Tumour markers are substances produced by a tumour or the body in response to a tumour. When released into body fluids, they are detectable by sensitive analytical methods. Tumour markers can be analysed by biochemical, immunochemical or molecular biology based methods.
An ideal tumour marker should be present only in tumour tissue and not normal tissue or tissue with other diseases. The marker should be organ specific, should be found in all patients with tumour, detectable in the early stages of tumour development and its concentration should be related to tumour burden.
Unfortunately, tumour markers are not perfect. Perhaps even more unfortunately, many patients and even doctors think that they are. As a result, tumour markers are widely used in general health screening programmes without a proper understanding of their interpretation. When inappropriately interpreted, or used in incorrect circumstances, results can either lead to a false sense of security or precipitate further investigations, some of which may be unnecessary or even potentially harmful in themselves. Hence it is important to understand the nature of tumour markers, how they occur and their correct application in clinical situations. This brief article reviews three commonly used tumour markers of the gastrointestinal tract which are commonly part of general health screening tests: Carcinoembryonic Antigen (CEA), Alpha Fetoprotein (AFP) and Carbohydrate Antigen 19-9 (CA19-9).
Carcinoembryonic Antigen (CEA)
Nature
The carcinoembryonic antigen (CEA) is a glycoprotein MW 180000 daltons. There are six different antigenic determinants. It is an oncofetal protein, repressed after birth, but reappears as a result of derepression in cells of some tumours
Location
CEA occurs in the gastrointestinal tract and serum of the fetus. Smaller quantities occur in intestinal, pancreatic and liver tissue of healthy adults. Very small amounts are found in the serum and other bodily fluids of healthy persons. High concentrations found in colorectal adenocarcinomas
Reference ranges
The upper limit of normal (ULN) for non smokers is 2.5 – 5 ng/ml depending on the assay method. Levels are influenced by smoking habits and alcohol consumption.
ULN for healthy smokers is 7 – 10 ng/ml, but those taking alcohol have a slightly lower level.
Clinical significance
Mild to moderate elevations of CEA are found in 20 – 50% of patients with benign diseases, especially of the colon, pancreas, liver and lungs. This phenomenon is therefore seen in cirrhosis of the liver, chronic hepatitis, pancreatitis, Ulcerative Colitis, Crohn’s disease, pneumonia, bronchitis, TB, emphysema, mucovicidosis and autoimmune diseases. In benign conditions, CEA rarely exceeds 10 ng/ml. Constant or intermittent slight elevations found in serial assays tend to disappear after clinical improvement of reversible conditions.
In untreated malignant tumours, CEA levels rise continuously, initially in exponential fashion. CEA level correlates with colorectal tumour stage: Dukes A: 8% of patients have elevated CEA above ULN, B: 42%, C: 56%, D: 94% Preoperative CEA correlates with duration of recurrence free postoperative period and survival time. Particularly high values of CEA are found in patients with bone, liver, lung or multiple metastases vs. isolated lymph node and/or skin involvement.
Application
CEA is used in monitoring progress and therapeutic response in patients with colorectal Ca. This is so well established in the above that it serves as a benchmark against which all new tumour markers are measured. CEA is more sensitive than CT scan, ultrasound, or endoscopy for monitoring patients after ‘curative’ operations. CEA reduces over 6-8 weeks to normal after successful curative operation and a secondary rise suggests recurrence or metastases. The percentage of rise over a period of time is a more sensitive diagnostic indicator than single value. Slow flat rise e.g. 2 to 4 ng/ml over a period of 6 months suggests local recurrence. More rapid steep rise suggests metastatic spread. In only a few cases of Ca colon is CEA negative. CA 19-9 then helpful.
CEA level in normal people is neither sensitive nor specific enough to be used as a population screening test for colorectal cancer and its use for this purpose is not recommended.
Alpha Fetoprotein (AFP)
Nature & Reference Range
Alpha fetoprotein (AFP) is a glycoprotein of MW 70000 daltons. It is formed physiologically in the yolk sac, fetal liver and fetal gastrointestinal tract. 3-7 epitopes have been identified via monoclonal antibodies. It is detected in fetal serum from 4th week of pregnancy and concentration reaches a peak between weeks 12 and 16, then falls until birth. By age 1, there is normal serum level of AFP, that is adult level, < 15 ng/ml.
Clinical Significance
AFP crosses the placenta and there is a high concentration in the maternal serum peaking between weeks 32 and 36 of pregnancy. AFP is substantially higher than the expected level for week of pregnancy in association with neural tube defects. Abnormally low AFP after 10th week pregnancy suggests Down’s syndrome. Markedly elevated AFP in amniotic fluid in a single pregnancy indicates a high chance of neural tube defect being present. Elevated AFP level is found in benign liver disease such as hepatitis, although generally this is only intermittent and only within the lower part of the pathological range (very rarely > 500 ng/ml). However, such patients have increased incidence of primary liver cancer or hepatocellular carcinoma (HCC).
Applications
The best known use of AFP is for detecting and monitoring HCC which mostly arise in cirrhotic livers. At time of diagnosis, 95% of patients have pathologic AFP levels, 68% over 100 ng/ml and 40% up to 10000 ng/ml. AFP is also used for monitoring therapeutic response of treatment for HCC. Finally it is also used for diagnosing germ cell tumours.
Elevated AFP is found in 9% of patients with liver metastases from breast, bronchial and colorectal Ca’s, though rarely above 100 ng/ml and scarcely ever above 500 ng/ml. Metastatic disease in the liver is more likely to have greatly increased CEA levels and thus differentiation between HCC and metastases is possible. AFP has a high sensitivity for HCC. Hence it is suitable for early detection of HCC in high risk groups. The usual routine is to monitor AFP twice yearly in conjunction with clinical evaluation and imaging.
Carbohydrate Antigen 19-9 (CA 19-9)
Nature
Carbohydrage Antigen 19-9 (CA 19-9) is a glycolipid and corresponds to a hapten of the Lewis (a) blood group determinants. Patients with the rare blood group constellation Le (a-b-) (3-7% of the population) are unable to express CA 19-9. In the serum it is a mucin with MW 10000 daltons.
Location & Reference Range
CA19-9 is found in the epithelium of the fetal stomach, intestine and pancreas. The are far lower concentrations in adults in pancreas, liver and lung. It is a component of many mucosal cells. The upper limit of the reference range is 37 U/ml.
Clinical Significance/Application
CA 19-9 is eliminated exclusively via the bile. Even slight cholestasis can cause considerable rises in CA 19-9. CA19-9 also found in various benign and inflammatory diseases of the GIT and liver (levels up to 500 U/ml, though mostly around 100 U/ml). It is found in Mucoviscidosis (Cystic Fibrosis – an autosomal recessive gene deletion which causes exocrine malfunction leading to thick viscoid secretions, cystic ductal dilatations and obstructions)
With a sensitivity of 70 – 80% regardless of degree of differentiation, CA 19-9 is the marker of choice for pancreatic carcinoma. There is no correlation between marker concentration and tumour mass. However, when CA19-9 level is >1000 U/ml it is usually indicative of lymph node involvement, while at levels >10000U/ml, almost all patients have distant metastases. CA 19-9 does not allow early detection of pancreatic carcinoma. Continuous rise in level even in the absence of, or more certainly in the presence of static signs of inflammation or cholestasis is strongly suggestive of Ca pancreas.
Over 60% of patients with resectable pancreatic tumours have elevated CA 19-9 levels and the level of tumour marker doubles in 0.5 to 3.5 months. Therefore patients over 45 years old with upper abdominal symptoms should have CA 19-9 assay after 2-3 weeks if the cause still unclear. CA19-9 has a sensitivity of 50 – 75% for hepatobiliary carcinoma.
CA19-9 is also associated with carcinoma of stomach, but it is less sensitive and specific and not generally used to screen for carcinoma of stomach.
Conclusion
No tumour marker is ideal and no tumour marker is sufficiently sensitive and specific to be used as a reliable screening marker to detect or exclude early, curable cancers in an asymptomatic population.
Acceptable use of markers include CEA for colon cancer, AFP for hepatocellular cancer and CA 19-9 for pancreatic cancer. When used in the appropriate clinical context, these are useful for diagnosis and monitoring of these tumours. But the cardinal principles are that these tumour markers must be used judiciously, their interpretation must be correlated with clinical features and other investigations and patients must be counselled as to the implications of positive or negative results in their own circumstances.
