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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EIn the literature, pathology is described as having revolutionized the management of lung cancer, yet the current understanding of lung cancer pathology has also presented new challenges. This article discusses considerations of molecular testing that is currently used in clinical practice.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERespiratory Cancers Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECancer\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERespiratory Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EOncology Genomics\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECancer\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EIn the literature, pathology is described as having revolutionized the management of lung cancer, yet the current understanding of lung cancer pathology has also presented new challenges. Keith M. Kerr, MD, Aberdeen University Medical School, Aberdeen, United Kingdom, presented considerations of molecular testing that is currently used in clinical practice.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003ESeveral studies suggest that finding actionable genetic alterations, which are mutations that can be targeted by therapy, is a worthwhile endeavor in lung cancer. In a trial conducted by the Lung Cancer Mutation Consortium, a survival benefit was clearly seen in patients who received driver detected-targeted therapy compared with patients who did not have genetic drivers detected and in those who did have drivers detected but did not receive targeted therapy [Kris MG et al. WCLC Sydney 2013]. This effect resulted primarily from mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Dr. Kerr pointed out that this benefit was not due to a prognostic factor related to the genetic driver, as patients with lung cancer driven by genetic aberrations who did not receive targeted therapy had similar overall survival as those who did not have genetic drivers. Pathology can now stratify lung adenocarcinoma into disease driven by EGFR mutations or by ALK or ROS1 rearrangements. These 3 genetic alterations can be targeted by specific therapies.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EHistologic subtyping of non-small cell lung cancer (NSCLC) can be accurately achieved by using simple hematoxylin and eosin staining of a small biopsy or cytology sample. There are cases, however, in which no differentiating features can be seen in the sample, which is designated as NSCLC not otherwise specified. Many times, this designation is made because only a few cancerous cells are present in the sample. However, immunohistochemistry (IHC) can then be used to determine if there are specific genetic markers that can lead to a more differential diagnosis. This approach has decreased the numbers of biopsy and, especially cytology samples that receive diagnoses of NSCLC not otherwise specified. However, Dr. Kerr pointed out, it is important to understand that although these molecular markers predict the subtype of NSCLC, they do not define the disease. Therefore, a pathologist may use the term \u201cprobably\u201d when IHC is used to determine the subtype of NSCLC.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EIn lung adenocarcinoma in Europe, EGFR is a driver in about 15% of cases, whereas ALK is a driver in about 5% (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Kerr KM. \u003Cem\u003EJ Clin Pathol\u003C\/em\u003E 2013]. Molecular drivers are closely associated with adenocarcinoma histology and adenocarcinogenesis. Therefore, all samples classified as adenocarcinoma, probably adenocarcinoma, partly adenocarcinoma, or \u201ccannot exclude\u201d adenocarcinoma should be tested for molecular markers. In addition, about half of patients with factors such as smoking, male sex, and certain ethnic heritages are likely to have one of these molecular markers. Therefore, patients who do not fit the typical clinical profile but have one of these characteristics should also undergo molecular testing. Furthermore, many guidelines also suggest that patients who never smoked or are long-time ex-smokers should also receive molecular testing.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Proportion of Oncogenic Drivers in Lung Adenocarcinoma\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1243197450\u0022 data-figure-caption=\u0022Proportion of Oncogenic Drivers in Lung Adenocarcinoma\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/3\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15827\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EProportion of Oncogenic Drivers in Lung Adenocarcinoma\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced from Kerr KM et al. Clinical relevance of the new IASLC\/ERS\/ATS adenocarcinoma classification. \u003Cem\u003EJ Clin Pathol\u003C\/em\u003E 2013;66(10):8320\u20138. With permission from the British Medical Journal Publishing Group.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-7\u0022\u003EDepending on the hospital, sometimes molecular testing of lung tumors is initiated by the pathologist or ordered by the oncologist (or tumor board). The advantages of a pathologist\u0027s initiating molecular testing are that testing occurs quickly, cases are less likely to be missed because molecular testing is routine, and the results are ready for tumor board decisions. However, disadvantages include the potential for wasted time, money, and tumor tissue, because some results of molecular testing will never be acted on. In contrast, the advantages of molecular testing initiated by an oncologist include testing that is performed only when needed, preservation of tissue, and no wasted laboratory time. However, the disadvantages are that the cost of testing is higher per sample, the turnaround for results is slower, and cases maybe missed.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EMolecular testing can be performed on tissue or cytology cell block sections, but it is critical that an appropriate proportion of tumor and normal cells be present in the sample. The appropriate proportion of tumor cells is approximately 10% to \u0026gt;50% of the sample. However, Prof. Kerr pointed out that it is very difficult to establish a specific amount or number of tumor cells that are needed for molecular testing especially for IHC or fluorescence in situ hybridization. Clearly, a tissue sample taken from a resection provides abundant tumor cells, whereas a lung biopsy provides less material, and a cell pellet harvested from a cytology sample provides the least material for molecular testing. Importantly, only about 33% to 50% of a malignant bronchial biopsy sample is tumor cells [Coghlin CL et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EPreparation of the sample is an important part of molecular testing. In particular, proper fixing of the tissue is critical: over- or underfixing of the tissue will lead to an unsuccessful test. Another important factor in sample processing is the amount of material; in particular, the laboratory performing the deoxyribonucleic acid extraction for molecular testing will need to know the quality and amount of material that is provided. A pathologist may mark the area of a fixed section, indicating where deoxyribonucleic acid should be extracted in an effort to \u201cpurify\u201d the sample to increase the proportion of tumor cells. Prof. Kerr stated that this extra \u201cpurification\u201d step makes a large difference in achieving successful testing.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EMultiple mutations can occur in EGFR. Some of these mutations result in different degrees of drug sensitivity, whereas other mutations may be associated with drug resistance [Sharma SV et al. \u003Cem\u003ENat Rev Cancer\u003C\/em\u003E 2007]. Therefore, it is important that the molecular testing that is performed adequately cover a large range of EGFR mutations. For testing with ALK rearrangements, fluorescence in situ hybridization is the gold standard, as it illustrates the presence of a rearrangement, although it does not guarantee that the rearrangement is active. IHC can be used to identify elevated levels of the ALK rearrangement protein, and multiplex polymerase chain reaction can identify the increasing number of types of ALK rearrangements. Many pathology laboratories now use IHC to prescreen samples for ALK rearrangement before moving on to fluorescence in situ hybridization in patients with elevated ALK protein levels.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EProf. Kerr outlined the testing algorithm that is used in his pathology laboratory, which includes subtyping malignant lung tumors and then simultaneously testing adenocarcinomas for molecular markers such as EGFR and ALK rearrangements, as well as KRAS and BRAF mutations. Some laboratories use a sequential approach to molecular testing; however, a recent study suggested that with this method, 30% of samples could not undergo required testing [Buettner R et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2013].\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EIn conclusion, Prof. Kerr highlighted that it is important that clinicians be aware that molecular testing may be required and that there is the need to safely maximize tissue collection. In addition, a multidisciplinary effort is needed to successfully perform molecular testing.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/3\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzpakd\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzpakd\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}