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"Next-generation" pathology and laboratory medicine.

Recent reports of genomic sequencing leading to innovative and effective clinical management--perhaps most notably the story of the Wisconsin boy for whom whole genome sequencing led to a curative bone marrow transplant (1)--provide a glimpse of a new world for diagnostic medicine and for diagnostic laboratories, in particular. Such genomic successes strongly suggest that "personalized medicine" will increase the role of clinical laboratories in patient management. These changes have profound implications for the discipline of pathology and laboratory medicine and for how laboratory diagnosticians relate to medicine as a whole. This "Editorial" provides a succinct, but challenging, vision from the perspective of large, academic pathology departments about how we anticipate the field of pathology will change during the next 5 to 10 years.

Deep-sequencing technology is just one of several remarkable opportunities for clinical laboratories. Technologic advances (automation, molecular diagnostics, pathology imaging, and informatics) are transforming the field. Automated systems now provide a large percentage of high-volume, fluid-based test results, and even the traditionally manual areas of histopathology may become automated in the near future. Molecular diagnostics has made inroads into nearly all areas of pathology, particularly cancer diagnosis, microbiology, and hereditary disease testing. The pace of change is dizzying, both in numbers of tests and in the complexity of the results, as is the emerging need to integrate massive data sets to reach a clinical interpretation. Informatics--information systems, computational informatics, and digital imaging and its applications--has made substantial inroads, not only based on new "-omic" data sets but also on conventional clinical laboratory data and histologic images with synoptic data capture of morphologic parameters. Such data are being incorporated at some institutions into huge and continuously updated data warehouses that can be mined for diagnostic and policy decisions. Indeed, the application of informatics and computational biology and its integration with hospital clinical systems may alter how we make diagnoses--leading to development of "computational diagnostics" as a tool for clinical laboratories.

Diagnostic laboratories are complicated places, with advanced technologies, large staffs, and detailed regulations. They remain oriented around the historically separate, technologically defined areas of clinical pathology and anatomic pathology. The changes described above, however, blur that traditional distinction. Molecular technologies are being implemented on both sides of the historic divide, and even the traditionally human interpretation-based areas of anatomic pathology are using automated approaches that rely on computer-assisted diagnostics. Overall, automation shifts physician emphasis away from technical oversight, creating opportunities to provide value in other ways.

With these changes, one can anticipate a day in which complete epigenetic, genetic, proteomic, and metabolomic signatures will be generated at high quality and low cost. In a value-oriented health care system, the pathologist will then become the integrator of large, complex data sets to continue to fulfill the classic central role of determining diagnosis, prognosis, and appropriate therapy. Furthermore, with this increase in clinical data, pathologists can extend their traditional roles in the appropriate use and integration of laboratory information. Pathologists would not only work to contain costs but also would justify testing in light of clinical necessities--putting considerable pressure on laboratory-based physicians to understand clinical and overall health care needs in detail.

The exponential growth of information makes the old model of a single pathologist running a hospital laboratory difficult to sustain. As in the rest of medicine, the complexity of biomedical information, the need for efficiency, and performance improvement are driving subspecialization in laboratory diagnostics. A major advantage of subspecialty practice is that pathologists become more integrated members of health care teams. Subspecialty pathologists are already core members of multidisciplinary cancer teams, as critical as the surgeon or oncologist. Indeed, subspecialization in pathology will become necessary because of subspecialization in the rest of medicine. Subspecialist physicians derive improved service from pathologists who speak their language, and who understand the details of their needs and the patients' needs.

A greater need for pathologist involvement has thus arisen at the interface of the laboratory with the clinic. The pathologist can no longer be solely within the laboratory, but must be positioned at the door, able to look both into and out of the laboratory. For instance, the growing number of different laboratory tests creates a challenge for the typical physician to remain appropriately informed. Furthermore, the complexity of individual tests has escalated: witness the difficulties of interpreting the significance of polymorphisms detected in genetic testing. Given that "shotgun" approaches to laboratory test ordering lead to wasteful overordering and affect quality outcomes adversely through delays in diagnosis and pursuit of false-positives, the laboratory diagnostician will need to define ordering practices, ensure cost containment and quality assessment to evaluate the utility of diagnostic procedures in specific clinical settings, and integrate information from different platforms.

Pan-laboratory subspecialization will likely provide the best model for all laboratory-based diagnostics relevant to a disease. In such a model, pathology reports would become comprehensive, integrating the results of imaging, biochemical, histologic, molecular genetic, cytogenetic, genomic, and epigenetic analyses into a cohesive, clinically relevant, and valuable diagnostic, predictive, and prognostic document. Such pan-laboratory subspecialization emphasizes the need for subspecialists to span the breadth of current laboratory technologies and to centralize them under the aegis of a particular organ system or group of diseases.

If this model is around the corner, pathology and laboratory medicine needs to prepare its trainees appropriately--to provide a strong foundation in emerging technologies and quality measures and to prepare pathologists to become credible consultants in their fields. This cannot be accomplished by simply extending the time of training, and pathology training programs may need to undergo transitions like those that occurred decades ago for subspecialties such as urology and neurosurgery--instead of full general surgical training, a year of general surgery followed by lengthy specialty training. It may be necessary for the next generation of pathologist trainees to undertake a single internship year in basic anatomic pathology and clinical pathology, followed by additional years of either organ-based or technology-based subspecialty training, which would include extensive exposure to laboratory diagnosis and clinical medicine. Pathologists would thus work together with their subspecialist laboratory colleagues, clinicians, and patients to develop their craft. Such programs will not be easy to generate and will require greater overlap with medical and surgical training tracks.

Pathology today is laboratory focused, with the attendant benefits of consistency and reliability. However, to foster the current opportunities in diagnostic laboratories, the discipline should transform rapidly into a subspecialty-oriented, pan-laboratory medical field that operates at the critical interface between the laboratory and the clinic--even closer to the medical and surgical specialties. Next-generation pathologists must ensure progress in obtaining faster, better, more-integrated results for patients, and they may look very different to their medical and surgical colleagues. With these changes, the old aphorism from Sir William Osler will remain true: "As is your pathology, so goes your clinical care."


(1.) Worthey EA, Mayer AN, Syverson GD, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med. 2011;13(3):255-262.

David N. Louis, MD; Herbert W. Virgin IV, MD, PhD; Sylvia L. Asa, MD, PhD

Accepted for publication August 10, 2011.

From the Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (Dr Louis); the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri (Dr Virgin); and the Laboratory Medicine Program, University Health Network and University of Toronto, Toronto, Ontario, Canada (Dr Asa).

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2011-0414-ED

Reprints: David N. Louis, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (e-mail: dlouis@
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Title Annotation:Editorial
Author:Louis, David N.; Virgin, Herbert W. IV; Asa, Sylvia L.
Publication:Archives of Pathology & Laboratory Medicine
Date:Dec 1, 2011
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