Epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements in lung cancer with nodular ground-glass opacity

BMC Cancer Epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements in lung cancer with nodular ground-glass opacity Sung-Jun Ko 1 Yeon Joo Lee 0 1 Jong Sun Park 0 1 Young-Jae Cho 0 1 Ho Il Yoon 0 1 Jin-Haeng Chung 2 Tae Jung Kim 5 Kyung Won Lee 5 Kwhanmien Kim 4 Sanghoon Jheon 4 Hyojin Kim 3 Jae Ho Lee 0 1 Choon-Taek Lee 0 1 0 Department of Internal Medicine, Seoul National University Bundang Hospital , 173-82 Gumi-Ro, Bundang-Gu, Seongnam 464-707 , Korea 1 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital , Seongnam , Korea 2 Department Pathology, Seoul National University College of Medicine , Seongnam , Korea 3 Department of Pathology, Seoul National University Hospital , Seoul , Korea 4 Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital , Seongnam , Korea 5 Department of Radiology, Seoul National University Bundang Hospital , Seongnam , Korea Background: Nodular ground-glass opacities (nGGO) are a specific type of lung adenocarcinoma. ALK rearrangements and driver mutations such as EGFR and K-ras are frequently found in all types of lung adenocarcinoma. EGFR mutations play a role in the early carcinogenesis of nGGOs, but the role of ALK rearrangement remains unknown. Methods: We studied 217 nGGOs resected from 215 lung cancer patients. Pathology, tumor size, tumor disappearance rate, and the EGFR and ALK markers were analyzed. Results: All but one of the resected nGGOs were adenocarcinomas. ALK rearrangements and EGFR mutations were found in 6 (2.8%) and 119 (54.8%) cases. The frequency of ALK rearrangement in nGGO was significantly lower than previously reported in adenocarcinoma. Advanced disease stage (p = 0.018) and larger tumor size (p = 0.037) were more frequent in the ALK rearrangement-positive group than in ALK rearrangement-negative patients. nGGOs with ALK rearrangements were associated with significantly higher pathologic stage and larger maximal and solid diameter in comparison to EGFR-mutated lesions. Conclusion: ALK rearrangement is rare in lung cancer with nGGOs, but is associated with advanced stage and larger tumor size, suggesting its association with aggressive progression of lung adenocarcinoma. ALK rearrangement may not be important in early pathogenesis of nGGO. Lung cancer; Adenocarcinoma; nGGO; ALK; EGFR - Background Low-dose chest computed tomography (CT) for lung cancer screening has increased the detection of solitary pulmonary nodules (SPN) not visualized on chest radiography, and has contributed to a reduction in lung cancer mortality [1]. Some of these visualized nodules are nodular ground-glass opacities (nGGOs). nGGOs on chest CT are defined as hazy, increased attenuation of the lung with preservation of bronchial and vascular margins, and are classified as pure and mixed GGOs, which contain a solid component [2]. Nodular GGOs can be found in eosinophilic lung disease, pulmonary lymphoproliferative disorder, and interstitial fibrosis, with a persistent nGGO being a possible sign of early lung cancer [3]. The natural development of nGGO follows a stepwise progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS: formerly bronchioloadenocarcinoma), to microinvasive adenocarcinoma (MIA), and finally to invasive adenocarcinoma (IA) [4]. However, some adenocarcinomas do not follow this pathway, manifesting as consolidation and/or solid mass, with different genetic profiles. Therefore, lung adenocarcinoma exhibits heterogeneity in pathogenesis and progression [5]. Several driver mutations have been identified in lung cancer, such as epidermal growth factor receptor (EGFR) and K-ras mutations and anaplastic lymphoma kinase (ALK) rearrangement. Lung cancers expressing EGFR mutations respond well to the EGFR tyrosine kinase inhibitors [6-8]. The fusion of echinoderm microtubuleassociated protein-like 4 (EML4) and ALK gene by rearrangement in non-small cell lung cancer was identified [9] and developed as a target of the ALK tyrosine kinase inhibitor, crizotinib [10,11]. These biomarkers predict response to these molecular targeting agents and testing for these markers is recommended in lung cancer patients [12,13], enabling personalized medicine for patients harboring EGFR mutations or ALK gene rearrangements. It is therefore very important to investigate the frequencies and clinical implications of these driver mutations in nGGOs, a specific type of lung adenocarcinoma. Many studies have reported that EGFR mutations are frequent in lung cancer with nGGOs, even in precancerous lesions such as AAH [14-17]; however, the role of ALK rearrangement in nGGOs remains unknown. We analyzed patients with lung cancer with nodular GGOs to investigate the correlation between biomarker status and clinicopathological and radiologic characteristics and to determine the roles of ALK rearrangements and EGFR mutations in nGGOs. Methods Patients Among the patients who underwent surgical resection of their CT-identified nGGOs between August 2008 and March 2013 at Seoul National University Bundang Hospital (SNUBH), we selected patients who were diagnosed with lung cancer by pathologic confirmation of the surgical specimen. Multiple nGGOs in a single patient were considered different cases of nGGO. Patient data were extracted from medical records, including those pertaining to the age at the time of surgery, sex, smoking history quantified by packs per year, tumor histology, pathologic tumor stage, and biomarker status. This study was approved and individual patient consent waived by the institutional review board of Seoul National University Bundang Hospital (B-1305-202-102). Radiologic evaluation Chest CT scans were performed preoperatively in each patient. All CT images were reviewed with a pulmonary window setting (window width, 2000 HU; window level, 500 HU) and mediastinal window setting (window width 440 HU, window level 45 HU). GGOs appear in pulmonary window images of chest CT, but disappear on mediastinal window images [3]. We included all nodules that contained any amount of GGO. To evaluate the proportion of the solid component in the nGGOs, we measured the maximum transverse diameter (Tmax) and maximum perpendicular diameter (Pmax) of both the pulmonary and mediastinal window settings (pTmax, mTmax, pPmax, mPmax) and calculated the tumor shadow disappearance rate (TDR) in all nGGOs. TDR was calculated using the following formula: TDR = 1 (mTmax mPmax /pTmax pPmax) [18]. Histopathology review Surgical specimens were reviewed by an experienced pathologist (J-H Chung) and another pathologist (H Kim). TNM classification was performed according to the Union for International Cancer Control and the American Joint Committee on Cancer staging system, 7th edition [19]. In some participants, lymph node dissection was not performed because lymphatic invasion was deeme (...truncated)