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Ovarian Cancer Tumour Markers
Brig Dilshad Ahmed KhanMBBS, MCPS, FCPS, FRC Path , PhD
Head of Chem Pathology & Endocrinology dept
AFIP, Rawalpindi
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Outlines
Introduction
Risk factors for development of ovarian cancer
Diagnosis of ovarian cancer
Clinical application of CA125
Clinical application of HE4
Algorithms for the estimation of the risk of ovarian cancer in
women with pelvic mass (ROMA)
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Introduction
Ovarian cancer are developed from three categories of cells
Epithelial Cells (65-70%)
Serous
Mucinous
Endometrioid
Transitional cell
Stromal cell– 15-20%
Germ cell – 5-10%:
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Ovarian Cancer Epidemiology
Incidence is 2 to 15 cases per
100,000 women
The 2nd most common
gynecologic malignancy
4th leading cause of cancer
death in U.S. (after lung, breast
and colon)
American Cancer Society, 20013
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Risk Factors
Age
Women over age 55 account for ~80% of all cases
Reproductive history
Early menarche or age >30 years at first child-
bearing, and late menopause
Hormone replacement therapy > 10 years
May be associated with 30% increased risk
American Cancer Society, 2013
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Risk Factors: Age
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Risk factors: Heredity
Up to 10% of epithelial ovarian cancer are familial
Familial breast-ovarian cancer and site-specific
ovarian cancer syndromes are associated with
mutations of the BRCA1 suppressor gene; account
for 90% of familial ovarian cancers
Rollins, G. Ann Int Med 2000;133:1021-1024.
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Diagnosis of Ovarian Cancer
Early detection is not an easy task
Pelvic examination
Ultrasound
CT Scan & MRI
Laparoscopic biopsy
Histological examination
Ovarian cancer tumor markers
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History : Symptoms of ovarian cancer
Asymptomatic
Lower abdominal pain/pressure
Pelvic mass
Abdominal enlargement
Vaginal bleeding
Urinary/bowel symptoms
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Images: U/S MRI, CT
Ultrasound Relatively inexpensive Delineates cystic vs solid structures
CT Scan Assesses other organs Excellent for retroperitoneum (1-5 mm)
MRI Allows for ID of soft tissue lesions Can differentiate normal from malignancy
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Epithelial ovarian cancer, stage 1C
ovarian capsule
Histopathology
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Ovarian Tumors: Classification
1.Surface epithelial – 65-70%:
Serous (tubal) Mucinous (endocx & intestinal) Endometrioid Transitional cell - Brenners. Clear cell
2. Stromal – 15-20%: Granulosa-cell tumor Thecoma Fibroma Sertoli-Leydig cell tumors
3.Germ cell tumors – 5-10%: Teratoma –
Benign cystic (dermoid cysts)
Solid immature Monodermal – struma
ovarii, carcinoid Dysgerminoma Yolk sac tumor
Choricarcinoma Mixed germ cell tumor
4.Metastatic tumors – 5%
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Ovarian Cancer : tumor stages
Because ovarian cancer cause few
symptoms,
>75% of patients are diagnosed stage III-IV:
5 year survival rate up to 25%
25% are diagnosed with
stage I: 5 year survival rate up to 90%
Stage II: 5 year survival rate up to 70%
Early detection has great promise to improve
clinical outcome
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Ovarian Cancer Biomarkers
CA 125
HE4
CA 15-3
CA 72-4
B7-H4 (Ov-110)
Transthyretin
IGFBP-2
SMRP (Mesomark™)
HK6
Cytokeratin 19
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CA-125 – Tumor Markers
CA125 is the first tumor marker of ovarian cancer
Discovered with a mouse monoclonal antibody
(OC125) produced by immunizing a mouse with a
serous ovarian cancer cell line
Glycoprotein with a molecular weight (>200 kD)
Reference range : Serum <35 U/mL
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CA125 is a tiny part of a very large molecule called MUC16
Ovarian Cancer cell
CA125
CA125
CA125
Blood
CA-125 – Tumor Markers
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• Increased in most ovarian cancers especially
80% of epithelial ovarian cancers1
• Elevated in 50% of Stage I disease
• Longitudinal assessment improve sensitivity
• Marker to test the recurrence of cancer
Clinical application of CA 125
1NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
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CA125
CA-125 – Serum CA125 Assay
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Clinical application of CA 125
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Diagnostic sensitivity is
related to tumor stage:
Stage I-II : 50%
Stages III-IV: 80-90%
CA125 : Diagnostic Sensitivity
Stage I
Stage IV
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CA125 : Diagnostic Specificity
Limitations
Poor specificity (elevated in many
gynecologic & non-gynecologic malignancies
as well as benign conditions
– increased in 0.2‐5.9% healthy women
–increased in 2.2‐27.8% of benign disease1,2
1NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
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CA125 : Diagnostic Specificity
Malignant conditions
Cervical CA
Fallopian tube CA
Endometrial CA
Pancreatic CA
Colon CA
Breast CA
Mesothelioma
Benign conditions
Endometriosis
Uterine fibroids
ovarian cysts
PID
Pancreatitis
Liver disease
Renal failure
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Monitoring Treatment Response
Gynecological cancer group criterion:
Complete responder: CA 125
concentrations fall within the reference
range after treatment.
At least 50% of CA 125 decrease
compared with the pre treated sample
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TumorCancer cell Time
Diagnosis and treatment
Monitoring Treatment Response
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Monitoring Recurrence
Useful in detecting residual
disease in the cancer patients
CA-125 can detect recurrence of
the cancer up to 75% accuracy
CA-125 correlate with ovarian
cancer progression or regression
in 80-90 % of cases.
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Monitoring Recurrence
Patients with normalized CA 125 level:
Increase in CA 125 ≥ 2 times of the upper limit of
reference on two occasions after treatment.
An absolute increase of CA 125 level ≥ 5U/mL
compared with its nadir value was a strong
predictor of recurrence
Gynecological Cancer Intergroup criterion (2011)
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Human epididymis protein 4 (HE 4)
HE4 is human epididymis protein 4
A new up-regulated biomarker for ovarian cancer
Gene located in chromosome 20q12–13.1
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HE4 has better diagnostic sensitivity in the early
diagnosis of ovarian cancer
Overexpressed in 93% of serous, 100% of
endometrioid and 50% of clear cell ovarian cancer
Not expressed in mucinous and germ‐cell ovarian
cancers
HE4 : Diagnostic Sensitivity
1NIH Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
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HE4 : Diagnostic Sensitivity
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HE4 has an increased diagnostic
specificity compared with CA 125, in the
ovarian malignancies
Overexpressed in pulmonary,
endometrial, and breast cancers and
mesotheliomas
Renal failure and pleural effusions are the most
important sources of false positive HE4.
HE4 : Diagnostic Specificity
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Monitoring the disease progression
HE4 correlated better with the PET/CT results as compared to CA 125
HE4 increased 5‐8 month before CA 125 in relapsed ovarian cancer
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Combination of HE4 and CA125
Tumor markers CA 125 and HE4 are approved
by FDA for monitoring the disease progression
The combination of HE4 and CA 125 are more
sensitive than either marker alone
Both tumor markers relate to stage and histology
of ovarian cancer
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Combination of HE4 and CA125
Higher serum concentrations in advanced stage
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Algorithms for the Estimation of risk of ovarian cancer in women with pelvic mass (ROMA)
To assess whether a woman who presents with
an ovarian adnexal mass is at high or low
likelihood of having malignancy
A quantitative test that combines serum HE4,
CA 125 & menopausal status into a numerical
score
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ROMA (Risk of Ovarian Malignancy Algorithm :Calculation
ROMA = exp(PI) [1+exp(PI)]*10
Premenopausal: Predicative Index (PI) =
cut off of ≥1.31
Postmenopausal: Predicative Index (PI) =
cut off of ≥ 2.77
Provide a specificity level of 75%.
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ConclusionsConclusions CA125 is the tumor marker of choice for monitoring ovarian cancer
HE4 diagnostic sensitivity is better than CA125 in early stages of
ovarian cancer
Combination of both tumor markers improved the detection of
ovarian cancer & specificity than either alone
Both correlated well with the tumour stage, histology and prognosis
ROMA estimate the risk of ovarian cancer in women with pelvic
mass