1. Diagnosis of Ovarian Cancer
State of the art
Diagnosis of Ovarian Cancer

2. A woman’s lifetime risk of developing ovarian cancer is
approximately 1 in 70

3. Ovarian cancer survival
5-years overall survival (%)

4. Ovarian Cancer: FIGO - Stage
I Ovaries %
II Small pelvis %
III Peritoneal metastasis 55%
IV Distant metastasis 15%

5. Key steps to diagnosing ovarian cancer1
1. Obtain careful history Remember that ovarian cancer will mimic many gastrointestinal disorders Both clinicians and patients can erroneously ascribe symptoms to the gastrointestinal tract
2. Perform a pelvic examination Most pelvic masses are easily palpated on rectovaginal examination but are NOT palpable on abdominal examination

6. Ovarian Cancer Symptoms
bloating
pelvic or abdominal pain
trouble eating or feeling full quickly
urinary symptoms such as urgency or frequency

7. Comparison between ovarian cancer patients and clinic controls
Symptom Odds ratio (95% CI)
Increased abdominal size 7.4 (3.8 – 14.2)
Bloating (1.8 – 7.0)
Urinary urgency (1.3 – 4.8)
Above three combined* 9.4 (5.0 – 17.7)
Pelvic pain (1.2 – 3.9)
* 44% of ovarian cancer patients had this triad of symptoms, compared to 8% of the patients visiting
primary care clinics.
Adapted from Goff et al. JAMA 2004

8. Key steps to diagnosing ovarian cancer1
1. Obtain careful history Remember that ovarian cancer will mimic many gastrointestinal disorders Both clinicians and patients can erroneously ascribe symptoms to the gastrointestinal tract
2. Perform a pelvic examination Most pelvic masses are easily palpated on rectovaginal examination but are NOT palpable on abdominal examination

9. Physical Examinations
Pelvic examinations, including a rectal exam, even under anesthesia, have shown limited ability to identify an adnexal mass, especially with increasing patient body
mass index (BMI) greater than 30

10. Key steps to diagnosing ovarian cancer2
3. In a general physical examination, look for: • Ascites (increased abdominal girth) • Omental cake (mass in mid to left upper abdomen) • Pleural effusion • Lymphadenopathy • Malnourished appearance (despite stable weight from increasing ascites)

11. Key steps to diagnosing ovarian cancer3
4. Perform the following diagnostic studies if ovarian cancer is suspected • Pelvic ultrasound (easiest way to assess ovaries and check for ascites) • Abdominal-pelvic CT (more expensive, but can evaluate for other pathology) • CA 125 blood test (not recommended as a single test, since this tumor marker is not accurate in premenopausal women and 50% of patients with stage I ovarian cancer will have normal CA 125 levels)

12. Modalities for the Evaluation of Adnexal Masses
Modality Sensitivity Specificity
Gray-scale transvaginal –91% 68–81%
ultrasonography
Doppler ultrasonography % %
Computed tomography % %
Magnetic resonance imaging % %
Positron emission tomography % %
CA 125 level measurement % %
Agency for Healthcare Research and Quality. Management of adnexal mass.
Evidence Based Report/Technology Assessment No AHRQ Publication No.
06-E004. Rockville (MD): AHRQ; 2006

13. Sonography Tumor Unclear palpation Abdominal symptoms Free fluid
Family history

14. Ovarian cancer sonography
6.6%
5/76
0.5%
1/201
(75mm)
0.3%
1/370 0%
0/13

15. Morphology Index for Ovarian Tumors
Smooth wall, sonolucent
Smooth wall, diffuse echogenicity
Wall thickening, less than 3 mm fine septa
Papillary projection equal to or
greater than 3 mm thick
Complex, equal to or
greater than 3 mm thick
Complex, solid and cystic areas
with extratumoral fluid
Liu JH, Gass M. Management of the perimenopause. New York (NY):
© The McGraw-Hill Companies, Inc; 2006.

16. 459 Adnexal mass (14% malignant)
SCORE
459 Adnexal mass (14% malignant)

17. Ovarian cancer doppler sonography
Neovascularisation results in an abundance of newly formed vessels.
Irregular branching and lumina, arterio-arterial loops and inter- vascular shunts.
Rapid flow with a high diastolic component resulting in high PSV and low PI and RI.

18. Doppler Ultrasound
benign
malignant

19. Ideal Tumor Markers Be specific to the tumor
Level should change in response to tumor size
An abnormal level should be obtained in the presence of micrometastases
The level should not have large fluctuations that are independent of changes in tumor size
Levels in healthy individuals are at much lower concentrations than those found in cancer patients
Predict recurrences before they are clinically detectable
Test should be cost effective

20. CA 125 Glycosylated Mucin - MUC-16
Expressed by amnion, fetal peritoneum and mullerian duct during embryonic development
Released from dying cancer cells and probably shed by proteolytic cleavage
The amount of CA 125 shed relates to surface expression and to proteolytic cleavage

21. CA 125 Expressed by 80% of epithelial ovarian cancers
Elevated in sera from >90% of ovarian cancer patients
Produced by cancer cells and activated mesothelial cells
Measured by double determinant immuno- assays with murine monoclonal antibodies

22. CA 125
Inter-assay coefficient of variation is <5%, permitting accurate monitoring
Half-life approximately 7-14 days
An apparent half-life >21 days indicates residual disease and poor prognosis
Values moderately elevated after laparotomy and return to normal within 1 month
Anti-murine antibodies in patient sera can provide false-positive elevations

23. CA-125 Distribution in patients with Malignant disease
% Distribution of CA-125

24. CA-125 Distribution in Healthy subjects and patients with Non-Malignant conditions
% Distribution of CA-125

25. Rationale of screening for ovarian cancer
Background:
Rationale of screening for ovarian cancer

26. ROCA: Risk of Ovarian Cancer Algorithm
Regular
CA-125 Test
Risk of Ovarian Cancer Calculation
based on longitudinal CA-125 values (ROCC)
Maximum of
3 intermediate
results per year
Normal
ROCC < low
Intermediate
low < ROCC < high
Elevated
ROCC > high
Repeat CA-125
in 3 months
Ultrasound
+ CA-125
Skates, JCO 2003

27. De Priest ovarian cancer screening study algorithm
DePriest, P. D. et al. J Clin Oncol; 21:194s-199s 2003

28. Background: Making the case for a randomised trial on a large scale
Sensitivity (%)
False + VE OPs per OvCa

29. Methods: Design UKCTOCS Multimodal screen group Ca 125 + USS 50,000
6 years
annual screening
200,000 women
years
& postmenopause
Ultrasound group
TV Ultrasound
50,000
Control group
no screening
100,000

30. Methods: USS protocol Transvaginal scanning
Morphology based scoring systems:
Abnormal level I screen - recall for level II screen
Abnormal level II screen - referral gyn onc opinion
Septa structure
Wall structure

31. Results: Specificity & PPV
Assumes incidence OC 40/100,000 per year and sensitivity 85% for both tests
Multimodal Ultrasound
Specificity % %
PPV % %
Operations per case % %

32. Results: Estimating lead time from prevalence screen
Yr1
Yr2
Yr3
Yr4
Yr5
Expected
cases/year
1 year lead
2 year lead
3 year lead
4 year lead
5 year lead
Actual cases 32 32 32 32 32 32 64 96
128
160 83
Suggests overall lead time ~ 2.6 years

33. We are in the ‘omics’-era

34. Sensitivity of 100% (95% CI 93–100),
Specificity of 95% (87–99)
Positive predictive value of 94% (84–99)

35. Cancer diagnosis using proteomic patterns

36. Use of proteomic patterns in serum to identify ovarian cancer
Sensitivity: 100%
Specificity: 95%
PPV: %
E. F. Petricoin, Lancet 2002; 359: 572–77

37. Proteomics
Nature, 2004

38. Differential Diagnosis of Adnexal Mass1
Gynecologic
Benign
Functional cyst
Leiomyomata
Endometrioma
Tuboovarian abscess
Ectopic pregnancy
Mature teratoma
Serous cystadenoma
Mucinous cystadenoma
Hydrosalpinx
Malignant
Epithelial carcinoma
Germ cell tumor
Sex-cord or stromal tumor
Breast cancer

39. Differential Diagnosis of Adnexal Mass2
Nongynecologic
Benign
Diverticular abscess
Appendiceal abscess or mucocele
Nerve sheath tumors
Ureteral diverticulum
Pelvic kidney
Paratubal cysts
Bladder diverticulum
Malignant
Gastrointestinal cancers
Retroperitoneal sarcomas
Metastases

40. Factors associated with clinician delay in diagnosing ovarian cancer
Omission of pelvic examination at first visit
Omission of diagnostic studies (Ultrasonography, CT, CA 125)
Having a multitude of symptoms
Younger age
Wrong initial diagnosis:
Nothing wrong
Depression
Stress
Irritable bowel syndrome
Gastritis
Adapted from Goff et al. Cancer. 2000

41. Diagnosis of Ovarian Cancer
Symptoms !!
Pelvic examination
Ultrasound/Doppler
CA-125
Laparoscopy

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