Download Clinical application of CA 125

Ovarian Cancer
Tumour Markers
Brig Dilshad Ahmed Khan
MBBS, MCPS, FCPS, FRC Path , PhD
Head of Chem Pathology & Endocrinology dept
AFIP, Rawalpindi
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)
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%:
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
Risk Factors
Age
 Women over age 55 account for ~80% of all cases
Reproductive history
 Early menarche or age >30 years at first childbearing, and late menopause
Hormone replacement therapy > 10 years
 May be associated with 30% increased risk
American Cancer Society, 2013
Risk Factors: Age
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.
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
History : Symptoms of
ovarian cancer
 Asymptomatic
 Lower abdominal pain/pressure
 Pelvic mass
 Abdominal enlargement
 Vaginal bleeding
 Urinary/bowel symptoms
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
Histopathology
ovarian capsule
Epithelial ovarian cancer, stage 1C
Ovarian Tumors: Classification
1.Surface epithelial – 6570%:





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%
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
Ovarian Cancer Biomarkers
 CA 125
 Transthyretin
 HE4
 IGFBP-2
 CA 15-3
 SMRP (Mesomark™)
 CA 72-4
 HK6
 B7-H4 (Ov-110)  Cytokeratin 19
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
CA-125 – Tumor Markers
CA125 is a tiny part of a very
large molecule called MUC16
Ovarian Cancer cell
Blood
Clinical application of CA 125
• 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
1NIH
Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
2ACOG Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
CA-125 – Serum CA125 Assay
CA125
Clinical application of CA 125
CA125 : Diagnostic Sensitivity
 Diagnostic sensitivity is
related to tumor stage:
Stage I
 Stage I-II :
50%
 Stages III-IV: 80-90%
Stage IV
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.
CA125 : Diagnostic Specificity
Malignant conditions
Benign conditions
 Cervical CA
 Endometriosis
 Fallopian tube CA
 Uterine fibroids
 Endometrial CA
 ovarian cysts
 Pancreatic CA
 PID
 Colon CA
 Pancreatitis
 Breast CA
 Liver disease
 Mesothelioma
 Renal failure
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
Monitoring Treatment Response
Diagnosis and treatment
Canc
er cell
Time
Tumor
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.
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)
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
HE4 : Diagnostic Sensitivity
 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
1NIH
Consensus Development Conference Statement. Gynecol Oncol. 1994;55:S4-S14.
Practice Bulletin. Obstet Gynecol. 2007;110:201-213.
2ACOG
HE4 : Diagnostic Sensitivity
HE4 : Diagnostic Specificity
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.
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
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
Combination of HE4 and CA125
Higher serum concentrations in advanced stage
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
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%.
Conclusions

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