Adequacy of CT-guided biopsies with histomolecular subtyping of pulmonary adenocarcinomas: influence of ATS/ERS/IASLC guidelines.

As metastatic pulmonary adenocarcinomas are routinely investigated for EGFR, KRAS, and ALK mutations/rearrangement, adequacy of CT-guided trans-thoracic needle biopsies (TTNB) needs to be evaluated in respect with the 2011 ATS/ERS/IASLC guidelines. Two series of consecutive TTNB with 18-gauge needles performed before and after the publication of the ATS/ERS/IASLC guidelines, were retrospectively compared regarding their adequacy for histological sub-typing and EGFR/KRAS mutations and ALK rearrangement testing; the first series included 43 TTNB collected from January 2010 to February 2011, and the second one 48 TTNB collected from March 2011 to December 2012. 28 women and 63 men were included; the 2 groups were comparable in age, in mean size of lesions (32.5 mm), and distance of the lesion from the pleura. By comparing the first to the second series, the number of biopsies increased from 1.6 to 1.85, their mean length increased from 10.9 to 12.5mm, and the mean number of stainings (TTF1, P63, CK5-6, mucins) per biopsy decreased from 2.6 to 1. Mean tumor cell percentage was 42%, mean total DNA extracted increased from 2.7 to 3.8 μg. In the first series, 85% of TTNB allowed EGFR exons 19 and 21 and KRAS mutations pyrosequencing and 72% additional EGFR exons 18 and 20 mutation analyses, versus 98% and 92% in the second. With respect to ATS/ERS/IASLC guidelines, radiologists, biologists and pathologists have improved their practice; accordingly, CT-guided TTNB enable a precise histological sub-typing and provide sufficient DNA amount for genetic analyses.

Ferretti GR ，Busser B ，de Fraipont F ，Reymond E ，McLeer-Florin A ，Mescam-Mancini L ，Moro-Sibilot D ，Brambilla E ，Lantuejoul S ... -  《-》

Mutational Profile and New IASLC/ATS/ERS Classification Provide Additional Prognostic Information about Lung Adenocarcinoma: A Study of 125 Patients from Brazil.

To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged ≤ 71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

de Melo AC ，Karen de Sá V ，Sternberg C ，Olivieri ER ，Werneck da Cunha I ，Fabro AT ，Carraro DM ，de Barros e Silva MJ ，Pimenta Inada HK ，de Mello ES ，Soares FA ，Takagaki T ，Ferreira CG ，Capelozzi VL ... -  《-》

EGFR L858R mutation is associated with lung adenocarcinoma patients with dominant ground-glass opacity.

To retrospectively identify quantitative computed tomographic (CT) features that correlate with the three major driver gene mutations in surgically resected lung adenocarcinomas with dominant ground-glass opacity (GGO) stratified by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) classification in a Chinese cohort of patients. Surgically resected lung adenocarcinomas from Shanghai Pulmonary Hospital were enrolled. EGFR, KRAS and EML4-ALK mutations were detected by qPCR. Clinical and pathological characteristics including gender, age, TNM stage, smoking status and CT pattern were analyzed. Histologic subtype was classified according to IASLC/ATS/ERS classification. At preoperative chest CT, the percentage of GGO volume, diameter, solid volume and total tumor volume of each tumor were measured by using a semiautomated algorithm. Distribution of driver gene mutations was evaluated by using the Fisher exact test, the Student's t test, and Pearson correlation analysis. 788 in total and 158 GGO tumors were taken in this cohort. GGO pattern occurred at a significantly higher frequency in younger, female and non-smoking patients. EGFR/KRAS mutations and EML4-ALK fusions were similar between GGO and solid adenocarcinomas. GGO volume and diameter showed correlation with EGFR mutation. With regard to association between lung adenocarcinoma histological subtypes and GGO features, GGO proportion was significantly higher in lepidic predominant adenocarcinomas, including adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant invasive adenocarcinoma. No significant differences of driver gene mutations were found between subtypes of lung adenocarcinoma. It is important that we understand GGO lesions of lung adenocarcinoma to identify molecular biomarkers including EGFR, KRAS and EML4-ALK. These markers would offer useful information for determining the appropriate strategy to treat lung adenocarcinoma with GGO lesions detected by helical CT.

Yang Y ，Yang Y ，Zhou X ，Song X ，Liu M ，He W ，Wang H ，Wu C ，Fei K ，Jiang G ... -  《-》

Identification of EGFR mutation, KRAS mutation, and ALK gene rearrangement in cytological specimens of primary and metastatic lung adenocarcinoma.

The identification of molecular alterations has an important therapeutic implication in patients with lung adenocarcinomas. In the current study, the authors evaluated their experience with the identification of epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, and anaplastic lymphoma kinase (ALK) gene rearrangement using cytological specimens of primary and metastatic lung adenocarcinoma. A total of 54 cases of lung adenocarcinomas (11 primary and 43 metastatic tumors) in which molecular tests were performed were retrieved. Molecular tests were performed on the cell block material of 19 effusions and 35 fine-needle aspirates. EGFR mutation was evaluated by polymerase chain reaction sequencing analysis of exons 18, 19, 20, and 21. KRAS mutation was tested using polymerase chain reaction-single-strand conformational polymorphism analysis of codons 12 and 13. ALK gene rearrangement was evaluated by fluorescence in situ hybridization using an ALK break apart probe. Molecular tests were successful in 49 of 54 cases (91%). Evaluation of EGFR mutation, KRAS mutation, and ALK gene rearrangement were performed in 49 cases, 14 cases, and 22 cases, respectively. EGFR mutations were found in 14 of 49 cases (29%), including 5 primary and 9 metastatic tumors. Three metastatic/recurrent adenocarcinomas demonstrated an additional EGFR T790M mutation that was not identified in the original specimens. KRAS mutation was detected in 3 of 14 cases (21%) including 1 primary and 2 metastatic tumors. ALK gene rearrangement was evident in 3 of 22 cases (14%), all of which were metastatic tumors. The results of the current study have demonstrated the feasibility of using cytological specimens for EGFR mutation, KRAS mutation, and ALK gene rearrangement analysis. Repeating molecular testing in metastatic/recurrent lung adenocarcinomas may uncover newly acquired molecular alterations.

Cai G ，Wong R ，Chhieng D ，Levy GH ，Gettinger SN ，Herbst RS ，Puchalski JT ，Homer RJ ，Hui P ... -  《-》

Molecular testing in lung cancer: fine-needle aspiration specimen adequacy and test prioritization prior to the CAP/IASLC/AMP Molecular Testing Guideline publication.

Subtyping of lung carcinoma with immunohistochemistry is essential for diagnosis, whereas molecular testing (MT) is required for therapy guidance. In the current study, the authors report on MT performed on fine-needle aspiration specimens at the study institution over a 2-year period preceding the April 2013 College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) Molecular Testing Guideline (MTG) publication. The database of the study institution was retrospectively queried for cases of lung and thoracic/lower cervical lymph node fine-needle aspiration specimens for 2011 through 2012. Of 246 selected cases, 26 featured a limited amount of material in cell blocks. MT increased significantly between 2011 and 2012 and was requested in 39.4% of cases (97 of 246 cases): 86 of those cases had at least 1 MT result and 11 had insufficient material for any MT. Anaplastic lymphoma kinase (ALK) testing was performed in 9 cases in which DNA was insufficient for epidermal growth factor receptor (EGFR) testing. In addition, 13 cases of adenocarcinoma/non-small cell lung carcinoma had at least 1 MT canceled because of insufficient DNA, but at the same time had an average of 3.46 immunohistochemical stains performed. Of all the cytology specimens, 10.6% featured limited material; however, no universally accepted testing sequence priority was available at the time the study was performed. As per the MTG, MT should take precedence over immunohistochemistry in cases of adenocarcinoma/non-small cell lung carcinoma. Approximately 5.3% of the specimens in the current study had insufficient material for MT while having multiple stains performed instead. The MTG also recommend performing EGFR before ALK testing; the authors found 9 cases with insufficient material for EGFR testing that had ALK testing performed. The results of the current study underscore the need for a testing prioritization algorithm in view of the MTG publication to serve as reference for both clinicians and pathologists.

Rafael OC ，Aziz M ，Raftopoulos H ，Vele OE ，Xu W ，Sugrue C ... -  《-》