In this article we will discuss about:- 1. Meaning and Uses of Tumor Markers 2. Types of Tumor Markers 3. Identification 4. Diagnosis 5. Specific Tumor Markers.
- Meaning and Uses of Tumor Markers
- Types of Tumor Markers
- Identification of Tumor Markers
- Diagnosis of Tumor Markers
- Specific Tumor Markers
1. Meaning and Uses of Tumor Markers:
A tumor marker is a biochemical indicator produced by neoplastic tissue and released into blood and detected in blood or in other body fluids. An ideal tumor marker should include – high sensitivity, high specificity, convenience, low price and should be safe.
Potential Uses of Tumor Markers:
i. Screening a healthy population or a high risk population for the presence of cancer.
ii. Monitor the progress of disease.
iii. Monitor the response to treatment.
iv. Making a diagnosis of cancer or of a specific type of cancer.
v. Determining the prognosis in a patient.
vi. Targets for therapeutic intervention.
2. Types of Tumor Markers:
The tumor markers are of the following types (Table 5.1):
i. Cell surface antigens.
ii. Cytoplasmic protein.
3. Identification of Tumor Markers:
A tumor marker can be identified based upon its location as follows:
Cell – Cytochemistry, Flow cytometry
On tissue – Cytosol assays, Histochemistry
In body fluids – Blood, Urine, Cerebro-spinal fluid, Amniotic fluid.
4. Diagnosis of Tumor Markers:
A tumor marker is used to differentiate tumor from normal tissue or to determine the presence of tumor based upon measurement in the blood or secretion. Two types of tumor antigens have been identified on tumor cells that help in the detection of tumors.
a. Tumor specific Transplantation Antigens (TSTA).
b. Tumor associated Transplantation Antigens (TATA).
i. TSTA is unique to tumor cells.
ii. These antigens are absent on normal cells of the body.
iii. Mutations in tumor cells may result to TSTA formation that generates altered cellular proteins.
i. TATA is not unique to tumor cells.
ii. TATA are proteins generally, these may be:
(1) Proteins expressed at extremely low levels in normal cells but in tumor cells they are expressed at much higher levels.
(2) Proteins that are expressed on normal cells during fetal development but not expressed in adults.
5. Specific Tumor Markers:
1. Oncofetal Antigens:
(i) Alpha Feto Protein – (AFP):
a. AFP is a marker for liver (hepatocellular) and germ cell carcinogen.
b. AFP is synthesized during embryonic development by gastro-intestinal tract, fetal yolk sac, kidney and liver.
c. Molecular weight of AFP is 70 kg.
d. It is a glycoprotein with 4% carbohydrate.
e. It is a major protein in fetal circulation.
f. Its half-life is 4-6 days
g. AFP exists in a number of isoforms which can be separated by their differential binding to lectins.
h. AFP is genetically and structurally related to albumin
i. AFP concentration begins to decline during later fetal development and albumin synthesis increases
j. Serum levels of AFP in –
(i) Healthy adults – <, 10 mg./l
(ii) Pregnant women – 500 mg/I during 3rd trimester
(iii) Fetus – 2 gl./l at 14th week
k. AFP levels greater than 1000µg/l are indicative of cancer (except in pregnant women).
l. Increased levels of AFP are associated with conditions like cirrhosis (liver inflammation) and hepatitis
m. Elevated levels of AFP after surgery indicate incomplete removal of tumor or metastasis. It is used to determine prognosis and monitor the therapy of hepato-cellular carcinoma. Color produced is directly proportional to AFP level.
(ii) Carcinoembryonic Antigen (CEA):
CEA is a marker for colorectal carcinoma, lung carcinoma, breast carcinoma and gastrointestinal (GI) carcinoma.
a. CEA is produced by GI tract, liver and pancreas.
b. Molecular weight of CEA is 200 kd.
c. CEA is a fetal glycoprotein with 45-55% carbohydrate.
d. CEA consists of 641 amino acids.
e. CEA is produced in pneumonia, hypothyroidism and pancreatic tumors
f. Reference value of CEA is < 5ng/ml
g. CEA level is elevated (< 10ng/ml) in smokers, inflammatory or peptic bowel disease, cirrhosis, renal failure, fibrocystic breast disease.
h. In breast carcinoma, elevated level of CEA is associated with metastatcs disease.
(i) Prostate Specific Antigen (PSA):
a. PSA is a tumor marker for prostate cancer.
b. PSA is a single chain glycoprotein with 7% carbohydrates
c. It has 237 amino acid residues
d. PSA is found in normal, benign, hyperplastic and malignant prostatic tissue.
e. This protein is purified from prostatic tissue.
f. Molecular weight of PSA is 28.43 kd.
g. Various isoforms exists because of which iso-electric points vary between 6.8-7.2
h. PSA is specific for prostatic tissue and not for prostate cancer. Therefore, PSA testing is not useful in screening or detecting early prostate cancer.
i. PSA is present in blood in two major forms-
(a) Free PSA
(b) PSA complexed with protease inhibitor
j. Complete gene for PSA has been sequenced and is present on chromosome no 19.
k. It’s half-life is 2-3 days.
l. PSA can be used to monitor the definitive treatment of prostate cancer. For example, In radical prostatectomy, whole of the prostate tissue is removed. Then the level of PSA is measured to confirm the success of radical prostectomy. The PSA level should be below the detection limit of assay. As the half-life of PSA is 2-3 days, it will take 2-3 weeks for the PSA level to come down. Is half-life is longer than normal, it can be interpreted that residual tumor is present.
(ii) Neuron Specific Enolase, (NSE):
a. NSE is an immunohistochemical marker for tumors of the central nervous system, neuroblastomas, and APUD tumors.
b. Neuron specific enolase is an isozyme of the glycolytic pathway that is found only in brain and neuroendocrine tissue
c. NSE is a prognostic factor in neuroblastoma
d. NSE occurs in neuroendocrine tumors – medullary carcinoma of the thyroid, carcinoid tumors, pheochromocytoma
e. NSE correlated with stage and bulk of disease
f. Use of NSE has been evaluated in lung cancer and neuroblastoma.
(i) Human Chorionic Gonadotrophin, (HCG):
a. hCG is a tumor marker for gestational trophoblastic disease and germ cell tumors.
b. hCG is normally produced by the syncytiotrophoblastic cells of the placenta, normal litre 20-30 mlU/ml
c. hCG level is elevated in pregnancy
d. hCG is a glycoprotein composed of 244 amino acids
e. Molecular weight of hCG is 36.7 kDa
f. Half-life of hCG is 32-37 hours
g. hCG has two subunits:
(i) α subunit – common to FSH, LH and TSH
(ii) β subunit – unique to hCG
h. The urine test may be a chromatographic immunoassay
i. The serum test is typically a chemilummescent or fluorimetric immunoassay
j. Free β subunit predominates in early pregnancy
k. Free α subunit predominates in late pregnancy
l. hCG can be detected in pregnancy one day after implantation, 8 days after ovulation and 9 days after LH surge.
m. hCG concentration rises exponentially until 9 to 10 weeks of gestation with a doubling time of 1.3 to 2 days.
n. hCG level
o. hCG concentration reaches its peak of around 105 IU/ml after 60 to 90 days of gestation.
p. hCG concentration decreases from this peak level to a plateau value of 10,000 to 20,000 IU/ml, which is maintained for the remainder of the pregnancy.
q. βhCG level comes to non-pregnant level of less than 5mU/ml, 21 to 24 days after delivery.
r. Higher level of hCG in cerebrospinal fluid may indicate metastasis to the brain.
(ii) Calcitonin, (CT):
a. CT is tumor marker for medullary thyroid cancer
b. CT is a hormone produced parafollicular C cells in the thyroid gland.
c. Ct regulate blood calcium levels
d. In medullary thyroid cancer, blood levels of CT are greater than 100 pg/ml.
(i) Carbohydrate Marker 125, (CA-125):
a. CA 125 is a marker for ovarian and endometrial carcinomas.
b. CA125 is an antigen present on 80 percent of non-mucinous ovarian carcinomas
c. CA 125 is a glycoprotein with 24% carbohydrate.
d. Molecular weight of CA 125 is 200 kDa.
e. CA-125 level is 35 u/l in healthy population
f. CA 125 level is elevated in non-ovarian carcinoma including endometrial, pancreatic, lung, breast, and colon cancer, and in menstruation, pregnancy, endometriosis, and other gynecologic and non-gynecologic conditions.
(ii) Carbohydrate Marker 19-9, (CA-19-9):
a. CA 19-9 is a tumor marker for digestive tract carcinoma
b. CA 19-9 level is elevated in 21 to 42 percent of cases of gastric cancer, 20 to 40 percent of colon cancer, and 71 to 93 percent of pancreatic cancer
c. CA 19-9 is proposed to differentiate benign from malignant pancreatic disease
d. Reference value for CA 19-9 is < 37U/ml
e. CA 19-9 level of > 1000ng/ml indicates metastasis