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Journal ArticleDOI

Comprehensive histologic analysis of ALK-rearranged lung carcinomas.

TL;DR: Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies.
Abstract: A subset (1% to 5%) of non-small-cell lung carcinomas harbors the EML4-ALK fusion gene. Data from previous studies on the histomorphology of ALK-rearranged lung cancer are inconsistent, and the specific histologic parameters that characterize this subset and how accurately such parameters predict underlying ALK abnormality remain uncertain. To answer these questions, we performed a comprehensive histologic analysis of 54 surgically resected, extensively sampled ALK-rearranged lung carcinomas and compared them with 100 consecutive resections of ALK-wild-type lung cancers. All 54 cases showed at least a focal adenocarcinoma component, and 3 and 2 cases had additional squamous and sarcomatoid differentiation, respectively. Solid or acinar growth pattern, cribriform structure, presence of mucous cells (signet-ring cells or goblet cells), abundant extracellular mucus, lack of lepidic growth, and lack of significant nuclear pleomorphism were more common in ALK-positive cancers. Two recognizable constellations of findings, a solid signet-ring cell pattern and a mucinous cribriform pattern, were present at least focally in the majority (78%) of ALK-positive tumors, but were rare (1%) in ALK-negative tumors. Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement. Characteristic histologies were present both in primary sites and in metastases. Thus, histologic findings may help to identify cases for ALK testing. However, none of the histologic parameters were completely sensitive or specific to ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies. ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear.
Citations
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Journal ArticleDOI
TL;DR: A deep convolutional neural network model is trained on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue and predicts the ten most commonly mutated genes in LUAD.
Abstract: Visual inspection of histopathology slides is one of the main methods used by pathologists to assess the stage, type and subtype of lung tumors. Adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are the most prevalent subtypes of lung cancer, and their distinction requires visual inspection by an experienced pathologist. In this study, we trained a deep convolutional neural network (inception v3) on whole-slide images obtained from The Cancer Genome Atlas to accurately and automatically classify them into LUAD, LUSC or normal lung tissue. The performance of our method is comparable to that of pathologists, with an average area under the curve (AUC) of 0.97. Our model was validated on independent datasets of frozen tissues, formalin-fixed paraffin-embedded tissues and biopsies. Furthermore, we trained the network to predict the ten most commonly mutated genes in LUAD. We found that six of them—STK11, EGFR, FAT1, SETBP1, KRAS and TP53—can be predicted from pathology images, with AUCs from 0.733 to 0.856 as measured on a held-out population. These findings suggest that deep-learning models can assist pathologists in the detection of cancer subtype or gene mutations. Our approach can be applied to any cancer type, and the code is available at https://github.com/ncoudray/DeepPATH .

1,682 citations

Journal ArticleDOI
TL;DR: In this mini-review, the application of digital pathological image analysis using machine learning algorithms is introduced, some problems specific to such analysis are addressed, and possible solutions are proposed.
Abstract: Abundant accumulation of digital histopathological images has led to the increased demand for their analysis, such as computer-aided diagnosis using machine learning techniques. However, digital pathological images and related tasks have some issues to be considered. In this mini-review, we introduce the application of digital pathological image analysis using machine learning algorithms, address some problems specific to such analysis, and propose possible solutions.

545 citations


Cites background from "Comprehensive histologic analysis o..."

  • ...By analyzing the relationship between these data, new clinicopathological relationships, for example, the relationship between the morphological characteristic and the somatic mutation of the cancer, can be found [34,35]....

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Journal ArticleDOI
TL;DR: Significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification are summarized.
Abstract: We summarize significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by an international core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lung cancer present with advanced stages, a new approach to small biopsies and cytology with specific terminology and criteria focused on the need for distinguishing squamous cell carcinoma from adenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumors previously classified as non–small-cell carcinoma, not otherwise specified, because of the lack of clear squamous or adenocarcinoma morphology should be classified further by using a limited immunohistochemical workup to preserve ...

475 citations

Journal ArticleDOI
TL;DR: The RET fusion gene occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
Abstract: Purpose The RET fusion gene has been recently described in a subset of non–small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene. Patients and Methods We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected. Results Of 936 patients with N...

460 citations

Journal ArticleDOI
TL;DR: The new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification provides, for the first time, standardized terminology for lung cancer diagnosis in small biopsies and cytology; this was not primarily addressed by previous World Health Organization classifications.
Abstract: The new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification provides, for the first time, standardized terminology for lung cancer diagnosis in small biopsies and cytology; this was not primarily addressed by previous World Health Organization classifications. Until recently there have been no therapeutic implications to further classification of NSCLC, so little attention has been given to the distinction of adenocarcinoma and squamous cell carcinoma in small tissue samples. This situation has changed dramatically in recent years with the discovery of several therapeutic options that are available only to patients with adenocarcinoma or NSCLC, not otherwise specified, rather than squamous cell carcinoma. This includes recommendation for use of special stains as an aid to diagnosis, particularly in the setting of poorly differentiated tumors that do not show clear differentiation by routine light microscopy. A lim...

370 citations

References
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Journal ArticleDOI
04 Jun 2004-Science
TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Abstract: Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

9,265 citations


"Comprehensive histologic analysis o..." refers background in this paper

  • ...The clinical importance of the molecular subtyping of cancer lies primarily in its therapeutic implications because different subtypes may respond to treatment in a different manner.(10,11) The recent discovery of a fusion gene that joins the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in a subset (1% to 5%) of non-small-cell lung carcinomas (NSCLCs) has added another molecular subtype to the classification scheme for lung cancers....

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  • ...For example, epidermal growth factor receptor and KRAS mutations, 2 major genetic changes seen in many adenocarcinomas, now delineate 2 different molecular subtypes characterized by different patient demographics and tumor histologies.(6,10,11,21) The clinical importance of the molecular subtyping of cancer lies primarily in its therapeutic implications because different subtypes may respond to treatment in a different manner....

    [...]

Journal ArticleDOI
TL;DR: Two new measures, one based on integrated sensitivity and specificity and the other on reclassification tables, are introduced that offer incremental information over the AUC and are proposed to be considered in addition to the A UC when assessing the performance of newer biomarkers.
Abstract: Identification of key factors associated with the risk of developing cardiovascular disease and quantification of this risk using multivariable prediction algorithms are among the major advances made in preventive cardiology and cardiovascular epidemiology in the 20th century. The ongoing discovery of new risk markers by scientists presents opportunities and challenges for statisticians and clinicians to evaluate these biomarkers and to develop new risk formulations that incorporate them. One of the key questions is how best to assess and quantify the improvement in risk prediction offered by these new models. Demonstration of a statistically significant association of a new biomarker with cardiovascular risk is not enough. Some researchers have advanced that the improvement in the area under the receiver-operating-characteristic curve (AUC) should be the main criterion, whereas others argue that better measures of performance of prediction models are needed. In this paper, we address this question by introducing two new measures, one based on integrated sensitivity and specificity and the other on reclassification tables. These new measures offer incremental information over the AUC. We discuss the properties of these new measures and contrast them with the AUC. We also develop simple asymptotic tests of significance. We illustrate the use of these measures with an example from the Framingham Heart Study. We propose that scientists consider these types of measures in addition to the AUC when assessing the performance of newer biomarkers.

5,651 citations


"Comprehensive histologic analysis o..." refers methods in this paper

  • ...The IDI is a measure of performance of prediction models based on integrated sensitivity and specificity and had been proven to offer incremental information over the conventional area under the receiver-operatingcharacteristic curve.(12)...

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Journal ArticleDOI
02 Aug 2007-Nature
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
Abstract: Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

4,826 citations


"Comprehensive histologic analysis o..." refers background in this paper

  • ...The recent discovery of a fusion gene that joins the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in a subset (1% to 5%) of non-small-cell lung carcinomas (NSCLCs) has added another molecular subtype to the classification scheme for lung cancers.(16) The EML4-ALK fusion seems to be formed by a small inversion within the short arm of chromosome 2, and the encoded chimeric protein is dimerized unliganded, leading to constitutive activation....

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Journal ArticleDOI
TL;DR: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients, and the drug resulted in grade 1 or 2 gastrointestinal side effects.
Abstract: Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

4,091 citations


"Comprehensive histologic analysis o..." refers background in this paper

  • ...%) of non-small-cell lung carcinomas (NSCLCs) has added another molecular subtype to the classification scheme for lung cancers.16 The EML4-ALK fusion seems to be formed by a small inversion within the short arm of chromosome 2, and the encoded chimeric protein is dimerized unliganded, leading to constitutive activation.5 To date, numerous fusion variants have been identified, and KIF5B was found to be an additional fusion partner of ALK.17 The importance of recognizing this molecular subtype was highlighted by an international phase I/II clinical trial in which the ALK inhibitor crizotinib (PF02341066) yielded encouraging overall response and disease control rates in a cohort of patients with ALK-rearranged NSCLCs.4 Although researchers agreed that most ALK-rearranged NSCLCs are adenocarcinomas, detailed histomorphologic studies have yielded somewhat conflicting results.1–3,13 Some researchers found that ALK-rearranged NSCLCs exhibited a conspicuous acinar growth pattern and extracellular mucus production.1–3 In contrast, othersCopyright r 2011 by Lippincott Williams & Wilkins From the *Pathology and Clinical Laboratory Division; JDivision of Thoracic Surgery; zDivision of Thoracic Oncology, National Cancer Center Hospital; wDepartment of Pathology, The University of Tokyo; zDivision of Genome Biology; #Division of Cancer Genomics, Center for Medical Genomics, National Cancer Center Research Institute; and yDepartment of Clinical Medicine (Biostatistics), School of Pharmacy, Kitasato University, Tokyo, Japan....

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  • ...1232 | www.ajsp.com r 2011 Lippincott Williams & Wilkins researchers,1–3 and the solid signet-ring cell pattern was reported mainly by the North American investigators.13 We confirmed that both patterns were similarly characteristic of ALK-rearranged NSCLCs....

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  • ...The importance of recognizing this molecular subtype was highlighted by an international phase I/II clinical trial in which the ALK inhibitor crizotinib (PF02341066) yielded encouraging overall response and disease control rates in a cohort of patients with ALK-rearranged NSCLCs.(4) Although researchers agreed that most ALK-rearranged NSCLCs are adenocarcinomas, detailed histomorphologic studies have yielded somewhat conflicting results....

    [...]

Journal ArticleDOI
TL;DR: Data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
Abstract: Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P = 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinib-refractory tumors (P = 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime ("never smokers"), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P = 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

4,071 citations


"Comprehensive histologic analysis o..." refers background in this paper

  • ...The clinical importance of the molecular subtyping of cancer lies primarily in its therapeutic implications because different subtypes may respond to treatment in a different manner.(10,11) The recent discovery of a fusion gene that joins the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in a subset (1% to 5%) of non-small-cell lung carcinomas (NSCLCs) has added another molecular subtype to the classification scheme for lung cancers....

    [...]

  • ...For example, epidermal growth factor receptor and KRAS mutations, 2 major genetic changes seen in many adenocarcinomas, now delineate 2 different molecular subtypes characterized by different patient demographics and tumor histologies.(6,10,11,21) The clinical importance of the molecular subtyping of cancer lies primarily in its therapeutic implications because different subtypes may respond to treatment in a different manner....

    [...]

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