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Alistair Robson's Blog

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Alistair Robson

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[center]"There is nothing new to be discovered in physics now.”[/center]
[center] - Lord Kelvin, 1900[/center]

In the 1990’s I was interviewed for a university position in pathology. The Chair, a Professor & Cambridge alumnus, informed me that we have “reached the limits of morphology” in pathology, and the era of molecular biology would revolutionise medicine. It was the first time I had heard such a view but by no means the last; indeed, the same claim was made by a dermatologist colleague at a recent conference dinner in Berlin. The nearly 20 years between these declarations have seen a prolific literature reflecting increasingly sophisticated molecular analyses applied to every aspect of dermatological disease. Despite this, there are few examples of molecular Eureka! moments that precipitated a paradigm shift in understanding, classification or any aspect of my practice.

There have been advances, of course; melanoma is increasingly being considered in terms of mutation pathways. BRAF v600 analysis and its inhibitors, the patched-hedgehog axis and vismodegib. These are exciting prospects, certainly. But, we have also had a reclassification of cutaneous lymphoma in that time, predicated on clinical and morphological observations, which has undoubtedly saved more lives than vemurafenib, as radiotherapy rather than chemotherapy became the mainstay of treatment for primary cutaneous follicle centre cell lymphoma. Small/medium pleomorphic CD4+ lymphoma and indolent CD8+ lymphoid proliferation of acral sites have only recently been recognised by those of us maintaining a supposed expertise in this field, moving them out of the peripheral T-cell lymphoma NOS category with its almost inevitable reflex consideration of aggressive chemotherapy or transplantation. Conversely, despite years of gene analysis in mycosis fungoides nothing has materialised of any use whatsoever in halting disease progression or enhancing survival.

It is instructive to reflect on revolutions, scientific or otherwise, and how the excitement of a promised land – be it a new society or era of knowledge – captivates. People get drunk on the illusion that they live in a privileged age. In a way, of course, it is true. At any one time never has so much been known by the world. But, few look back and reflect that many have felt this, many times, and each time it has been superseded by a subsequent generation of equal conviction.

The immunohistochemical revolution of the 1980’s, PCR in the 1990’s, and now deep gene sequencing (is it a coincidence that even the term “deep gene sequencing” smacks of some mysterious unfathomable secret of the universe?) have rendered some dizzy with expectation of unlocking secrets of the universe. Well, they have hardly ever done this……so why now? Less cynically, molecular advances indeed prove adjuncts to our understanding, and of course edge us ever closer to defeating disease. But I would suggest that to leave behind the seemingly tedious hackneyed bricks & mortar of our knowledge, founded upon years of experience, tried & tested, is folly indeed; or to fail to realise that such new technologies are almost always predicated upon the solid if unfashionable foundation of empiricism that careful morphology has built, and serves us imperfectly yet wonderfully well, is a mistake. The truth is, it is a commonplace to believe ones own point in time represents an “arrival” in terms of knowledge&understanding that somehow renders historical comparison irrelevant. The “rare” lymphoid proliferations cited above have almost certainly been before our eyes for decades, just as helicobacter sat in gastric mucosa undetected. There are, I believe, many many more insights that are presented to us each day but are as yet unseen.

So, revolution tomorrow is unlikely unless it’s the other kind of revolution, turning full circle, and once again we have to listen to (usually) non-pathologist colleagues, medical Lord Kelvins, lamenting the plateau of our knowledge and declaiming the New Order. Our ignorance is [i]not[/i] going to precipitously give way to enlightenment, and we should continue with acute and careful intelligent morphological observations, open to alternative viewpoints of commonalities. Perhaps, one day, an objective molecular reality will hold sway. But don’t hold your breath.
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Mark A. Hurt MD

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Alistair,

Wonderful post. My speculation about the application of molecular technology to the process of diagnosis is that it's just another tool. We have many tools today in our arsenal: historical perspective, dictionaries, clinical differentials, basic morphology (H and E), "lineage" markers (IHC), and molecular probes to determine specific gains or losses of genes, etc, or the production of an abnormal protein as a consequence.

I once read an interesting idea about the development of concepts, in general, that I think applies equally well to diagnostic concepts. It goes something like this: if humans were the size of atoms, the identification of a building would be an enormous conceptual identification. This is because the further something is removed from direct perception, the more abstract the identification becomes.

In our present situation, humans have the capacity to perceive the building by direct perception; it is a relatively small matter to identify it under the concept "building." But, we do not have the capacity to identify easily a subset of melanomas; to do so, we need extended technology through 3, 4, or even 5 steps removed from direct perception. We can get lineage and pattern from IHC, but it takes an enormous investment of time and follow-up of many patients to have any confidence that the genomic abnormalities mark these lesions as melanoma.

This is why historical perspective and morphological differentials will always be with us; they are the "window" or "anteroom" to the "small stuff" of genetic applications.

Mark
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