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

2. I have no financial disclosures

3. Wind River Range, WY
July, 2017

4. 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

5. 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

6. 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

7. 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

8. Lessons Learned Tumor morphology helps stratify cancer risk
Screening trial Surgeries per cancer
UKCTOCS
PLCO
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

9. 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

11. 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; , 2008

12. 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; , 2008

13. ADNEX Risk Model Belgium, Italy, Czech Republic, Poland, UK, Sweden Van Calster et al. BMJ, 2014
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14. 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

15. 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

16. 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

17. Diagnostic Triage Comparison
Biomarkers
Diagnostic
Triage
Comparison

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

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

20. 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

21. 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

22. 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

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

24. 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

25. 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

26. 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

27. 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

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

29. 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

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

31. 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

32. 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

33. 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

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

35. 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

36. Questions?