ANTI-MALIGNIN ANTIBODY--A SCREENING TEST FOR CANCER?

erf@alum.uhs.edu

[Editor: I have had numerous inquiries about the Anti-Malignin Antibody Test. The following should help anyone who is going to rely on this test. John H. Renner MD]

I am a pathologist, board-certified in both anatomic and clinical pathology. I operate the world's largest public pathology site, which includes a free personalized help line. I have received about ten inquiries in the past few years about the "anti-malignin antibody in serum" blood test (AMAS). This is said to be an extremely accurate way of determining whether cancer is present somewhere in the body. This is every pathologist's dream. As its proponents point out, such an assay could replace the current methods of cancer screening, and would render most biopsies and other invasive studies unnecessary. "Anti-malignin antibody" has been promoted as such for over twenty years by a single husband-wife team, with occasional brief reports in the medical literature. The team operates the only lab which offers the test. They claim to assay for a substance called "malignin", and for antibodies against it. Unlike other independent medical thinkers, the team is not presenting a mysterious, arcane, or secret substance. They claim instead that it's a tumor antigen, like many others that are known -- except that it is ubiquitous among malignant cells and distinguishes them from their benign counterparts. They have conducted themselves decently, and obviously believe in their test. The team is the only group offering the assay. There is an Italian report, not from the main group, but in the obscure International Journal of Biological Markers from 1997 which I presently have on order. The promoter's website states that Smith-Kline labs also did the test and published results in symposium proceedings in 1983, though nothing in the refereed scientific literature. That's all.

The wording of the claims for "anti-malignin antibody" never actually say that a person can forego pap smears, mammography, or biopsy of suspicious lesions. But some of the test's proponents suggest that this is possible, and this makes me worry about a public health hazard.

I have no first-hand knowledge of the team that offers the test, and am relying (as is the norm in real science) on publications. According to the 1999 AMA directory, he is boarded in neurology-psychiatry, but practicing immunology and oncology. She is listed as practicing psychiatry and "other", and as unboarded. He also made some contributions in mainstream neurochemistry before 1980, and has a recent publication on virus receptors and dementia in a theme issue of Annals of the New York Academy of Sciences.

Except as noted, after over 20 years, no other group has published in the refereed literature on "malignin" or given any independent evidence that the substance actually exists. (Nor has anybody reported being able to confirm the existence of "astrocytin," another substance which the same team claimed to have discovered at the same time as "malignin".) Again, I have no personal experience either with this supposed substance or with the people who describe it. But I am familiar with assays and procedures of the kinds described in their publications.

The account of the origin of "malignin" is itself curious. According to one source linked below, the principal proponent of the test "discovered that the outer coating on cancer cells contain [sic] sugar molecules over an inner layer of protein (glycoproteins). Cancer cells bump into each other and the outer layer is ground off -- exposing the inner protein layer and the malignin antigen."

I've spend a good amount of my life looking at cancer cells. This business about them bumping into each other just isn't true, especially in the early stages. In fact, they're no more mobile than the surrounding cells, and much less mobile than the benign cells of the bloodstream, bone marrow, or lymphoid organs, where collisions among cells happen constantly.

At another site, there is a more sophisticated-sounding account. "Early in the process of malignant transformation, there is a 50% loss in the amount and heterogeneity of the carbohydrate constituents of the cell membrane glycoprotein GlycolOB which results in the appearance of peptide epitopes (malignin) in AglycolOB." Visitors should know that the claim that there is a 50% loss of carbohydrate content and heterogeneity in the cell membrane when a cells turns cancerous is unsubstantiated at best, and ... a "Medline" search over the refereed literature shows no other mention of either GlycolOB or AglycolOB. If the author is referring to OB, the leptin receptor (an appetite regulator), the above account makes no sense. I am presently tracking down all of the team's publications. Except for three letters to Lancet, they are in obscure medical journals. I was startled, though, by the Lancet letter from July 18, 1981. Pathologists routinely use antibodies as stains to identify particular types of cells. In fact, anti-malignin antibody is promoted to the public as a way for pathologists to distinguish benign from malignant cells under the microscope. The "Lancet" letter announces the use of anti-malignin antibody as a stain, and the fact that it successfully stained three different types of cancer cells in wet preparations.

But what is most curious is that the writer does NOT mention trying out the antibody on any non-cancerous cells. This would be extremely easy to do. If the antibody is really specific for cancer cells, it would leave benign (non-canceous) cells unstained. If the author really believed his own fundamental claim, he would stain sections of tissue containing both benign and malignant cells (i.e., the edges of cancer masses). If he is right, he would see stain only on the cancer cells. After eighteen years, we still have no photos or reports of any such investigations.

Even without a blood assay, if the antibody had demonstrated the predicted ability to distinguish benign and malignant cells, the photographs would have been published within the lead article of the prestigious medical journal of the author's choice. And any second-year medical student knows this. On this evidence alone ... at least for now, I will draw the obvious conclusion.

To the team's credit, they engage in no dark talk of conspiracies to suppress a breakthrough. But the truth is that the screens that actually work (i.e., that work in more than one person's lab) are quickly taken by big-money corporations and used to earn huge profits. It is inconceivable that no biotechnology corporation has tried to reproduce the work on "malignin". And no major lab has told an audience of fellow-scientists that "malignin" even exists.

Real science is the serious business of trying to make sense of the world, constantly testing and taking elaborate precautions against self-deception. No one can say with real confidence exactly what's going on here. I believe in the sincerity and good intentions of the persons offering the test, and those promoting it. For now, I must simply caution physicians and patients alike against basing clinical decisions on the "anti-malignin antibody serum test." The principal website promoting anti-malignin antibody is: amascancertest.com

Follow Up

I have now (July 27, 1999) obtained and reviewed the other major publications on "malignin". I found the following to be the most revealing. J Med. 13:49, 1982. The team presents data on staining of cells from patients known to have cancer, and those known not to have cancer. What's astounding is that the team did not focus on whether the actual cells they were staining were cancerous, but only whether the patients had cancer. On the evidence, the team took any cells that were handy. There were 22 specimens, evidently all liquid (effusions, brushings, or aspirations), since duplicates were sent to pathologists for papanicolaou examination. The authors report "Standard Papanicolaou stain examinations performed blind on duplicates of these specimens by other pathologists were correct in 17/22 specimens (77%)." It is commonplace for a person with cancer to produce specimens that do not contain cancer cells, and visual examination by a pathologist remains the gold standard for diagnosis. If I understand English, this means that the group is reporting that its antibody stains cells from cancer patients even if there are no cancer cells in the specimen. This is weird, since the team also claims that only cancer cells express malignin. The photos that accompany the article are also curious. The pattern of staining on the supposed squamous lung cancer cells looks coarse and very irregular. (I can't tell that this isn't just nonspecific dye binding to a bit of lung debris.) The "lymphocytic leukemia cell from blood" (somebody did a papanicolaou stain on blood?) looks like a normal lymphocyte though I can't exclude a very low-grade leukemia. The "ovarian carcinoma cells at surgery" appear not to be stained at all, and the "anaplastic astrocytoma at surgery" photo is probably not really stained either, since there is no nuclear-cytoplasmic differentiation. The remaining photo isn't even from one of the 22 patients, but from a cell culture of a squamous cancer from a group in Florida, which I found despite the article's reference to the mainstream journal Cancer Research being incorrect. Something is not right here.

Neurochem Res 4:465, 1979. The team described two more proteins, which they named "recognins". Nobody else has ever reported that either of these even exists. Cancer Det Prev 6: 317, 1983. An author in Germany reviewed tumor markers in the CNS, mentioning astrocytin and malignin and the team's claims. He adds that "These findings remain to be confirmed by others" -- as true today as it was 16 years ago. Int J Biol Mark 12:141, 1997. The Italian NCI team reviews the original team's work uncritically. There is no "Materials and Methods" section, and no new data. In other words, even these people do not have an independent assay for "malignin", and has not even described the substance independently. My local biochemist reviewed the articles and pointed out: The team writes about supposed phylogenetic relationships without even reporting a sequence; The team writes about carbohydrates components of the molecules they have supposedly discovered, without ever describing what the carbohydrates are; The team gives molecular weight by chromatography rather than by ultracentrifugation, which was the norm even 20 years ago.