Share this article on:

Molecular Pathology: On the “Plateau of Productivity”

Gocke, Christopher D. MD

doi: 10.1097/PCR.0b013e3181e92f62

From the Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.

Reprints: Christopher D. Gocke, MD, Department of Pathology, Johns Hopkins University School of Medicine, 600 N. Wolfe St/Park SB202, Baltimore, MD 21287. E-mail:

“Trough of Disillusionment,” “Peak of Inflated Expectations,” “Plateau of Productivity.” Dante parody? Bad Broadway musical? From the lexicon of the business world come these phrases, courtesy of the research and consulting company Gartner, Inc. They describe stages of the “hype cycle,” a graphic view of the evolution of a new technology over time (Figure). And I suggest that they provide a playful orientation to the subject of this issue of Pathology Case Reviews: Molecular Pathology.



Molecular Pathology—the use of molecular biologic methods to answer pathology questions—has had a brief but exciting life. Dating from the application of molecular techniques to immunoglobulin and T-cell receptor gene rearrangements in leukemia and lymphoma and the identification of microbes from clinical samples in the late 1970s and 1980s, the field has grown rapidly in size and scope. By most measures—number of routine clinical assays available, number of Molecular Genetic Pathology fellowship programs and trainees, dollars spent in the growing commercial market, number of diagnostic companies entering the arena—the field has experienced a meteoric rise. I remember moments in the early 1990s when pathologists feared that microscopes would go the way of the leech. Peak of Inflated Expectations, indeed.

There was a let-down when it became clear that molecular testing had its limitations. Specimen processing and handling provided substantial hurdles. Laboratory platforms proliferated to the point that it was difficult for a laboratory to maintain a rational test menu. Costs were—and remain—significant, from both the laboratory manager's and insurance company's point of view. Molecular tests turned out to be no different than other assays in requiring careful quality control, attention to sensitivity and specificity issues, and in the need for standardization. Thanks to the efforts of numerous individual investigators and work by professional societies and diagnostic companies, I believe that we have largely traversed our trough and are well along the Slope of Enlightenment. This journal issue highlights the successes of Molecular Pathology. We cover topics of day-to-day interest to the practicing pathologist, at the surgical bench and at lunch table conversations with the GYN surgeon or endocrinology colleague.

Drs. Sholl and Lindeman begin with a discussion of mutation testing of the EGFR gene in lung adenocarcinoma. Because of the association of effective targeted cancer therapy with EGFR mutations, this area has shown a recent explosion in interest from pathologists and clinicians alike. The linkage of genetic alterations identified by molecular testing with cancer-specific and, eventually, patient-specific drugs will be a major theme for us in the next few years. This is followed by Dr. Tsiatis's article highlighting the issue of microsatellite instability testing in colorectal cancer. This testing began as an effort to identify patients with an inherited genetic cancer syndrome of defective DNA mismatch repair (hereditary nonpolyposis colorectal cancer or Lynch syndrome), but is now being revisited as a risk predictor and prognosticator for all colorectal cancer patients.

The potential specimen mix-up is a frightening but real occurrence in the surgical pathologist's practice. Taking a page from forensic pathology, Dr. Harada and Dr. Gocke demonstrated the ability of molecular testing to resolve problems of specimen identity. The genetics of thyroid cancer have been steadily teased apart, with the University of Pittsburgh group playing a prominent role in exploring new test algorithms. In particular, papillary thyroid cancers frequently carry mutations in the BRAF gene. The use of fine needle aspiration in evaluation of thyroid nodules pushes the limits of what Molecular Pathology can achieve, as covered in an article by Dr. Bansal and Dr. Nikiforov. Hydatidiform moles provide a fascinating insight into one of the odd corners of genetics, explain Dr. Murphy and Dr. Ronnett. Complete and partial moles are molecularly separable because they show different contributions of parental chromosomes. A combination of immunohistochemistry and molecular testing may provide a solid classification of these tumors, useful for both clinical management and scientific study.

The field of virology provided an early foothold for what would become Molecular Pathology. The Nobel Prize-winning discoveries of zur Hausen on the role of human papilloma virus in cervical cancer quickly translated to the pathology laboratory and are changing the face of cancer screening. Dr. Sabath and Dr. Kiviat conclude the issue with a review of Molecular Pathology's place in the detection and classification of cervical neoplasia.

I would like to thank Dr. Steven Silverberg and Dr. Olga Ioffe for the opportunity to assemble this timely issue, and my coauthors for their contributions. Molecular Pathology will continue to extend its reach into the daily practice of pathologists, whether we are acting as diagnosticians or consultants. I anticipate that the discipline will move increasingly to quantitative rather than qualitative assays, panels of results will be more common than single analytes, and pharmacogenomics (drug selection and dosing based on the genetics of a patient or a patient's disease) will explode. Looming on the horizon, pushed by the National Institutes of Health's $1000 Genome and The Cancer Genome Atlas projects, is the promise of advanced DNA and RNA sequencing. Knowing the entire sequence of an infectious organism or of a patient's tumor could be a most powerful tool. There are substantial barriers to adopting this technology, most notably how we capture all this information and what we do with it. But let's not get too far into a new hype cycle! Given the state of Molecular Pathology today, on to our Plateau of Productivity.



© 2010 Lippincott Williams & Wilkins, Inc.