Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread

Chung, Jin-Haeng; Choe, Gheeyoung; Jheon, Sanghoon; Sung, Sook Whan; Kim, Tae Jung; Lee, Kyungwon; Lee, Jae-Ho; Lee, Choon Taek

doi:10.1097/jto.0b013e3181bc9731

Cited by 98 publications

(75 citation statements)

References 20 publications

(28 reference statements)

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“…Subsequently, in 2007, Yoshida et al (43) reported that EGFR mutations exhibited no correlation with the appearance or increase in consolidation within pGGO. In 2009, Chung et al (44) examined 56 pulmonary nodules presented with GGO from 24 patients to analyze the mutation status of the EGFR and KRAS genes and any pathological-radiological correlations. The authors found that the rate of EGFR mutation was 38.4% in pGGO cases, 41.6% in mGGO cases and 50% in sGGO cases, while only two KRAS mutations were identified in sGGO cases.…”

Section: Discussionmentioning

confidence: 99%

Impact of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage IA adenocarcinoma of the lung: Correlation between computed tomography images and EGFR and KRAS gene mutations

Wang

Zhang

Han

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to compare pathological diagnoses, as determined by the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification, with conventional radiological features. In addition, the present study aimed to evaluate the correlation among clinical characteristics, computed tomography (CT) images and gene mutation status in patients with stage IA adenocarcinoma of the lung. A total of 212 patients with stage IA lung adenocarcinoma were included in the study. The patients were classified into pure ground-glass opacity (pGGO), mixed GGO (mGGO) and solid GGO (sGGO) by CT imaging. Histological subtype was classified according to the IASLC/ATS/ERS classification of lung adenocarcinoma. In addition, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) mutation assays were performed, and 36.8% of patients (78/212) were determined to have an EGFR mutation, while 8.5% of patients (18/212) were found to have a KRAS mutation. According to the IASLC/ATS/ERS classification, 44 cases were diagnosed as adenocarcinoma in situ (AIS; 20.8%), 62 cases were diagnosed as minimally invasive adenocarcinoma (MIA; 29.2%) and 106 cases were classified as invasive adenocarcinoma (IAC; 50.0%). pGGO image patterns were observed in 39.2% of patients (n=83), while mGGO and sGGO patterns were observed in 28.8% (n=61) and 32.0% (n=68) of patients, respectively. From pGGO to sGGO, cases of AIS and MIA were shown to have a decreasing trend, while IAC cases exhibited an increasing trend (P=0.036). Analysis of the correlation between CT image patterns and gene mutations demonstrated that L858R point mutations, exon 19 deletions and KRAS mutations were more common in lesions with a lower GGO proportion (P=0.029, 0.027 and 0.018, respectively). Therefore, according to the IASLC/ATS/ERS classification, GGO imaging patterns were shown to correlate with subtypes of adenocarcinomas. In addition, EGFR and KRAS mutations were found to be associated with lesions with a low GGO proportion. Therefore, analysis of GGO lesions may offer useful indications of the histological subtype of an adenocarcinoma in patients with stage IA lung adenocarcinoma, and predictive value for EGFR and KRAS mutations.

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Section: Discussionmentioning

confidence: 99%

Impact of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage IA adenocarcinoma of the lung: Correlation between computed tomography images and EGFR and KRAS gene mutations

Wang

Zhang

Han

et al. 2015

Experimental and Therapeutic Medicine

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“…The development of peripheral pulmonary ADC involves multiple genetic alterations [3]. Mutations of epidermal growth factor receptor (EGFR) or K-ras genes have been detected in preinvasive lesions such as AAH, AIS (formerly BAC), and ADC [2,[4][5][6][7][8][9][10][11][12]. Somatic mutations and increased expression of p53 were detected in advanced ADC [13].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profile during multistage progression of pulmonary adenocarcinomas

et al. 2011

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Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.

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“…Suda et al reported that the expression of EGFR mutant protein and EGFR gene copy number do not change as a consequence of tumor progression, based on biopsy specimens from metastases as a surrogate for primary tumor (13). However, as described above, the heterogeneity in the EGFR mutation status is increased in patients with multiple primary lung cancer (3)(4)(5). Chen et al reported that the EGFR mutation discordance rates in paired multiple pulmonary nodules was 24.4% (5).…”

Section: Discussionmentioning

confidence: 99%

“…Some studies have reported cases of multiple synchronous lung cancer possessing different driver mutations in each lesion (3)(4)(5). However, most of those cases were double primary cancer, and resected triple synchronous primary lung cancer with different EGFR mutations is rare (just 1 case in 59; 1.7%).…”

Section: Discussionmentioning

confidence: 99%

A case of different EGFR mutations in surgically resected synchronous triple lung cancer

et al. 2018

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We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases. At eight months after surgery, a new lesion emerged in the right lower lobe. Given that the most advanced tumor had an EGFR del-19 mutation, the patient was orally administered afatinib. Since then, the treatment response of the patient has been assessed as stable disease (SD) for about two years. This is a very rare case of resected triple synchronous primary lung cancer on the same lung side in which the lesions all had a different EGFR mutation status, and this report highlights the clinical utility of surgical resection of multifocal lung nodules without lymph node metastasis or distant metastasis in order to optimize therapy for patients with known driver mutations.

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Epidermal Growth Factor Receptor Mutation and Pathologic-Radiologic Correlation Between Multiple Lung Nodules with Ground-Glass Opacity Differentiates Multicentric Origin from Intrapulmonary Spread

Cited by 98 publications

References 20 publications

Impact of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage IA adenocarcinoma of the lung: Correlation between computed tomography images and EGFR and KRAS gene mutations

Impact of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage IA adenocarcinoma of the lung: Correlation between computed tomography images and EGFR and KRAS gene mutations

DNA methylation profile during multistage progression of pulmonary adenocarcinomas

A case of different EGFR mutations in surgically resected synchronous triple lung cancer

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