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Sunday, January 5, 2014

What the public (and many doctors) don't understand about cancer

Gilbert Welsh has published another commentary in the New York Times (Welch NYT Dec 29, 2013). What he writes in the piece is interesting as usual, although not especially novel. His comments were based upon the results of a study published in JAMA Internal Medicine in the previous week. He wrote a similar commentary piece published as a companion piece in the JAMA Internal Medicine journal. He has presented his arguments skeptical of cancer screening before but his message is very well worth restating. Because his reasoning is counter-intuitive, it takes a while for the message to sink in and, for many people, it simply is met with blank stares. Some view this with great hostility. Check out the comments. They are perhaps as interesting as the article.

Why is that? I think the reason is that there is emotional baggage associated with the word "Cancer" (well dah!). In addition and perhaps more importantly there is a gross misunderstanding of how cancer is diagnosed and the limits of pathology as a tool to predict biological behavior. This issue needs to be pushed front and center into the debate because  the response to divergent responses to his message come down to reasonable people hearing different things when they hear the word "CANCER".

The origins of pathological (histological) diagnosis of disease date back to the mid-to late 19th century. The German chemical industry developed out of the demand for new dyes for cloth. It created vast libraries of chemical compounds which resourceful entrepreneurs sought new applications in other industries. One set of applications was found in the developing pharmaceutical business. Many of even our current drugs are based upon dye backbones.

A second set of applications was found in laboratory medicine, initially at the autopsy table. Tissue was removed from corpses, fixed in formaldehyde, embedded in wax, sectioned and placed on a slide, and then stained with a variety of dyes borrowed from the textile business. An empiric approach led to the foundations of contemporary histology. With the advent of anesthesia, samples of tissue could more readily be taken from live human beings, processed as cadaveric tissue had been processed, and examined under the microscope.

The power of the pathologic exam of tissue became apparent because it could be validated at the autopsy table. The microscopic appearance of a large mass (for example a breast mass) biopsied from a live person may bear a stark resemblance to the microscopic appearance of tissue obtained from another at autopsy. It is not a huge leap to predict that one living with such a mass will suffer the fate of those already on the autopsy table. In contrast, if the pathology of the large mass showed something distinctly different, such as an abscess, one could predict that they would experience a different fate. At this point pathological diagnosis was pretty black and white.

Fast forward a century and the tool that is used to predict patient's fate is essentially unchanged. We are still placing pieces of tissue into fixative, embedding in wax, staining with textile dyes, and looking under the microscope. However, what we look at has changed dramatically. We no longer look at large pieces of tissue taken from people with advanced disease but instead look at tiny slivers taken from patients who are essentially well. Because this transition tool place over many decades, we have lost sight of the gradual changes of the inputs and the contextual change. We no longer have the autopsy to validate whether the increasingly subtle changes observed by pathologists have any biological significance. Most patients diagnosed with cancer currently do not die of their cancer.The 5 year survival rates of breast and prostate cancer are 89% and 99% respectively according to the SEER numbers.

I pose the question: why should we be able to predict the future by taking human tissue, fixing it in formaldehyde, embedding it in wax, placing them on slides, staining with clothing dye, and looking at them under the microscope? I have no doubt that within certain clinical contexts this technique has value but as one moves away from advanced tumors, when does this technique lose value? The value of the diagnosis is that it can predict who will be done in by their disease and identify who will benefit from some sort of intervention to prolong and/or improve their lives.

This is not some trivial question of interest only to the high priests of academic medicine. Read the comments to Gilbert Welch's article and our understanding of cancer and  the ability of pathologists to make these diagnoses and make reasonably accurate predictions rests at the center of this problem. No one appears to want to state the obvious. The tools used to make these predictions is simply not up to the task. In particular the gold standard for looking at those screened and identifying real disease with a high likelihood of killing those affected is using histologic tools - anatomic pathology. Just how good or bad are these tools at giving us the information we desire?

It appears they are not so robust and perhaps when applied in certain circumstances border on simply terrible. Try to use them in neonatal screening contexts and you end up with epidemics of neuroblastomas of no clinical significance. I could go on and on. The public has no clue and much of the medical community is equally as blind to the limits of this tool. Anatomic pathology operates like the Oz in the Wizard of Oz.
"I am Oz, the Great and Terrible. Why do you seek me?"
They looked again in every part of the room, and then, seeing no one, Dorothy asked, "Where are you?"  
"I am everywhere," answered the Voice, "but to the eyes of common mortals I am invisible. I will now seat myself upon my throne, that you may converse with me." Indeed, the Voice seemed just then to come straight from the throne itself; so they walked toward it and stood in a row while Dorothy said: "We have come to claim our promise, O Oz."
"What promise?" asked Oz.
What is the promise of the pathologist? If is the promise to be able to look at a specimen, apply a test,  and tell  their clients whether they face a terrible fate. It has been said that extraordinary claims should require more stringent levels of proof and what claim is more extraordinary than a claim that a healthy and well person is going to die. Remember it is simply a test and like all tests it has inherent problems with specificity and sensitivity, all of which is context specific. Anatomic pathology is completely subjective and requires the operator to define thresholds. The test is only as good as its ability to provide useful information.

What useful information is provided when a specimen is sent in to rule out a malignancy? When the term cancer is invoked by a pathologist, the general public sees this as a prediction of death. However to the pathologist the term cancer can be invoked when there is little or no expectation of malignant behavior. How useful is that to use a term implying aggressive biological behavior for classes of growths than are essentially benign? We end up using tortured terms such as non-progressive cancers or non-malignant malignancies. This is like describing a cold hot summer day, a rock hard soft pillow, a short tall man. or a skinny obese person.

The term cancer needs to be redefined or at least its meaning needs to be clarified. I propose that if this used as a diagnostic term by a physician, it must be attached to some sort a prediction of the likelihood of death if left untreated. If a 60 year old woman is found to have DCIS after screening mammography, what are the odds of her dying of breast cancer if left untreated? I suspect that physicians, especially pathologists, would be much less willing to use the term cancer if they were required to attach a relatively precise prediction to it. As long as they can remain behind the curtain like the great Oz they can label people as having cancer without having to explain to them what the meaning of this label is. As long as they can use the term in a clinical vacuum, confusion will reign. It is reasonable for patients to insist that all cancer be treated if they assume that all cancers are malignant. One perhaps make the case that aggressive treatment is warranted if 90% are aggressive would go on to kill the host.What about 50%? 10%? 1%?

What does this confusion look like? Read the comments on Dr. Welch's article. The numbers are stark that he presents and provide little evidence that current cancer surveillance practices do what they intend to accomplish for the overwhelming majority of those involved. However, the cancer label invokes such a visceral response that these numbers are meaningless. Once the term cancer is used all nuance tends to disappear. What doctor in their right mind would recommend leaving cancer untreated?

I suspect that if patients knew how crude anatomic pathological tests are and how meaningless the label of cancer might actually be, they would initially be relieved followed by simply being appalled.  The JAMA Internal Medicine article which the Welch commentary was based surveyed over 300 randomly selected people between 50 and 70 and found that less than 10%  had been informed of the numbers behind the screening push for cancer and that most would not agree to common screening tests (PSA or mammograms) once they were informed of just how good (or bad) these test function.

I would be remiss for not mentioning another set of incentives and pressures which have driven this process, that being the threats of litigation for a missed diagnosis. Pathologists are terrified at the prospects of missing a diagnosis of cancer with the prospect of over diagnosis rarely being hyped. However, if the limits of the test were recognized, this is not such an issue. All tests are struck between the rock of sensitivity and the hard place of specificity. Call everything cancer and  you will never miss a case.

These concepts are not new. I became aware of them through the work of Dr. Elliott Foucar more than 20 years ago. They received scant attention from the broader medical community but now that the concept of over diagnosis is rising to the attention of the general public, the source of this systemic error is going to shine a brighter light on the limits of anatomic pathology as being the gold standard of cancer diagnosis. Using legacy approaches in anatomic pathology to make extraordinary claims is reaching the end of its useful lifetime. The curtain should be pulled back on the pathology Oz.

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