More Discussion about Integration of Surgical Pathology with Molecular Diagnostics

My recent note about molecular autopsies (see: Molecular Autopsy -- an Emerging Pathology Meme) prompted the following comment from Dr. Karl Robstad (boldface emphasis mine):

Molecular techniques are the new frontier. Whether it be because of their actual utility or because of the insistent hype, it has become incumbent upon the pathologist to be familiar with them. The inherent nature Hematopathology has lent itself to be a forerunner in the field with an abundance of easily separable fresh tissue as well as a phonebook full of distinct, reproducible genetic alterations that have become mainstays in diagnosis, prognosis and treatment. I feel that AP almost gets a bad rap because the differences between HP and general AP aren't fully appreciated whilst making such judgements. Given, this there have been some definitive breakthroughs in solid tissue tumor genomics in the past couple of years from Her2 or p53 in breast to EGFR in lung to MSI in colon, the list goes on... My only knock on the progress, is that I wonder how much of the motivation is based on truly meritorious intentions and how much is financially motivated. It seems that every meeting you go to, molecular testing is being jammed in your face no matter where you look, which makes me at least a little suspect. Are these reservations warranted? Perhaps not, but I think a metered amount of caution is fair to exercise as we navigate further into these waters in the coming years...FWIW there is a spectacular recent review on solid tumor molecular testing in the January issue of Archives. If you'd like to be updated on what's here and what's coming down the pipe.

As usual, Rob make a number of very interesting points, which I roughly summarize below:

• Hematopathology inherently lends itself to the integration of morphology and molecular diagnostics because of ready access to fresh tissue (i.e., circulating malignant cells in the blood and marrow/node biopsies) and a "phonebook" of distinct, reproducible genetic alterations.
• Solid tissue tumor genomic testing is perhaps being "hyped" in order to sell products.
• We may be entering an era in which the surgical pathologist willl be as dependent on the molecular testing of solid tumors as hematopathologists are on their own type of cellular testing.

All excellent points and let me add one more about the hemtopathologists compared to surgical pathologists. The former generally manage the hematopathology labs in hospitals in addition to their surgical pathology duties. The latter include the interpretation of solid tumors such as diseased lymph nodes. Because they span the AP-CP divide managerially as well as professionally, they are equally comfortable with morphologic observations, the use of special stains, and the analysis of quantitative lab test data.

After some reflection about this whole issue, I think that Rob is right. Because of the nature of the discipline and ready access to "liquid biopsies", hematopathologists were willing and able to become the consummate integrators of CP and AP (see: Does the New Term "Liquid Biopsy" Make Any Sense?; Rapid Adoption of the Term "Liquid Biopsy" on the Web; Continuing Discussion about the "Liquid Biopsy"). With rapid progress in solid tumor molecular testing and also ready access to "liquid biopsies" (i.e., circulating tumor cells or tumor cell antigens) in the near future, surgical pathologists may also end up as proficient data integrators.

Comments

[Doug Mitchell, MD]

I think solid ("AP") tumors will be orders of magnitude harder to subdivide "molecularly" than hematologic ones.

- Homogenized gross lesions contain neoplastic and non-neoplastic stromal, epithelial, and hematologic genetic material

- "Microdissect!" some say. But what in a tumor is neoplastic and what isn't? Some cells are microscopically obviously so, but how confidently can one say the surrounding ones aren't?

- Subsets of solid tumors are probably *combinations* of mutations -- not just in visibly neoplastic cells, but also in so-called "supporting cells,"
E.g., A(epithelial mutations) x B(neovasculature mutations) x C(stromal mutations)...etc.. = a *lot* of permutations.

I'm not suggesting that molecular diagnostics has no role in SP. I'm just wary of labs that say, in effect, "Hack off a chunk of tumor, blend it up, send it to us, and we'll tell you what it is."