The Limitations of Cancer Tests

Cancer patients present unique challenges for even the most basic laboratory testing. The frequency of these challenges is increasing in line with the growing incidence and prevalence of cancer in our aging populations. And the numbers are telling: in 2015, the US cancer incidence was ~1,658,370, with a mortality of 589,430, while predictions for 2030 suggest a global incidence of 21.7 million and a mortality of 13 million (1).

Health workers are dependent upon accurate laboratory results for monitoring their patients’ progress and for making timely and informed decisions on their treatment and care. However, it is important to recognize that many laboratory tests are affected in unexpected ways by the patient’s disease or medication; therefore, it is critical to take account of the entire clinical picture when interpreting test results.  In cancer patients, for example, normal cellular mechanisms involved in inflammation, wound healing, and hemostasis are hijacked by tumor cells to support proliferation and metastasis. So markers of the activation of these processes become useless in cancer patients, particularly as the disease advances. Examples include acute phase reactants such as C-reactive protein (CRP), haptoglobin, and ferritin; the coagulation cascade markers, D-dimer and fibrinogen; and the inflammation markers procalcitonin and lactic acid. All of these can become markedly elevated in cancer, often to much higher levels than are normally seen in the usual activation of these pathways in other diseases.

Furthermore, cancer patients may exhibit unique result outliers for nearly every analyte in the standard comprehensive metabolic panel. For example, although potassium levels may be truly elevated in cancer patients, it is more common to find that results are falsely elevated by pre-analytical errors such as hemolysis. Pseudohyperkalemia can also occur when high numbers of fragile cells  (for example, leukemia cells) are centrifuged or otherwise manipulated. And other complications may arise due to the production of discordant low or high potassium levels – known as reverse pseudo-hyperkalemia – associated with some heparin collections.

Different cancers may bring different challenges. Patients suffering from multiple myeloma are particularly problematic due to elevated levels of protein in their serum. Interference of serum protein with test methodologies may give spurious results, such as pseudohyperbilirubinemia, pseudohyponatremia, pseudochloridemia, pseudohypercalcemia, falsely low albumin, pseudohypolipidemia, pseudohyperphosphatemia and pseudohypophosphatemia. Corrections or alternate methodologies are therefore recommended in such cases.

Naturally, tumor markers are among the analytes normally monitored in cancer patients. An ideal tumor marker test should have the following five attributes: high positive and negative predictive values; inexpensiveness and simplicity; clearly defined reference levels; patient acceptability; and validation from a large prospective trial. Unfortunately, no such ideal tumor marker exists! And with the current generation of tumor marker tests, tremendous variability is seen in the results generated by different products and methodologies. Efforts are underway to minimize variability by standardizing these tests, but this is an ongoing process. In addition, methodologies need to be checked for uncommon but potentially important interferences due to cross-reactivity and heterophile antibodies. Inter-laboratory variation may also be problematic, and where possible should be eliminated by using the same laboratory and methodology for tumor marker tests.

Also, we need to be aware of non-routine cancer markers, particularly where a poor appreciation of their link to cancer may contribute to a misdiagnosis or delay in treatment. The human chorionic gonadotropin (hCG) marker used for pregnancy testing is a perfect illustration of this problem. In addition to its various degradation products, the hCG molecule has five different forms: intact hCG and hyperglycosylated hCG molecules (consisting of an alpha and a beta chain), produced by the placenta during pregnancy; sulfated hCG, produced during the menstrual cycle by the pituitary gland; and hCG beta and hyperglycosylated hCG beta, produced by advanced malignancies. The different hCG forms are excreted in urine with varying efficiency, such that the isolated beta chain is most abundant. Furthermore, different pregnancy testing methods detect the different forms with varying efficiency (which we should expect, because the tests were only developed for comparing pregnant with non-pregnant healthy females). Given that up to 48 percent of cancers have detectable urine hCG beta, a number of non-pregnant cancer patients will test positive on a routine pre-surgical urine pregnancy screen. This often results in significant delay of surgery for these patients.

Finally, new treatments for cancer, such as immunotherapies, can have unexpected effects on laboratory testing. For example, we have seen an experimental antibody therapy for multiple myeloma, aimed at the CD38 antigen, cause a positive pan-agglutinin-type result in the blood bank antibody screen.

In summary, the best advice for laboratory staff is to work closely with their oncology colleagues when unexpected laboratory results occur in cancer patients, as it is very possible that the cancer or the treatment is playing a significant role.