GUIDE- PROF. S.MAJUMDAR DR.P.S.DUTTA PRESENTED BY – DR. IPSEET MISHRA TUMOUR MARKERS AND THE SURGEON
Dec 11, 2015
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)
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
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