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Lung cancer and the future of pathology.

Molecular diagnostics and molecular therapy have an escalating role in patient management and the implications for pathologists have not always been clear. (1-4) Of course, pathologists, with their command of laboratory methods, test standardization and validation, quality assurance, and laboratory regulations are the obvious choice to direct molecular diagnostic laboratories. Nevertheless, for the foreseeable future, there will be many more pathologists practicing conventional surgical pathology than supervising molecular diagnostic laboratories. And most residents and fellows in pathology continue to emphasize traditional diagnostic skills in their training. (4) At first glance, these observations might appear to suggest that most pathologists will be less valuable in the world of personalized health care. However, if pathologists are willing to adapt, the role of the surgical pathologist has not been diminished by personalized health care, but rather, it has been enhanced, and it is important that other medical specialties, government agencies, third-party payers, and pathologists themselves recognize this.

No current field of personalized health care better illustrates the value of the surgical pathologist's traditional training and expertise than molecular-targeted therapy of lung cancer. Histologic classification by the surgical pathologist using familiar tools is uniquely intertwined with the new molecular diagnosis and targeted therapy of lung cancer. The pathologist's active discourse with oncologists and other specialists about a patient's case is more essential than ever.

For decades, care of patients with lung cancer was mired in limited treatment options, generally with dismal outcome. The contribution of the surgical pathologist to patient care was largely restricted to differentiating small cell carcinoma from non-small cell carcinoma on small biopsies and cytology specimens and to staging of nonsmall cell carcinoma resections. (5) In the early 1990s, there were predictions that molecular classification of lung cancers would one day be essential, but without successful molecular-targeted therapies to provide impetus, that idea had no substantive meaning in clinical practice. (6,7)

Molecular-targeted therapies involve drugs that "target" specific cell receptors and signaling pathways in lung cancers. So far, most of the drugs for lung cancer that have been approved, are pending approval, or are under investigation target tyrosine kinase receptors or their ligands. (8-13) These include epidermal growth factor receptor (EGFR) 1; anaplastic lymphoma kinase receptor (ALK), primarily as the echinoderm microtubule-associated proteinlike 4-ALK fusion gene (EML4-ALK); vascular endothelial growth factor (VEGF) and the VEGF receptor (VEGFR); and epidermal growth factor receptor 2 (HER2/ ERBB2). Drugs are also under investigation for targets in signaling pathways downstream of the tyrosine kinase receptors, including BRAF, KRAS, MEK, PI3K, and mTOR.

The presence of EGFR mutations are the best predictor of response to EGFR tyrosine kinase inhibitors. EGFR mutations occur in lung cancers with adenocarcinoma histology. Indeed, there is an association with specific subtypes of adenocarcinoma, such as lepidic (bronchioloalveolar), papillary, and micropapillary patterns. The EML4-ALK fusion gene is also reported to be associated with adenocarcinoma histology, in particular the signetring pattern and solid subtype. To date, most targeted therapies for lung cancer are effective in adenocarcinoma compared with other cell types, and the corresponding mutations are often more frequently associated with specific subtypes of adenocarcinoma. (14-19)

Differentiation of adenocarcinoma from squamous cell carcinoma by the pathologist is applicable to lung cancer for several current agents. (5,16-19) Bevacizumab is a monoclonal antibody to VEGF and is effective as a first-line agent in many adenocarcinomas. However, patients with squamous cell carcinoma who receive bevacizumab are at risk of developing severe, even life-threatening, hemorrhage. Pemetrexed is a new antifolate agent, and adenocarcinomas may respond to pemetrexed, whereas squamous cell carcinomas do not. In both of these situations, differentiation of adenocarcinoma from squamous cell carcinoma by the pathologist is already recognized as critical for selecting appropriate treatment for patients. (5,16-19)

When selecting tissue samples for predictive biomarkers for any type of cancer, there will always be a need for a pathologist to differentiate cancer from noncancer, viable tissue from nonviable tissue, adequate sample size from inadequate sample size, etc. In addition to these universal needs for all cancer samples, there are novel factors with lung cancer samples that call for the expertise of a pathologist. (5,14-19) Histology does not trump molecular analysis in predicting which lung cancers have mutations and are likely to respond to targeted therapy. However, the association of specific mutations with specific histologic types and subtypes means that the pathologist has a role in suggesting which molecular tests are most likely to yield positive results for a given cancer. This is particularly true if there are restrictions because of sample size, test costs, availability of tests, or turnaround time and, therefore, specific tests are ordered on a case-by-case basis. In this scenario, histology becomes a prescreening tool in the hands of the pathologist. If there is adequate tissue, the pathologist may be able to perform screening by employing antibodies to specific mutations to establish their presence by immunohistochemistry. (20-22) The pathologist's input is pivotal to correlation of clinical management and expectations with histology, triage of tissue samples, and decisions about follow-up. Therefore, the pathologist is not only the uniquely educated broker of tissues, a role that no one else can replace in this setting, but also an expert consultant to the oncologist and an integral part of the patient care team. Although histology of lung cancer is more important than ever, this does not mean that a surgical pathologist who is not primarily a molecular pathologist does not have to acquire a basic understanding of the various biomarker tests and targeted therapies to interact successfully with other medical disciplines on the patient's behalf.

Rather than ordering specific tests on a lung cancer sample on a case-by-case basis, some institutions may require reflex testing of all lung cancers once they are diagnosed by the pathologist. (23,24) Reflex testing of all lung cancers introduces concerns about costs and logistics but does not diminish the need for the pathologist's skills and training: First, most adenocarcinomas have mixed histologic patterns in resection specimens. If we are going to correlate mutation identification and response to targeted therapy in future clinical trials with the differing histologic patterns within a single tumor, the pathologist is needed for proper classification and sampling of the heterogeneous histologic patterns. It would make sense that the pathologist sample each of these subtypes within the tumor for molecular analysis because each subtype may have differing target mutations, which has potential implications for the selection of therapy. As imaging techniques for in vivo histologic diagnosis become available in the future, the pathologist can direct biopsies of differing subtypes within a heterogeneous tumor for therapy of lung cancers that do not undergo resection. (25) No one else but the pathologist is trained and educated to properly execute this mission and counsel oncologists and other specialists about a tumor's heterogeneity and the subsequent implications.

Second, many new, predictive biomarkers and new molecular therapies for lung cancer will be investigated in the future, some of which will eventually be approved for clinical use. The pathologist is needed to correlate histology with new biomarkers and new targeted therapies in all specimens as these undergo investigation and approval for clinical use. Once again, the pathologist performs a vital role in personalized health care based on traditional knowledge and skills and offers essential guidance that no other specialist can offer.

Thus, for patients with lung cancer, the role of the surgical pathologist has expanded from simply diagnosing non-small cell carcinoma versus small cell carcinoma to a much more complex, involved, and time-consuming process in the era of personalized health care. The same applies to many other types of cancer. Surgical pathologists of the 21st century provide indispensable preanalytic services for the proper identification, sampling, and processing of cancer tissues for molecular analysis, using skills and tools that they have honed for decades. More than ever, because of his or her unique knowledge, the pathologist's intellectual input and counsel on a patient's case are necessary for the appropriate care of a patient with cancer. Even when the pathologist does not perform the actual molecular analysis for predictive biomarkers, the extensive contribution of the pathologist to personalized health care is crucial to the management of patients with cancer. With personalized health care, the workload for surgical pathologists is increasing, not decreasing. The vital role of the surgical pathologist in modern personalized health care should not be underrecognized or undervalued.

References

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Philip T. Cagle, MD; Sanja Dacic, MD, PhD

Accepted for publication January 20, 2011.

From the Department of Pathology, The Methodist Hospital, Houston, (Dr Cagle);and the Department of Pathology, University of Pittsburgh Medical Center-Presbyterian Hospital, Pittsburgh, Pennsylvania (Dr Dacic).

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

Reprints: Philip T. Cagle, MD, Department of Pathology, The Methodist Hospital, 6565 Fannin St, Main Bldg, Room 227, Houston, TX 77030 (e-mail: pcagle@tmhs.org).
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Title Annotation:Editorial
Author:Cagle, Philip T.; Dacic, Sanja
Publication:Archives of Pathology & Laboratory Medicine
Date:Mar 1, 2011
Words:2167
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