GUIDE- PROF. S.MAJUMDAR

DR.P.S.DUTTA

PRESENTED BY – DR. IPSEET MISHRA

TUMOUR MARKERS AND THE SURGEON

DEFINITION

Substances determined in the tumour tissue (qualitative) or in serum or other body fluids (quantitative) of a patient with neoplastic disease that provide information about biological characteristics of the tumour.

What are Tumor Markers？

Biological substances synthesized and released by cancer cells themselves

or produced by the host in response to the presence of tumor

Most tumor markers are proteins Detected in a solid tumor, in circulating

tumor cells in peripheral blood, in serum, lymph nodes, in bone marrow, or in other body fluid (urine, stool, ascites)

When are they useful ?

Screening

Early Detection

Diagnosis Monitor

The Various Putative Utilities

1. Screening To identify early cancer risk

2. Diagnosis To corroborate the diagnosis

3. Staging To assess & stratify the risk

4. Prognosis To predict the outcome

5. Localization To locate the primary

6. Therapy To target the therapy

7. Surveillance To detect recurrence in Follow-Up

8. Monitoring To evaluate response to Rx.

Tumor Markers - Drawbacks

1. Cancer heterogeneity

2. Lack of Specificity – false positives

3. Lack of Sensitivity - false negatives

4. Benign diseases - positive CA 125 or CEA

5. Smokers have raised CEA

6. Normal persons also have small amounts

7. Higher levels only with large tumor volume

8. Some cancers never have higher levels

Tumor Markers

Antigens Hormones

EnzymesTissue

Specific

TUMOR

Specific Classes of Tumor Markers

Enzymes (PSA, NSE, VMA, HVA)

Cell membrane receptors (ER, PR)

Tumor antigens (CEA, AFP)

Antibodies (IgA, IgG, IgM, IgD)

Antigens (p53, ki-62)

CA-specific proteins(CA 19-9, CA 124)

Gene mutation products (BR CA 1, 2)

Tissue-specific proteins (PSA, hCG)

Special hormones (b-hCG, hCG)

Catecholamines (VMA, HVA, ACTH)

Polyamines

Cytoplasmic / Nucleic material (DNA)

Products of cell turn-over (TNF)

Cellular modulators (ki-62, c-erb-2)

How to Detect Tumor Markers?

ELISA Immuno-histochemistry (IHC) Polymerase chain reaction (PCR) Fluorescence in situ hybridization

(FISH) Cluster Kits ( All-in-One Kit)

Detects profiles

Patterns

Prototypes

Constellations

Tumor Markers: PSA

Prostate Specific Antigen(PSA) is a glycoprotein

Ideal as a tumor marker, high tissue specificity

High sensitivity for prostate cancer

Also elevated in BPH & prostatitis

Useful in Dx. & follow up of prostate Ca, Prognostic factor

To monitor recurrence & response to treatment

? For screening of prostate cancer along with DRE

Free PSA： PSA not bound to the plasma anti proteases α1-antichymotrypsin & α2-macroglobulin

An ↑in ratio of free/total PSA is associated with increased probability of prostate cancer

97% specificity, 96% sensitivity for prostate Ca

For population screening and diagnosis an increase of 0.75 ng/ml per year in any given patient has high sensitivity and specificity for prostate cancer vs BPH, especially when combined with DRE and TRUS

Tumor Markers: CA-125

80% of non-mucinous ovarian cancer detected by the monoclonal antibody to CA-125. Serous > Endometriod, Clear cell > mucinous

Useful in monitoring ovarian Ca recurrence & Rx. For follow up, an increase may predict recurrent disease, precedes clinical recurrence by months

Correlates with tumor bulk.

Elevated in Ovarian, Endometrial, Pancreatic, Lung, Breast, Colon cancers

Also in Menstruation, Pregnancy, Endometriosis, PID and other gynecological and non gynecological conditions.

Screening of high risk population (BRCA1-2 Carriers); Not useful for routine screening

Tumor Markers: AFP

A serum fetal glycoprotein synthesized by the liver, yolk sac, gastrointestinal tract

In Hepatocellular Cancer: It is diagnostic (>500) and also useful for screening of high risk population (HBV, HCV)

Benign conditions: hepatic parenchymal inflammation, hepatic necrosis, pregnancy, primary biliary cirrhosis, EHBO give positive test.

Testicular germ cell tumor (embryonal or endodermal): For Diagnosis, Prognosis, to monitor recurrence & response The absolute AFP level correlates with tumor bulk Raised in Cancers of pancreas, colon, stomach & bronchogenic

Ca

Tumor Markers: CEA

Complex glycoprotein associated with the plasma membrane of tumor cells

Elevated specially in Colon cancer, MTC, AdenoCa uterus

Also in Pancreatic, Gastric, Lung, breast & Ovarian Ca Also in cirrhosis, inflammatory bowel disease, chronic

lung disease, pancreatitis, fibrocystic breast disease 19% of smokers, 3% of healthy population Normal pre Rx CEA indicates no metastasis Not satisfactory for screening for a healthy population Good for monitoring recurrence & to monitor Rx.

Tumor Markers: CA 19-9

Elevated in 20-40% colonic Ca , 21-42% gastric Ca and in 71-93% pancreatic Ca cases

For D/D of benign from malignant disease

Dx, FU, Relapse - 70% specificity & 90% sensitivity

It is a mucin, does not during pregnancy

Monitor patients who do not express CA 125, mucinous (76%) > serous (27%)

βeta HCG

Glycoprotein synthesized by syncytiotrophoblastic cells of normal placenta

Serum and urine HCG ↑ in early gestation and peak in the first trimester (60~90 days)

Elevated in Gestational trophoblastic disease (a progressive rise in after 90 days of gestation → highly suggestive), choriocarcinoma

Elevated in testicular cancer, βHCG after surgery Monitor treatment response, relapse & recurrence

Breast Cancer and ER

2 isoforms： ERa and ERb ERa → better prognosis, predictor of relapse useful when deciding on adjuvant hormone

treatment As diagnostic marker when it is a primary unknown

tumor ERb → Good prognostic factor, correlates with low

grade and negative axillary LN status

Breast Cancer Oncogenes

HER-2/neu oncogene (using monoclonal antibody) - over expression related to poor prognosis in breast cancer

Oncogene c-erbB-2 gene： over expressed in 30% of breast cancers, correlation between c-erbB-2 gene positivity, positive axillary node status, reduced time to relapse and reduced overall survival

BRCA1 gene on chromosome 17q： familial breast-ovarian cancer syndrome, and breast cancer in early-onset breast cancer families → high risk screening

Breast Cancer and CA15-3

↑ in 20% with localized breast cancer, ~80% with metastatic disease, esp. if with bone involvement

To monitor Rx. & to detect recurrence in BR Ca

Specificity of 86%, sensitivity of 30%

Also ↑ in gastric, pancreatic, cervical & lung cancer

Melanoma

Tyrosinase

Use RT-PCR to detect hematogenous spread of melanoma cells from a solid tumor in peripheral blood S100B protein

For confirmation of amelanotic malignant melanoma by immunohistology

↑in 70% with stage IV metastasized melanoma MIA (melanoma inhibitory activity)

Preoperative: 59% at stage III, 89% at stage IV

Thyroid Cancer

Thyroglobulin

Tissue-specific, glycoprotein produced by thyroid follicular cells

Also increased in breast or lung cancer

Thyrocalcitonin

From thyroid C cells & medullary thyroid cancer

Effective to screen patients with 1st degree relatives affected by medullary thyroid cancer and multiple endocrine neoplasia type 2 (MEN2)

Neuroendocrine Tumors

Neuron-specific enolase (NSE) A neuronal isoenzyme of cytoplasmic enzyme

enolase, in neuroendocrine cells As a prognostic factor in neuroblastoma Occurs in neuroendocrine tumors: medullary

carcinoma of the thyroid, pheochromocytoma, carcinoid tumors; immature teratoma, small cell carcinoma of lung, non-small-cell cancer, melanoma. Correlate with stage and bulk of disease

N-myc oncogene in neuroblastoma N-myc copy number is associated with stage and prognosis

Common Tumor Markers

Thank You

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