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, ItalySettled 900-400 BC
Walled city by 12th century1st Palio race in 1656
Il Palio di Siena
Outline■ The challenge of ovarian tumors■ Value of specialists in ovarian cancer■ Essentials in preoperative evaluation
Examination Imaging Biomarkers
■ Algorithms ACOG RMI
■ Summary
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)
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
Ovarian Tumors
Premenopausal Postmenopausal
Cancer Mortality1930-2003
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
1930
1940
1950
1960
1970
1980
1990
1998
2000
2002
0
10
20
30
40
Colon & rectum
UterusStomach
Ovary
Rate Per 100,000
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”
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
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
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
Pelvic Exam
Ultrasound P-value
Age ≥ 55 0.30 0.74 < 0.001
Patient wt ≥ 200 lb 0.09 0.73 < 0.001
Uterine wt ≥ 200 g 0.16 0.80 < 0.001
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
When Cysts are NOT Malignant
Unilocular cysts
Septated ovarian cysts
Saunders B. et al. Risk of Sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol 118: 278-282, 2010.
Modesitt et al. Risk of malignancy in unilocular ovarian cystic tumors. Gynecol Oncol 102:594-599, 2003
UltrasoundKentucky Morphology Index
Ueland et al. Gynecol Oncol, 2003
Ascites
Kentucky Morphology Index
5 6 7 8 9 100
10
20
30
40
50
60
70
80
90
100
High Risk 5-10
% Benign % Cancer
2032
38
92 77 83
Ueland et al. Gynecol Oncol, 2003
Sensitivity 0.98
Specificity 0.81
PPV 0.41
NPV 0.99
Ovarian Tumor Ultrasound
Definition of (+) US varied with each author
Author N Prevalence Sens (%) Spec (%) PPV (%) PPV (20%)
Kobayashi, 1976 406 15 70 73 31 39
Hermann, 1987 241 21 82 93 75 73
Finkler, 1988 102 36 62 95 88 75
Benacerraf, 1990 100 30 80 87 72 62
Granberg, 1990 180 22 82 92 74 73
Sassone, 1991 143 10 100 83 37 59
Ueland, 2003 442 12 98 81 41 56
CA125 HE4 CEA CA19-9
■ LDH■ β-hCG■ AFP■ OVA1
Ovarian Biomarkers
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
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
1. Quest Diagnostics Website www.questdiagnostics.com2. He4 Product Insert, Fujirebio Diagnostics, Inc.
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
HE4
Risk of Malignancy Algorithm
CA125 and HE4 Accrual from tertiary centers
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.
All Subjects(N= 503)
Premenopausal(N= 236)
Postmenopausal(N= 267)
Sensitivity 89 76 92
Specificity 75 75 75
PPV 60 34 74
NPV 94 95 93
Prevalence= 34%
CEA Mucinous neoplasms
CA19-9 Gastrointestinal (pancreatic)
LDH* Dysgerminoma
*Most beneficial in young women with solid tumors
■ β-hCG*■ Pregnancy■ Trophoblastic disease■ Choriocarcinoma
■ AFP*■ Hepatic neoplasms■ Endodermal sinus tumors
Other Ovarian Biomarkers
FDA NEWS RELEASE
For Immediate Release: Sept. 11, 2009
Media Inquiries: Peper Long, 301-796-4671, [email protected] 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.
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%
Range 0-10 Premenopausal Postmenopausal
Low Risk < 5.0 < 4.4
High Risk ≥ 5.0 ≥ 4.4
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Referral Guidelines
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
Premenopausal Women Postmenopausal Women
ACOG Committee Opinion: number 280, December 2002. Obstet Gynecol 2002;100:1413-6
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
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
ACOG Performance
All Subjects(N= 516)
Premenopausal(N= 235)
Postmenopausal(N= 281)
ACOGModified ACOG
ACOGModified ACOG
ACOGModified ACOG
Sensitivity 77 80 58 76 84 81
95% CI 70 to 83 73 to 85 43 to 71 61 to 86 77 to 90 73 to 87
Specificity 68 71 77 70 56 71
95% CI 63 to 72 66 to 75 71 to 83 64 to 77 49 to 64 64 to 77
PPV 52 55 38 38 58 66
95% CI 46 to 58 49 to 61 27 to 50 28 to 48 50 to 65 58 to 74
NPV 87 88 89 92 84 84
95% CI 82 to 90 84 to 92 83 to 92 87 to 96 76 to 90 77 to 89
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG PerformancePremenopausal women
Cancer Stage
Early Late
Sensitivity 47 100
95% CI 26 to 69 72 to 100
Specificity 77 77
95% CI 71 to 83 71 to 83
PPV 16 19
95% CI 8 to 28 11 to 31
NPV 94 100
95% CI 89 to 97 98 to 100
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Revisited OVA1 replacing CA125
All subjectsN=516
PremenopausalN= 235
PostmenopausalN= 281
Sensitivity 94 91 95
95% CI 89 to 97 79 to 97 89 to 98
Specificity 35 43 26
95% CI 30 to 40 36 to 50 19 to 33
PPV 40 28 47
95% CI 35 to 45 21 to 35 41 to 54
NPV 93 95 88
95% CI 87 to 96 89 to 98 75 to 94
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG PerformanceUnivariate comparison
ACOG Criteria Modified ACOG CriteriaOdds Ratio (95% CI)
P Value Odds Ratio (95% CI)
P Value
Menopausal status 3.0 <.001 3.0 <.001
CA125-II level 11.6 <.001 9.3 <.001
Ascites 7.8 <.001 7.8 <.001
Evidence of metastasis 11.7 <.001 11.7 <.001
Nodular or fixed mass 3.3 <.001 -- --
FH of breast cancer 1.9 0.036 -- --
FH of ovarian cancer 1.5 0.332 -- --
Presented at SGO Annual Meeting, San Francisco, CA March, 2010
ACOG Simplified*
1. OVA1 (+)
2. Nodular or fixed mass
3. Ascites
4. Metastases
*presence of any criterion warrants referral to a gynecologic
oncologist
Sensitivity93%
Specificity40%
PPV41%
NPV93%.
Risk of Malignancy IndexU x M x CA125
US Meno Size CA125 HR Score
RMI 1 Jacobs 1990 0, 1, 3 1, 3 NA U/mL >200
RMI 2 Tingulstad 1996 1, 4 1, 4 NA U/mL >125
RMI 3 Tingulstad 1999 1, 3 1, 3 NA U/mL >200
RMI 4 Yamamoto 2006 1, 4 1, 4 1, 2* U/mL >450
RMI 5 Lee 2010 ? ? NA U/mL ?
*<7 cm or ≥7 cm
Risk of Malignancy IndexCutoff = 200
Manjunath et al. Gynecol Oncol 81:225-229, 2001.
Sens Spec PPV NPV0
10
20
30
40
50
60
70
80
90
100
73
91 93
67
RMI 1RMI 2RMI 3
Ultrasound with Biomarker
US* with OVA1 US* with CA125
n/N Sensitivity 95% CI n/N Sensitivity 95% CIAll stages3
102/105 97 92 to 99 82/105 78 69 to 85
Stage I 28/31 90 75 to 97 16/31 52 35 to 68
Stage II 18/18 100 82 to 100 14/18 78 55 to 91 Early stage (I & II) 46/49 94 84 to 98 30/49 61 47 to 74 Late stage (III & IV) 54/54 100 93.4 to 100 52/54 96 88 to 99Premenopausal women
Early stage (I & II) 14/17 82 59 to 94 5/17 29 13 to 53
Late stage (III & IV) 10/10 100 72 to 100 9/10 90 60 to 98Postmenopausal women
Early stage (I & II) 32/32 100 89 to 100 25/32 78 61 to 89
Late stage (III & IV) 44/44 100 92 to 100 43/44 98 88 to 100
*US= solid, papillary projections, ascites onlyData from OVA1 trial presented at SGO, 2010
Correlation of OVA1 and Cancer
High risk imaging Low risk imaging
OVA1 score % Malignant Odds Ratio % Malignant Odds Ratio
4.4 as cut-off 50.5 8.8 16.7 5.2
5.0 as cut-off 51.7 4.9 16.3 3.3
6.0 as cut-off 66.1 8.4 24.4 4.9
7.0 as cut-off 79.5 13.4 31.6 5.4
8.0 as cut-off 82.5 12.0 50.0 10.6
9.0 as cut-off 84.8 10.9 100.0 NC
Evaluation of an ovarian tumor
Unilocular/septate Complex morphology1
US surveillanceevery 3-4 months
CA125 (or OVA1; RMI; ACOG)
Surgery with gynecologist
Surgery with gynecologic oncologist
US surveillanceevery 6 months
persistent low risk high risk2
*Perform tumor morphology indexing (MI)1Complex morphology: solid or papillary areas, ascites, metastases, or MI ≥ 52High risk: CA125 > 200 U/mL (pre), >35 U/mL (post), OVA1 (+), RMI > 200, or per ACOG guidelines
Ovarian tumorultrasound*
complex
low risk
Patient Referrals
Specificity doesn’t correlate with referral decisions
Ovarian cancer prevalence for GYO 20-40%
OVA1 trial 72% of all benign tumors referred to GYO for surgery 45% referred despite a NEGATIVE physician
assessment Physicians lack confidence in impression Non-medical factors
Top Related