregular multilocular solid, largest diameter 10 cm M5 Very strong blood flow B1 Unilocular B2 Solid component < 7 mm B3 Presence of acoustic shadows B4 Smooth multilocular tumor, largest diameter < 10 cm B5 No blood flow Timmerman et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol 31; 681-690, 2008 3

Simple Rules Malignant If one or more M-rules apply in the absence of a B-rule, the mass is classified as malignant Benign If one or more B-rules apply in the absence of an M-rule, the mass is classified as benign. Indeterminate If both M-rules and B-rules apply, the mass cannot be classified. If no rule applies, the mass cannot be classified Timmerman et al. Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet Gynecol 31; 681-690, 2008 ADNEX Risk Model Belgium, Italy, Czech Republic, Poland, UK, Sweden IOTA - ADNEX model 1. Age of the patient at examination (years) 2. Oncology center (referral center for gyn-oncol)? 3. Maximal diameter of the lesion (mm) 4. Maximal diameter of the largest solid part (mm) 5. More than 10 locules? 6. Number of papillations (papillary projections) 7. Acoustic shadows present? 8. Ascites (fluid outside pelvis) present? 9. Serum CA-125 (U/ml) Clear Van Calster et al. Evaluating risk of ovarian cancer before surgery using the ADNEX 14model. BMJ, 2014 Kentucky Morphology Index Kentucky MI Ueland F, DePriest P, Pavlik E, et al. Gynecol Oncol, 2003 MI Total Malignant ROM (%) 1 2,349 1 0.04 2 2,365 0 0.00 3 2,635 3 0.11 4 1,579 7 0.44 5 1,061 29 2.73 6 241 9 3.73 7 87 11 12.64 85% 8 30 8 26.67 9 18 5 27.78 10 3 1 33.33 Total 10,368 74 0.71 Ueland F, DePriest P, Pavlik E, et al. Gynecol Oncol, 2003 Sensitivity 86% Specificity 98% 4

Comparing Models ADNEX Model ROM correlates with increased cancer risk 52% of cancers in lowest ROM groups Efficacy in surveillance is unknown Misses stage 1 cancers Kentucky MI ROM correlates with increased cancer risk 15% of cancers in lowest ROM groups MI change over time is useful for surveillance Identifies stage 1 cancers Biomarkers Diagnostic Triage Comparison Lefringhouse J, Ueland F, Ore R, et al. SGO, 17 2016 Diagnostic Biomarkers CEA CA19 9 LDH β hcg AFP HE 4 CA125 Triage Biomarkers OVA1 * ROMA Overa + CA125 Performance * Multivariate Index Assay + MIA2G 19 Myers et al. Management of adnexal mass. Rockville (MD): U.S. Department of Health and Human Services, 2006 20 5

OVA1 Triage Biomarker Tests FDA-cleared September, 2009 Multivariate Index Assay Range 0-10 Premenopausal Post Low Risk < 5.0 < 4.4 High Risk 5.0 4.4 ROMA FDA-cleared September, 2011 Dual marker test Range 0-10 Premenopausal Post Low Risk < 1.31 < 2.77 High Risk 1.31 2.77 CA125 + HE4 Triage Biomarker Tests Overa FDA-cleared September, 2016 Multivariate Index Assay-2G CA125, HE-4, FSH, Apolipoprotein A1, Transferrin Range 0-10 Result Low Risk < 5.0 High Risk 5.0 21 22 Comparing Biomarkers Sensitivity Overa 1 OVA1 2,3 ROMA 4 CA125 II 2,5 All malignancies 91% 93% 89% 69% Epithelial ovarian cancers 95% 99% 94% 82% Early stage EOC 89% 98% 75% 66% Premenopausal women 90% 94% 76% 36% Postmenopausal women 92% 100% 92% 80% Specificity All malignancies 69% 54% 75% 87% Recommended Evaluation Determine Malignant Risk with Ultrasound 1. Low risk surveillance 2. Indeterminate secondary testing 3. High risk refer to Gynecologic Oncologist OVA1 detected 76% of malignancies missed by CA125 1 1) Coleman R, Herzog T, Chan D, et al. Am J Obstet Gynecol, 2016 2) Ueland F, DeSimone C, Seamon L, et al. Obstet Gynecol, 2011 3) Bristow R, Smith A, Zhang Z, et al. Gynecol Oncol, 2013 4) Moore R, McMeekin S, Brown A, et al. Gynecol Oncol, 2009 5) Myers et al. Management of adnexal mass. Rockville (MD): U.S. Department of HHS, 2006 6

Recommended Evaluation Low Risk Malignant Risk Low Indeterminate High Distribution 65% 25% 10% US morphology Secondary testing Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections No YES No Surgery No Maybe YES Smooth-walled Unilocular or septate Unilocular cyst 1,2 Septate cyst3 25 1) Modesitt et al. Gynecol Oncol, 2003; 2) Bailey et al. Gynecol Oncol, 1998; 3) Saunders B. et al. Gynecol Oncol, 2010 Malignant Potential for Low Risk Resolution for Low Risk Resolution Time Type of Abnormality Cyst Cyst & Septae Cyst & Solid Solid Summary of Valentin et al, 2013 33% unilocular 1% malignant 0.54% Premenopausal 2.76% Postmenopausal 7/11 had solid or papillary component on visual surgical inspection Valentin, Ameye, Franchi et al. Ultrasound Obstet Gynecol, 2013 27 Scans 6,239 1790 581 154 Abnormalities 1,288 366 122 24 Average Scans 4.8 4.9 4.8 6.4 Mean (mo) 31.0 26.5 23 26.4 Median (mo) 17 14.1 8.3 12.7 75th percentile (mo) 38.4 36.0 33.8 38.7 90th percentile (mo) 70.9 64.5 64.3 93.8 Ore R, Ueland F, Lefringhouse J, et al. SGO Annual Meeting abstract, 2016 28 7

Recommended Evaluation Malignant Risk Low Indeterminate High Distribution 65% 25% 10% Indeterminate Risk Small, irregular wall abnormalities Partly solid Atypical, non-papillary projections US morphology Secondary testing Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections No YES No Surgery No Maybe YES 29 30 Serial Morphology Index Tumor type MI score Malignant Increase Non malignant Stable or gradual rise Resolving Decrease Elder J, Pavlik E, Long A et al. Gynecol Oncol 135; 8-12, 2014 31 Surgery for epithelial ovarian malignancy * 24 subjects had 1 scan only N MI P-value MI per month P-value 50 * 1.9 P<0.001 0.9 P<0.001 Surgery for non-malignancy 272 0.7 P<0.001 0.2 P<0.001 Resolved ovarian cysts 5811-2.7 P<0.001-1.1 P<0.001 8

Recommended Evaluation High Risk Malignant Risk Low Indeterminate High Distribution 65% 25% 10% US morphology Secondary testing Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections No YES No Surgery No Maybe YES Irregular, solid Papillations Ascites ROM >25% Refer to Gyn Oncologist 33 34 Summary Questions? 1. Ultrasound is the preferred test to evaluate an ovarian tumor 2. Risk of malignancy Low- monitor without surgery 6 months, then annually for 5 years Indeterminate- secondary testing Serial ultrasound Biomarker testing (OVA1, ROMA, Overa) High- surgery Refer to a Gynecologic Oncologist 35 9