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What are we anyway? The role of pathologists in the 21st century.

Advances in the molecular understanding and classification of leukemia1 illustrate the challenges that we are going to face in many areas of pathology, not just hematopathology. For someone who specializes in hematopathology, it is a sobering fact that keeping track of the molecular alterations in patients with acute myeloid leukemia (AML) alone is getting unmanageable. Undoubtedly, even more abnormalities remain to be discovered. In this regard, almost 24% of AML cases are still a "black box" in that we don't know which genetic abnormalities drive these tumors, but we can be sure that we will find them soon. Moreover, it is complex enough if each alteration occurs in isolation but daunting when alterations occur in synergistic combinations that interact in complex ways. Obviously, there are many more common diseases than AML for which molecular biomarkers are likely to play an increasingly important role, for example, prostate cancer, lung cancer, and breast cancer. It appears inevitable that there will be much more lab testing of tumors in the future, driven by advances in targeted therapies and new platforms for detecting these biomarkers.

Laboratory testing is always a target for cost reduction because it is a big expense to health care. However, I think we need to reframe the usual arguments about cost cutting to reemphasize our impact on patient care. For example, when we sequence the ABL gene for a patient with leukemia and find a particular point mutation, then an expensive drug can be discontinued and replaced with another that works. Hence, we save money and save resources. I think we need to keep thinking about how molecular testing can help save money in health care and enable better care of patients. Viewing it purely in terms of cost puts us at a disadvantage.

How should we be responding to this explosion of molecular testing? At the University of Michigan, Ann Arbor, we have hired not only a laboratory director but also a technical director with a PhD whose primary responsibility is introducing new molecular tests. Having a robust outreach program (MLabs) helps bring in additional revenue, but in addition, it shifts the make-versus-buy equation, allowing us to bring more cases in-house. As molecular pathology becomes more central to patient care, we have also worked to reduce turnaround time. The days when we could wait weeks for molecular test results to come back are long gone. This level of service isn't going to work in modern health care. To help address the challenge, we have enlisted 3 additional research-oriented faculty members to assist in sign-out and bringing on new diagnostic tests. We have molecular pathology sign-out 5 days a week now and do DNA isolation and work on weekends as well. Since 2002 we have reduced our average 8-day turnaround time for molecular testing to 3 days. At the same time, the volume and complexity of testing continues to rise. One of our concerns is that the growth rate in molecular testing isn't going to be linear, but rather, exponential. The rapid increase in number and complexity of tests and in their interpretation is going to pose major challenges for current and especially for future pathologists.

Informatics infrastructure and continuing medical education are also going to pose ever increasing challenges for pathologists. In order for this testing to be truly useful, informatics will need to develop integrated reports for hematopathology in which all the lab data is aggregated electronically. (2) We do this now at the University of Michigan, so that complete blood counts and differential counts performed on peripheral blood and bone marrow aspirates are already automatically loaded into the reports. In the future, integrating flow cytometry, cytogenetics, and molecular pathology data will be necessary in order to formulate a diagnosis. The growth of technology and testing now exceeds our ability to absorb information. Some useful online resources are currently available; however, we don't yet have a Web-based, regularly updated compendium of data that could be linked to a path report to better define the therapeutic implications for the patient in a customized manner, using evidence-based medicine.

Contemporary research is teaching us how fast things can change. In the Michigan Center for Translational Pathology, led by Arul Chinnaiyan, MD, PhD, professor of Pathology and Urology, we have multiple ultrahigh throughput sequencing instruments that can read 2000 megabases per run. As part of a demonstration project, Dr Chinnaiyan's group sequenced the transcriptome of the K562 cell line, which has a BCR-ABL translocation, and readily "rediscovered" the BCR-ABL translocation. This approach is now leading to the discovery of translocations in a variety of solid tumor types. (3)

Finally, the way we now treat patients is rather primitive. The drugs we use to treat AML have been in use for more than 40 years and they are not "tailored" for specific molecular lesions. We do very little to take advantage of "cooperating" mutations, such as activated kinases, that synergize the effects of translocations. We also study various chemotherapy regimens by enrolling patients in clinical trials. Essentially, we're doing an experiment in vivo, and if it doesn't work, then we try something else. But there are other ways of looking at clinical trials that use a strategy akin to microbiology. If we treated the patient's cells in culture with a panel of kinase inhibitors, for example, we might be able to define a chemotherapy-sensitive profile. This has already been performed as a demonstration project in my laboratory with a variety of cell lines using a panel of more than 100 kinase inhibitors in a 384-well microplate format. By using this platform, cell lines or patient's tumors can be assayed with a wide range of kinase inhibitors, many of which are actually in clinical trials. So one of the things that may be on the horizon is a different role for pathologists in which we're actually trying to predict how a patient is going to respond by culturing the patient's cells, perhaps in a microfluidic device in vitro. While complicating factors, such as the prosurvival effect of bone marrow stromal cells, remain, it is likely that pathologists will become increasingly involved in this type of predictive testing.

Clearly, our field is changing rapidly, but our mission remains the same. While this seems obvious, it is worth remembering that, for the long-term health of our patients as well as our profession, we aren't just microscopists. Instead, we generate data that are useful for patient care. We analyze and interpret these data and make sure they are conveyed to our clinicians in as clear a form as possible. It's how we do all this that is changing so rapidly.

My last point is prompted by a personal experience. One day recently, I dropped off my car to be serviced. The same day, I also had a doctor's appointment. When I dropped off the car, the mechanic put my keys into a reading device, and the screen displayed the history of everything that had ever been done to the car. They had the complete history of the car, they knew everything about it, and they knew immediately what type of servicing was needed. Then I went to my doctor's office, where I was handed a clipboard with 5 sheets of paper and a dull pencil, with the same questions I had filled out at my last visit a few weeks earlier. After filling out the forms they asked, "OK, what's the problem?" and I replied that a recent electrocardiogram (EKG) had shown some abnormalities that required further evaluation. They responded by asking where the EKG had been done (it had been done in that office).

Why is this happening? It is easy to say "we have to be lifelong learners," "we should challenge the status quo," "we need to develop better tools," and "someone should fix the problems of medicine." But who, exactly, will do these things? Pathologists? Everyone in health care is busy with his or her own problems, but we've got to address the larger issues of quality and patient satisfaction. We're the ones with the deepest understanding of personalized medicine. We're the ones with the information technology and operations management expertise. We need to lead change rather than fight it. We shouldn't wait for the clinicians to say that it would be great if we got better turnaround time. We need to improve how we do things, build new tools, and be the innovation leaders in health care. If we do this, clinicians and hospital administrators, even payers, will increasingly respect us and turn to us to help them do better. If, however, we don't see that as part of our job, it's going to be bad for the field of pathology and bad for patients.

References

(1.) Betz BL, Hess JL. Acute myeloid leukemia diagnosis in the 21st century. Arch Pathol Lab Med. 2010;134(10):1427-1433.

(2.) Hess JL. What hematopathology tells us about the future of pathology informatics. Arch Pathol Lab Med. 2009;133(6):908-911.

(3.) Maher CA, Kumar-Sinha C, Cao X, et al. Transcriptome sequencing to detect gene fusions in cancer. Nature. 2009;458(7234):97-101.

Jay L. Hess, MD, PhD

Accepted for publication June 9, 2010.

From the Department of Pathology, University of Michigan Medical School, Ann Arbor.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Jay L. Hess, MD, PhD, Department of Pathology, University of Michigan Medical School, M5240 Medical Science Bldg 1, 1301 Catherine Ave, Ann Arbor MI (e-mail: jayhess@med.umich.edu). Jay L. Hess, MD, PhD, received a bachelor's degree in biophysics from Johns Hopkins University (Baltimore, Maryland) in 1982, and in 1989 he received his medical degree and doctorate degree in molecular biology from the Johns Hopkins University School of Medicine. After completing residency training in anatomic pathology at Brigham and Women's Hospital/Harvard Medical School (Boston, Massachusetts), Dr Hess completed fellowships in hematopathology and surgical pathology at Brigham and Women's Hospital and Memorial Sloan-Kettering Cancer Center (New York, New York).

He served as Assistant Professor of Pathology and Codirector of the Hematopathology Training Program at Washington University School of Medicine (St Louis, Missouri) from 1993-1999. He joined the faculty of the Department of Pathology and Laboratory Medicine at the University of Pennsylvania Health System (Philadelphia) in 1999 as associate professor and was promoted to the rank of professor in 2004. While at the University of Pennsylvania, Dr Hess served as Director of Hematopathology and Codirector of the Hematologic Malignancies Program at the Abramson Cancer Center.

Dr Hess is board certified in anatomic pathology and hematopathology and serves on the editorial board for a number of journals including the American Journal of Clinical Pathology, International Journal of Clinical and Experimental Pathology, Clinical and Translational Science, and Experimental Hematology.

His research focuses on mechanisms of Hox gene regulation by the mixed-lineage leukemia protein and the role of Hox genes in hematopoiesis and leukemia.

Dr Hess joined the faculty of the Department of Pathology at the University of Michigan (Ann Arbor) in July 2005 as the Carl V. Weller Professor of Pathology and Chair.
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Author:Hess, Jay L.
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2010
Words:1848
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