To reduce the main causes of False Positives (FP) in the results of Tumor Markers (TM) in serum, a group of 4 criteria (called Barcelona Criteria), have been determined by the Spanish Society of Clinical Biochemistry and Molecular Pathology, Cancer Biomarker Commission to properly evaluate them:
- Tumor Markers Serum concentrations.
- Discard benign pathology by the exclusion of main source False Positive results.
- Follow-up if Tumor Markers moderate results (Grey Zone/Undetermined).
- Technical interference.
Tumor Markers Serum concentrations
Serum levels of most Tumor Markers, seen in the absence of neoplasia, are usually low or moderate. The greater the concentrations of a Tumor Marker detected in a patient, the greater the likelihood of being a malignant tumor.
For example, levels of NSE less than 40 ng/mL can be detected in numerous benign diseases, but levels above that value indicate a high probability of cancer or hemolysis. The same occurs with CA 125 and/or CA19.9 concentrations higher than 1000 U/mL, or CEA greater than 25 ng/mL, indicating a greater than 95% probability of a malignant tumor.
Please note, negativity of the Tumor Markers does not exclude at 100% the possibility of a malignant epithelial tumor.
Discard benign pathology by the exclusion of main source False Positive results
Faced with an increase in a Tumor Marker, it is necessary to rule out the existence of certain benign pathologies that can also increase it.
Most Tumor Markers are catabolized at the hepatic level and excreted via the renal route. Alterations of these organs will cause less catabolism and/or elimination and indirectly cause their accumulation, with values higher than the range considered normal.
The majority of Tumor Markers (CA 125, CEA, CYFRA, ProGRP, among others), have moderate increases (2 to 4 times the upper limit of normal) in patients with liver Cirrhosis or Renal Failure.
By other way, some Tumor Markers in patients with Renal Failurecan reach serum concentrations similar to those found in neoplastic disease and can not be used in these patients, such as SCC, S-100 or HE4.
Besides, alterations in tissues that produce a specific Tumor Marker may also increase, usually moderate (depending on the severity of the injury), such as PSA in Prostatitis or Benign Prostatic Hypertrophy, CEA in Ulcerative Colitis or Crohn’s Disease.
Occasionally, serum increases may be so high that they require very high levels for the differential diagnosis, as occurs with CA 125 in the presence of Effusions, mainly with mesothelial lesions, or that make it impossible to use as SCC in dermatological pathology, such as Pemphigus or Psoriasis.
Finally, there are also mixed causes of False Positives such as CA19.9 in Chronic Liver Disease with Jaundice or due to stimulation by various drugs, as with CA 72.4.
Follow-up if Tumor Markers moderate results (Grey Zone/Undetermined)
The finding of elevated levels of any Tumor Marker, in isolation, is of limited value.
When doubts exist about a result, two or three serial determinations (evolutive control), should be performed with a longer time interval than the plasma half-life (15-20 days for most Tumor Markers). If the Tumor Marker figures have a continuous increase (above the interassay coefficient of variation) over time (above the normal level), it can be said that with a high probability it is of tumor origin, as they reflect tumor growth.
On the contrary, if serum levels do not change or have a tendency to descend, the origin will have to be sought in another non-neoplastic pathology.
This aspect becomes increasingly relevant. The reasons may be due to: lack of antibody specificity; high‐dose hook interference, cross-reactions with other molecules; or the presence of heterophile antibodies.
In addition, also it must be considered Hemolysis, Icteric and Lipemia Coagulation in blood samples.