Tumour Markers

Cancer is a term used for diseases characterized by uncontrolled division of cells, the ability of these cells to invade other tissues by direct growth into adjacent tissues (= invasion) or by implantation into distant sites (= metastasis).
Cancer cells spread to other parts of the body through the blood and lymph systems. There are more than 100 different types of cancers which are named for the organ or type of cell in which they appear e.g., lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer and stomach cancer.
Cancer is the second leading cause of mortality in EU countries after the disease of the circulatory system. Cancer is responsible for +/- 26% of death causes in the EU. Lung cancer accounts for the greatest number of all cancer deaths, while breast cancer accounts for the highest number of cancer death in woman.


Cancer markers are a group of proteins, hormones, enzymes, receptors and other cellular products that are produced in higher than normal amounts by malignant cells. TM are usually normal cellular constituents that are present at very low levels in the blood of healthy persons. If the substance in question is produced by the cancer, its levels will be increased in blood or other body fluids or in the tissue of origin.
The use of TM for diagnosis, prognosis and follow up are still in debate and there exist different guidelines for different clinical and scientific organisations like EGTM, NACB.

CEA: The carcinoembryonic antigen test measures the amount of this protein that may appear in the blood of some people who have certain kinds of cancers, especially large intestine (colon and rectal) cancer. It may also be present in people with cancer of the pancreas, breast, ovary, or lung.

CEA is normally produced during the development of a foetus. The production of CEA stops before birth, and it usually is not present in the blood of healthy adults.

The carcinoembryonic antigen (CEA) test is used to:

  1. Find how widespread cancer is for some types of the disease, especially colon cancer.

  2. Check the success of treatment for colon cancer.

  • CEA levels may be measured both before and after surgery to evaluate both the success of the surgery and the person's chances of recovery.

  • CEA levels may be measured during treatment with medicines to destroy cancer cells (chemotherapy). This provides information about how well the treatment is working.

     3. Check to see if cancer has returned after treatment.

PSA: Prostate cancer is the most common tumor in men. It is the second cause of death from cancer in men after lung cancer. Although prostate cancer is lethal in some patients, most men die with rather than of their cancer.In the last 20 years the cancer cases in the western world were raised quite significantly, probably due to new detection methods and increased public awareness. The prostate is a small gland that encircles the upper urethra in males. The prostate produce and store fluid, that is usually constitutes 25-30% of the volume of the semen along with spermatozoa and seminal vesicle fluid. The function of this white fluid is to protect the DNA of the sperm cells and to give the sperm a better motility.

There are three main prostatic disorders: prostatitis, benign prostate hyperplasia and prostate cancer. Prostatitis is an inflammation of the prostate gland, which is mostly treated with antibiotics. Benign prostate hyperplasia (BPH) is a non-cancerous enlargement of the prostate. As the volume of the prostate increases, it can put pressure on the urethra, causing a slowdown in the urine stream and/or a frequent and urgent need to urinate. It can also cause urine retention, which can weaken the bladder muscle and increase the risk of developing a urinary tract infection and/or kidney stones. In severe cases of BPH, urine may back up into and damage the kidneys. The type and severity of symptoms experienced will vary from person to person and may vary over time. BPH becomes a very common condition in men as they are getting older. Prostate cancer (PCa) is cancer of the prostate cells

In order to cure PCa patients successfully, it is important to detect the disease as early as possible and to be able to monitor its progress accurately. Currently available diagnostic techniques are prostate biopsies, digital rectal examination (DRE), transrectal ultrasonography (TRUS) and assaying prostate-specific antigen (PSA).

DRE and TRUS are widely used but are very limited in their ability to diagnose CaP and do not provide the ability to distinguish between BPH and PCa.

Biopsies of the prostate, which is a pathohistology examination of prostate tissue, is the golden standard in prostate cancer detection it can clearly discriminate between PCa and BPH. However, the biggest disadvantage of this examination is the need of an operation in order to obtain the tissue for testing.

Using biomarkers overcomes the problem of quantification, and thus can provide a more accurate way for early diagnosis of PCa and for monitoring its progression. The tumor marker specific for the prostate is PSA (Prostate Specific Antigen).

PSA is a 33 kDa glycoprotein, which belongs to the family of human kallikerin proteins and is a neutral serine protease. The function of PSA is the liquefaction of the seminal fluids which will enhance the mobility of the spermatozoids. In healthy men PSA has a low concentration in the blood, where its function of PSA in the blood is unknown and it is consider as a passive leakage of PSA from the prostate.

PSA exists in the blood in multiple forms, approximately 60% to 70% of the PSA found in the circulation is complexed with protease inhibitors that circulate in the blood, like α -chymotripsine (ACT), α2-macroglobin and the remainder is free PSA.

The PSA molecule is highly specific for the prostate however it is not specific for prostate cancer. PSA will be elevated with prostatitis, benign prostate hyperplasia (BPH) and prostate cancer. Also PSA levels will go up with age, prostate volume and can be different due to race.

The PSA assay measures the total PSA concentration in serum, this is complexed and free PSA fractions.

AFP: Alpha-fetoprotein is a homolog of albumin and is thought to act as a carrier protein in the fetus. During pregnancy, AFP is initially produced by the yolk sac and later by the fetal liver. After birth, circulating concentrations decrease, with a half-life of 5 days, falling to adult levels at 8–10 months of age.

AFP is a glycoprotein with a molecular weight of 70,000 Daltons containing 4.3% carbohydrate, of which approximately 20% is sialic acid Initially the test was used as an aid in the diagnosis of hepaticas (4), since increased serum AFP concentrations were first observed. Elevated serum AFP levels may a be observed in patients with primary hepatocellular carcinoma, non-seminomatous testicular carcinoma. During successful therapy AFP levels decline, so serial monitoring of serum AFP levels in such patients has been shown to facilitate the clinical management of the disease.


PSA occurs in 2 major forms in the blood. One form is attached to blood proteins mostly ACT while the other circulates free. The percent-free PSA (ucPSA) is the ratio of how much PSA circulates free compared to the total PSA level. The percentage of free PSA is lower in men who have prostate cancer than in men who do not.

This test is used to help decide if a prostate biopsy is necessary when the PSA results are in the borderline range (between 4 and 10ng/ml). A lower percent ucPSA means that the risk of prostate cancer is higher than BPH and the patient should undergo a biopsy.

Breast carcinoma-associated antigen coded by the human MUC-1gene is identified by several names including MAM 6, milk mucin, 27.29 and CA 15-3 (Fujirebio Diagnostics, Inc.). As indicated by epitope mapping, inhibition of antibody binding, tracer exchange and clinical correlation studies, 27.29 is similar, if not identical, to CA 15-3. This antigen is a glycoprotein (Molecular weight 300 - 450 kDa) which contains 20-amino-acid tandem repetitive sequence of the mucin core and carbohydrate of more than half of the molecule. The number of tandem repeats and the degree of glycosylation is variable between individuals, so that 27.29 is very heterogeneous in structure. In malignant cells, 27.29 is overexpressed on the entire cell surface, and increasing amounts are shed into the circulation. Tumors involving glandular organs, such as the breast, can produce high concentration of 27.29 in serum, making it useful as a tumor marker.

Monoclonal antibodies that recognized distinct epitopes on 27.29 and CA 15-3 antigen molecules have been used to develop immunoassays. 27.29 was developed with a monoclonal antibody that recognized an 8 amino acids in the tandem repeat portion of the polypeptide chain.. Since the antigen levels correlated closely with disease regression or progression, 27.29 proved reliable in the follow-up of patients with advanced breast cancer.

Sla (CA19.9) is a high-molecular weight mucin, defined by monoclonal antibody reacting with repetitive carbohydrate epitope of the heterogeneous family of mucins, with a carbohydrate structure (sialylated-lacto-N-fucopentose II) whose antigenic determinant is a sialized substance from the Lewis blood group. Elevated plasmatic levels of Sla have been found in patients with pancreatic and biliar carcinoma, as well as in patients with colorectal, gastric and hepatic neoplasias.

Carbohydrated antigen (CA-19.9) has been associated with both pancreatic neoplasms and other abdominal malignancies. Results from five significant trials are fully consistent (56-60). Approximately 80% of patients with pancreatic cancer may be correctly diagnosed using this monoclonal antibody, versus 8% of patients with pancreatitis and 1% of incorrectly identified healthy subjects. Steinberg reported thatl CA-19.9 was statistically more specific than CEA (86.5 versus 48.4%) but only slightly more sensitive than CEA (92.5 versus 87.3%) (56). Data reported by Piantino showed identical superiority for CA-19.9 (57). Tempero suggested that CA-19.9 may be a useful clinical marker to detect pancreatic cancer progression in patients with either recurrent or advanced disease.

OVCA (CA125) was identified using a monoclonal antibody (OC 125) directed against the cancer cell line OVCA433 derived from a patient with ovarian serious carcinoma. CA125 can be used for the diagnosis as well as in the evaluation of the success of the treatment of ovarian cancer, due to good correlation between CA125 and the tumor mass. Preoperative levels are prognostic in epithelian ovarian cancer. In second line CA125 can be used for monitoring pancreatic cancer.

BMG: Human ß2 microglobulin is a polypeptide, identical to the light-chain of the major histocompatibility complex class antigens. BMG is expressed in all nucleated cells. Determination of serum BMG is of diagnostic value in a variety of disorders.

BMG concentrations are increased in serum and urine in inflammatory diseases, renal dysfunction, autoimmune diseases and some viral diseases. It can provide a measure of tumor burden and prognosis in patients with multiple myeloma, B cell lymphoma and chronic lymphocytic leukemia.

SCC: Squamous-cell carcinoma is a cancer of a kind of epithelial cell, the squamous cell.

These cells are the main part of the epidermis of the skin, and this cancer is one of the major forms of skin cancer.

However, squamous cells also occur in the lining of the digestive tract, lungs, and other areas of the body, and SCC occurs as a form of cancer in diverse tissues, including the lips, mouth, esophagus, urinary bladder, prostate, lung, vagina, and cervix, among others.

Despite sharing the name squamous cell carcinoma, the SCCs of different body sites can show tremendous differences in their presenting symptoms, natural history, prognosis, and response to treatment.

SCC is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of cells of epithelium, or cells showing particular cytological or tissue architectural characteristics of squamous cell differentiation, such as the presence of keratin  tonofilament bundles, ordesmosomes, structures involved in cell-to-cell adhesion.

SCC is still sometimes referred to as "epidermoid carcinoma" and "squamous cell epithelioma", though the use of these terms has decreased.

SCC-Ag or Squamous Cell Carcinoma antigen is a tumor-associated protein of squamous cell carcinoma.

Squamous cells are epithelial cells found in many parts of the body: in the mouth and on the lips, on the cervix of the uterus, as well as in the middle layers of the skin. Squamous cells are the flat, as opposed to square (cuboidal) or rectangular (columnar) epithelial cells.

As squamous epithelial cells can be found in different places in the body the squamous cell carcinomas (SCC) can also been develop in different places: in the epidermis, the oral cavity, neck and esophagus, but the most life treated SCC’s are found in the cervix of the uterus.

SCC-Ag is an excellent serological tumour marker for patients with carcinoma of the cervix.

SCC-Ag is not sufficiently sensitive (particularly in early stage disease) or specific for cervical cancer for use in screening. The best test for screening of SCC of the cervix is the PAP smear.

Serum SSC levels correlate significantly with tumour stage and can used as a prognosis parameter, it is also useful in monitoring the course of squamous cell cervical cancer treatment and serum SCC-Ag level has a sensitivity of +/-71% and specificity of +/- 92% for detecting recurrent squamous cell cervical cancer.

PIVKAII or des-γ-carboxy prothrombin is an abnormal prothrombin with­out carboxylation of 10 glutamic acid residues at its N-terminus and is devoid of coagulation activity, raising when there is a vitamin K deficiency in normal patients,  and in hepatocellular carcinoma (HCC) cases.

HCC is responsible for half million death world wide per year (all liver cancers represent 3 % of all cancer cases).Alpha-fetoprotein (AFP) is mostly used to detect and monitor HCC, but PIVKA-II can also be used to detect HCC.


The combined use of AFP and PIVKA-II will increases sensitivity as well as specificity for HCC,
AFP is superior to PIVKA-II as a diagnostic tool for early detection of HCC.
PIVKA-II can be used as a clinical prognostic factor for recurrence and survival during treatment of HCC as PIVKA-II is more correlated with the size of the Tumor and the aggressiveness.