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 non– small 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
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Open Access
Jan 1, 2014
Makoto Maemondo 
