Ovarian Cancer Tumour Markers

Brig Dilshad Ahmed KhanMBBS, 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 child-

bearing, 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

Epithelial ovarian cancer, stage 1C

ovarian capsule

Histopathology

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%

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

HE4

CA 15-3

CA 72-4

B7-H4 (Ov-110)

Transthyretin

IGFBP-2

SMRP (Mesomark™)

HK6

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

CA125 is a tiny part of a very large molecule called MUC16

Ovarian Cancer cell

CA125

CA125

CA125

Blood

CA-125 – Tumor Markers

• 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.

CA125

CA-125 – Serum CA125 Assay

Clinical application of CA 125

Diagnostic sensitivity is

related to tumor stage:

Stage I-II : 50%

Stages III-IV: 80-90%

CA125 : Diagnostic Sensitivity

Stage I

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

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

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

TumorCancer cell Time

Diagnosis and treatment

Monitoring Treatment Response

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 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.

HE4 : Diagnostic Sensitivity

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

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%.

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