Ultrasonographic Imaging of Ovarian Masses Surgery or Surveillance? Frederick R. Ueland, MD Professor and Director Division of Gynecologic Oncology University of Kentucky

I have no financial disclosures

Wind River Range, WY July, 2017

Ovarian Tumor Overview Past 1980’s “palpable ovary syndrome” 2000’s observation of unilocular cysts 2010’s observation of septate cysts Present 10% of women undergo surgery for adnexal mass in their lifetime1 13%-21% of these masses are malignant2 Need to think of US as a biomarker Moore, McMeekin, Brown et al. Gynecol Oncol, 2009 Jordan. Current Biomarker Findings, 2013

Ovarian Tumor Overview Premenopausal Postmenopausal 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 Few tumors, many cancers 50% are malignant Epithelial ovarian cancer Metastatic cancer Granulosa cell tumors Benign tumors Cystadenoma Fibroma Thecoma

Ovarian Tumor Overview 21% Low risk 9% High risk 6% solid 35% unilocular 85% postmenopausal 15% premenopausal Premenopausal Incidence 15% Prevalence 35% Postmenopausal Incidence 8% Prevalence 17% 30 million postmenopausal women Incidence 2.4 million Prevalence 5 million 35% septate Pavlik E, Ueland F, Miller R, et al. Obstet Gynecol, 2013

Ultrasound Lessons Learned Reducing Subjectivity IOTA: Simple Rules, ADNEX Model Kentucky Morphology Index Comparison Need a system that is easy, reproducible, and effective A system that works for generalists. Not everyone is an ‘expert’ at sonography. Some subjectivity

Lessons Learned 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 UKCTOCS (Menon, 2009): Panel 1: Classification of ovarian morphology on ultrasound Normal • Ovary of uniform hypoechogenicity and with a smooth outline with or without a single inclusion cyst or spots of calcifications • Inclusion cyst must be single, less than 10 mm in diameter and not distort the outline of the ovary Simple cyst • A single, thin walled, anechoic cyst with no septa or papillary projections Complex • Any case in which the ovary has any non-uniform ovarian echogenicity, excluding single simple or inclusion cysts 10-Nov-18

Reducing Subjectivity First International Consensus Report1 International Ovarian Tumor Analysis (IOTA) Simple Rules2 ADNEX3 Kentucky Morphology index4 Serial ultrasonography5 1) J Ultrasound Med 2017; 2) Ultrasound Obstet Gynecol 2008; 3) BMJ 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

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 Van Calster et al. BMJ, 2014 ___ __________ _____________ ____________________ ______ _______ ______ _____ _____

Kentucky Morphology Index 10 point system that captures the essential morphology components. Most scoring systems use the same criteria assembled in different ways. Ueland F, DePriest P, Pavlik E, et al. Gynecol Oncol, 2003

Kentucky MI MI Total Malignant ROM (%) 1 2,349 0.04 2 2,365 0.00 3 0.00 3 2,635 0.11 4 1,579 7 0.44 5 1,061 29 2.73 6 241 9 3.73 87 11 12.64 8 30 26.67 18 27.78 10 33.33 10,368 74 0.71 Sensitivity 85% Specificity 87% PPV 4% NPV 99% Accuracy 85% Sensitivity: 86% Specificity: 98% Ueland F, DePriest P, Pavlik E, et al. Gynecol Oncol, 2003

Comparing Models ADNEX Model ROM has non-linear correlation with CA risk 52% of cancers in lowest ROM groups Clustering limits utility as clinical aid Misses stage 1 cancers Kentucky MI ROM has linear correlation with CA risk 15% of cancers in lowest ROM groups MI useful for decisions of surgery vs. surveillance Identifies stage 1 cancers 10-Nov-18 Lefringhouse J, Ueland F, Ore R, et al. SGO, 2016

Diagnostic Triage Comparison Biomarkers Diagnostic Triage Comparison

‘Diagnostic’ Biomarkers Triage Biomarkers CEA CA19-9 LDH β-hCG AFP HE-4 CA125 OVA1* ROMA Overa+ *Multivariate Index Assay + MIA2G

CA125 Performance Myers et al. Management of adnexal mass. Rockville (MD): U.S. Department of Health and Human Services, 2006

Triage Biomarker Tests OVA1 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 CA125 + HE4 Range 0-10 Premenopausal Post Low Risk < 1.31 < 2.77 High Risk ≥ 1.31 ≥ 2.77

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

OVA1 detected 76% of malignancies missed by CA1251 Comparing Biomarkers Sensitivity Overa1 OVA12,3 ROMA4 CA125-II2,5 All malignancies 91% 93% 89% 69% Epithelial ovarian cancers 95% 99% 94% 82% Early stage EOC 98% 75% 66% Premenopausal women 90% 76% 36% Postmenopausal women 92% 100% 80% Specificity 54% 87% OVA1 detected 76% of malignancies missed by CA1251 Coleman R, Herzog T, Chan D, et al. Am J Obstet Gynecol, 2016 Ueland F, DeSimone C, Seamon L, et al. Obstet Gynecol, 2011 Bristow R, Smith A, Zhang Z, et al. Gynecol Oncol, 2013 Moore R, McMeekin S, Brown A, et al. Gynecol Oncol, 2009 Myers et al. Management of adnexal mass. Rockville (MD): U.S. Department of HHS, 2006

Recommended Evaluation Determine Malignant Risk with Ultrasound Low risk- surveillance Indeterminate- secondary testing High risk- refer to Gyn Oncologist for surgery

Recommended Evaluation Malignant Risk Low Indeterminate High Distribution 65% 25% 10% US morphology Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections Secondary testing No YES Surgery Maybe

Low Risk Smooth-walled Unilocular or septate Septate cyst3 Unilocular cyst1,2 1Modesitt et al. Gynecol Oncol, 2003; 2Bailey et al. Gynecol Oncol, 1998; 3Saunders B. et al. Gynecol Oncol, 2010

Malignant Potential for Low Risk 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 IOTA database. Define papillary projection as ≥3 mm. If <3 mm, classified as unilocular with irregular wall. Cannot simply disregard a unilocular cyst in postmenopausal woman if risk approaches 3%- need surveillance % is very misleading because it doesn't count all the surveillance unilocular cysts. Modesitt 0/133 for surgery but 0/2763 counting those surveilled Unpublished Italian data says 2100 surgically remove unilocular cysts. 0.6% pre and 1.9 (anechoic, unilocular) to 3.2% (unilocular) postmeno risk of CA. 10-Nov-18 Valentin, Ameye, Franchi et al. Ultrasound Obstet Gynecol, 2013

Resolution for Low Risk   Resolution Time Type of Abnormality Cyst Cyst & Septae Cyst & Solid Solid Scans 6,239 1790 581 154 Abnormalities 1,288 366 122 24 Average Scans 4.8 4.9 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

Septate Ovarian Tumors N= 1114 spontaneously resolving septate cysts Saunders B, Podzielinski I, Ware R, et al. Gynecologic Oncology 118; 278–282, 2010

Recommended Evaluation Malignant Risk Low Indeterminate High Distribution 65% 25% 10% US morphology Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections Secondary testing No YES Surgery Maybe

Indeterminate Risk Small, irregular wall abnormalities Partly solid Atypical, non-papillary projections 10-Nov-18

Serial Ultrasound 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

Surgery for epithelial ovarian malignancy 50* 1.9 0.9 ∆MI P-value per month Surgery for epithelial ovarian malignancy 50* 1.9 P<0.001 0.9 Surgery for non-malignancy 272 0.7 0.2 Resolved ovarian cysts 5811 -2.7 -1.1 *24 subjects had 1 scan only

Recommended Evaluation Malignant Risk Low Indeterminate High Distribution 65% 25% 10% US morphology Unilocular or septate Partly solid, small wall abnormalities Mostly solid, papillary projections Secondary testing No YES Surgery Maybe

High Risk Irregular, solid Papillations Ascites ROM >25% Refer to Gyn Oncologist Irregular solid, ascites 10-Nov-18

Summary Ultrasound is the preferred test to evaluate an ovarian tumor 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

Questions?