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UbiquitinC-terminal hydrolase-L1 (UCH-L1) is a cysteine hydrolase. It functions as a ubiquitin hydrolase, stabilizes the ubiquitin monomer, and affects cell division through cell cycle protein deubiquitination. Abnormal UCH-L1 expression is closely related to the occurrence and development of several tumors. Although some in vitro studies have demonstrated the significance of UCH-L1 in non-small-cell lung cancer (NSCLC), only few clinical studies have focused on the UCH-L1 expression in NSCLC, and the results are controversial and non-uniform. We investigated the UCH-L1 expression in 401 cases of surgically resected NSCLC, including 286 cases of adenocarcinoma (ADC) and 65 cases of squamous cell carcinoma. The associations between the UCH-L1 expression and clinicopathological features, programmed cell death-ligand 1 (PD-L1) expression, and prognostic significance were analyzed. For NSCLC, the UCH-L1 expression is associated with sex, smoking history, tumor size (>3 cm), lymphocyte infiltration, advanced pathological stages, and shortened overall survival (OS; 89.72 vs. 114.55 months; P = 0.005), but not PD-L1 expression. The UCH-L1 expression in ADC is associated with advanced pathological stages, pleural invasion, and shortened OS (90.38 vs. 118.55 months; P = 0.010). Multivariate analysis confirmed that UCH-L1 expression was an independent poor prognostic factor for NSCLC (OS: hazard ratio [HR], 1.854; 95% confidence interval [CI], 1.132-3.038; P = 0.014). Our results suggest that the UCH-L1 expression differs across tumors with different clinicopathological features, and it is related to poor prognosis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are both small tumors with good prognosis after surgical resection, and most of them present as ground glass opacities (GGOs) on computed tomography (CT) screening. However, the differences in clinicopathologic features and genetic alterations between AIS and MIA are poorly elaborated, and few studies have evaluated the prognosis of MIA with different invasive components. Meanwhile, the histological features of lung lesions presenting as unchanged pure GGOs are barely understood., Methods: Clinicopathologic features and genetic alterations of AIS (n = 59) and MIA (n = 62) presenting as GGOs were analyzed. Long-term preoperative observation (ranging from 2 to 1967 days) and postoperative follow-up (ranging from 0 to 92 months) was conducted., Results: The tumor size and consolidation/tumor ratio were significantly larger in the MIA cohort than those in the AIS cohort both on CT and microscopy images. Immunohistochemically, the expression of p53, Ki67, and cyclin D1 was higher in MIA than in AIS. The EGFR mutation rate was significantly higher in MIA, while other genetic alterations showed no differences. Six MIA cases showed recurrence or metachronous adenocarcinoma and all the cases with a predominant micropapillary invasive pattern demonstrated this feature., Conclusions: The current CT measurements may be helpful in distinguishing AIS from MIA, but show limited utility in predicting the histology of unchanged pure GGOs. The invasive pattern may have an influence on the postoperative process of MIA; therefore, further studies are needed to evaluate the current diagnostic criteria and treatment strategy for MIA.

Background: This study aimed to comprehensively investigate the effect of spread through air spaces (STAS) on clinicopathologic features, molecular characteristics, immunohistochemical expression, and prognosis in lung adenocarcinomas (ADC) and squamous cell carcinomas (SQCC) based on the 8th edition AJCC/UICC staging system., Methods: In total, 303 ADC and 121 SQCC cases were assessed retrospectively. Immunohistochemical staining was performed for E-cadherin, vimentin, Ki67, survivin, Bcl-2, and Bim. Correlations between STAS and other parameters were analyzed statistically., Results: STAS was observed in 183 (60.4%) ADC and 39 (32.2%) SQCC cases. In ADC, the presence of STAS was associated with wild-type EGFR, ALK and ROS1 rearrangements, low E-cadherin expression, and high vimentin and Ki67 expression. In SQCC, STAS was associated with low E-cadherin expression and high vimentin and survivin expression. Based on univariate analysis, STAS was associated with significantly shorter disease-free survival (DFS) and overall survival (OS) in ADC. In SQCC, STAS tended to be associated with shorter OS. By multivariate analysis, STAS was an independent poor prognostic factor in ADC for DFS but not OS. Stratified analysis showed that STAS was correlated with shorter DFS for stage I, II, IA, IB, and IIA ADC based on univariate analysis and was an independent risk factor for DFS in stage I ADC cases based on multivariate analysis., Conclusions: Our findings revealed that STAS is an independent negative prognostic factor for stage I ADC using the new 8th edition AJCC/UICC staging system. Stage I patients with STAS should be followed up more closely and might need different treatment strategies.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Despite significant advances in its research of tumor biology and therapy, the prognosis for this neoplasm has still remained poor. The great majority of anticancer agents, regardless of their mechanisms of action, exert their lethal actions on cancer cells by inducing apoptosis following drug-induced cellular damage. Many reported studies have evaluated the prognostic and therapeutic implications of apoptosis in lung cancer, but their exact clinical value has remained unclear. Therefore more prospective studies are currently required to further validate apoptosis as prognostic and predictive biomarkers in lung cancer patients. The current study reviewed the studies on the prognostic and predictive significances of Bcl-2 family proteins in NSCLC. We also discussed potential treatment strategies which could target apoptotic proteins in lung carcinoma cells. Exception for Bcl-2 itself, studies of the prognostic significance of other Bcl-2 family proteins is markedly limited. The abundance of literature suggests that targeting apoptosis in NSCLC is feasible. However, many troubling questions arise with the use of new drugs or treatment strategies, and new biomarkers are needed., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Cancer stem cells (CSCs) are a small subset of tumor cells that exhibit stem cell-like properties and contribute in treatment failure. To clarify the expression and prognostic significance of several CSC markers in non-small cell lung cancer, we retrospectively analyzed 368 patients with adenocarcinoma (n = 226) or squamous cell carcinoma (n = 142). We correlated the expression of six CSC markers - CD133, CD44, aldehyde dehydrogenase 1 (ALDH1), sex determining region Y-box 2 (SOX2), octamer binding transcription factor 4 (OCT4), and Nanog - with clinicopathologic and molecular variables and survival outcomes. In adenocarcinoma, CD133, ALDH1 and CD44 expression was associated with low pathologic stage and absence of lymphovascular invasion, while Nanog expression correlated with high histologic grade, lymphatic invasion and increased expression of Snail-1, a transcription factor associated with epithelial-mesenchymal transition. CSC marker expression was also associated with histologic subtypes in adenocarcinoma. Multivariate analysis showed that high Nanog expression was an independent factor associated with a poor prognosis in adenocarcinoma. CSC markers had no prognostic value in squamous cell carcinoma. These results suggest that Nanog is an independent negative prognostic factor that may be associated with epithelial-mesenchymal transition in lung adenocarcinoma., Competing Interests: The authors declare no conflicts of interest.

Background: Sodium-potassium-chloride cotransporter isoform 1 (NKCC1) is an active ions cotransporter and modulates cellular volume and migration. NKCC1 blockers can inhibit cancer cell growth., Aim: We aimed to elucidate the expression and prognostic significance of NKCC1 in non-small cell lung cancer (NSCLC)., Methods: We retrospectively analyzed 788 NSCLC patients with either adenocarcinoma (n = 503) or squamous cell carcinoma (n = 285) by immunohistochemistry to correlate NKCC1 expression with clinicopathologic and survival outcomes., Results: In adenocarcinoma, high NKCC1 expression was associated with larger tumor size (P = 0.013), vascular invasion (P < 0.001), lymphatic invasion (P < 0.001), perineural invasion (P = 0.019) and advanced pathologic stage (P < 0.001), but there are no significant correlations between NKCC1 expression and clinicopathological parameters in squamous cell carcinoma. Patients with high NKCC1 expression had significantly shorter disease-free survival (DFS;P < 0.001) and shorter overall survival (OS;P < 0.001) than those with low NKCC1 expression in adenocarcinoma. In squamous cell carcinoma, NKCC1 expression was not associated with prognosis. Multivariate analysis revealed that high NKCC1 expression was an independent prognostic factor for DFS in lung adenocarcinomas (HR, 1.709; 95% CI 1.029-2.130;P = 0.033) and for OS inEGFR-mutated adenocarcinoma patients (HR, 3.165; 95% CI 1.424-7.035;P = 0.005)., Conclusion: NKCC1 high expression predicted a bad clinical outcome for lung adenocarcinoma patients andEGFR-mutated subgroup. Therefore, NKCC1 may play a role in lung adenocarcinoma and novel therapeutic tactics could be developed by targeting NKCC1 protein., (© The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: ROS1 rearrangement has been found in a subset of lung cancer and ROS1-rearranged tumors are sensitive to ALK kinase inhibitors. This study sought to evaluate the clinicopathological implications and histomorphological characteristics of ROS1-rearranged tumors, especially micropapillary and aerogenous spread growth and to investigate the usefulness of ROS1 immunohistochemistry as a diagnostic test for ROS1 rearrangement., Materials and Methods: ROS1 rearrangement characterizations by fluorescence in situ hybridization and ROS1 protein and E-cadherin expression by immunohistochemistry were performed using 754 non-small cell lung cancer surgical specimens., Results: ROS1 rearrangement was identified in 10 samples. Histologically, all 10 ROS1-rearranged tumors harbored an adenocarcinoma component. Significantly, we noted a high association between ROS1 rearrangement with a micropapillary component (p<0.001), aerogenous spread (p=0.002), and E-cadherin loss (p=0.049). Survival analysis showed that ROS1 rearrangement was significantly associated with a higher risk of tumor recurrence (p=0.024). The best criterion to detect ROS1-rearrangement by immunohistochemistry was an H-score of ≥100, with a sensitivity and specificity of 90% and 93.5%, respectively., Conclusions: ROS1-rearranged adenocarcinoma exhibited distinct morphological and clinicopathological features. Decreased membranous E-cadherin expression and aerogenous spread may be associated with worse disease-free survival. ROS1 immunohistochemistry correlated well with ROS1 gene rearrangement., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

ROS1 has attracted much attention as a possible oncogenic driver and ROS1-rearranged tumors show sensitivity to most ALK inhibitors. We aimed to clarify the prevalence of ROS1 gene rearrangement and investigate the clinical implications of ROS1 gene copy number gain (CNG) in non-small cell lung cancer (NSCLC) patients. We carried out fluorescent in situ hybridization with ROS1 and centromere enumeration 6 probes and immunohistochemistry for ROS1 protein expression. ROS1 rearrangement was detected in 3 of 375 samples (0.8 %); all of whom were female, never-smokers, and harbored an adenocarcinoma component. ROS1 gene CNG was found in 18 cases (4.8 %). ROS1 gene CNG was significantly associated with shorter disease-free survival (DFS, 12 vs. 58 months; p = 0.003) and shorter overall survival (OS, 40 vs. 67 months; p <0.001) than the group without CNG. Multivariate analysis confirmed that ROS1 gene CNG was significantly associated with poorer DFS (hazard ratio [HR]=2.16, 95 % confidence interval [CI] = 1.22-3.81, p = 0.008), and OS ([HR] = 2.53, 95 % [CI] = 1.31-4.89, p = 0.006). ROS1 protein overexpression was observed in 5.0 % (18 out of 357), of which 2 cases harbored ROS1 gene rearrangement. There was no statistically significant correlation between ROS1 gene CNG and protein overexpression. This study demonstrated ROS1 gene rearrangement was detected in 0.8 % of surgically resected NSCLC; and ROS1 gene CNG is an independent poor prognostic factor. This survival analyses may contribute to future studies on the utility of ROS1-targeted therapy for patients.

Background: Yes-associated protein (YAP) has been reported to be associated with the prognosis of various cancers and also to affect epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) activity in ovarian cancer cell lines. However, few studies have evaluated YAP protein expression in lung cancer, and the results have lacked consistency., Methods: YAP expression was evaluated in a total of 205 curatively resected lung adenocarcinomas and 36 cases of EGFR-mutated TKI-treated patients. Correlations between the expression of YAP and clinicopathologic features, response to EGFR-TKI treatment, and prognostic significance were analyzed., Results: High cytoplasmic YAP expression was positively correlated with the clinicopathologic parameters that have been associated with favorable prognosis. Multivariate analysis revealed that high cytoplasmic YAP expression was an independent prognostic factor in lung adenocarcinomas (progression-free survival: hazard ratio [HR] 0.659; 95 % confidence interval [CI] 0.431-1.010; p = 0.050; overall survival: HR, 0.474; 95 % CI 0.263-0.854; p = 0.013) and EGFR-TKI-treated patients with EGFR mutation (progression-free survival: HR, 0.346; 95 % CI 0.146-0.818; p = 0.016; overall survival: HR, 0.291; 95 % CI 0.125-0.676; p = 0.004)., Conclusions: High cytoplasmic YAP expression predicted a good clinical outcome for patients with lung adenocarcinoma and in EGFR-TKI-treated patients. Therefore, YAP may play a role in EGFR-TKI-treated lung cancer, and YAP targeting may enhance therapeutic effects in combination with other cancer drugs.

FGFR1 amplification has been identified recently as an important therapeutic target in non-small-cell lung cancer (NSCLC), particularly squamous cell carcinoma (SqCC). However, data from previous studies on the clinical implications of FGFR amplification in NSCLC are inconsistent. We evaluated FGFR1 gene copy number (GCN) in 369 cases of surgically resected NSCLC using five previously reported criteria and investigated associations between clinicopathologic parameters and FGFR1 amplification. FGFR1 amplification was found in 32/369 (8.7 %) of NSCLC and was more frequent in SqCC (18.0 % in SqCC, 3.0 % in adenocarcinoma; p < 0.001) and in smokers (p < 0.001). On univariate analysis, FGFR1 amplification was significantly associated with shorter overall survival (OS, 58.6 vs 80.0 months; p = 0.033) and shorter disease-free survival (DFS, 58.5 vs 80.0 months; p = 0.042) in patients with SqCC, but this was not statistically significant on multivariate analysis (OS: hazard ratio [HR] = 1.79, 95 % confidence interval [CI] = 0.83-3.87, p = 0.139; DFS: HR = 1.73, 95 % CI = 0.93-3.21, p = 0.081). The correlation between FGFR1 amplification and protein expression was poor (rho = 0.08; p = 0.123). These results suggest that FGFR1 amplification is associated with smoking history and squamous cell carcinoma histology and might indicate poor prognosis.

Objectives: Activating mutations in the epidermal growth factor receptor (EGFR) kinase domain are correlated with dramatic clinical responses in non-small cell lung cancer patients treated with EGFR-tyrosine kinase inhibitors (TKIs). The two most common EGFR mutations, representing 85-90% of EGFR mutations, are the E746&#95;A750 deletion in exon 19 and the L858R point mutation in exon 21. We conducted this study to evaluate the suitability of mutation-specific antibodies that can detect E746&#95;A750 deletion and L858R mutant EGFR proteins by immunohistochemistry (IHC)., Materials and Methods: In a cohort of consecutive patients with surgically resected lung adenocarcinomas (n=240), mutant EGFR protein expression was assessed by IHC using specific antibodies (clone SP111 and SP125) to the 2 major forms of EGFR mutations. Immunoreactivity was scored as 0-3, and the results were compared with the EGFR-mutational status., Results: With a cutoff value of IHC 2+ for SP 111 (anti-EGFR E746&#95;A750 del antibody) and SP 125 (anti-EGFR L858R antibody), both antibodies showed high specificity (99.0% and 89.7%, respectively) and sensitivity (70.6% and 80.4%, respectively). While cases with IHC scores of 3 using these 2 antibodies positively correlated with the EGFR-mutational status, cases with IHC scores lower than 3+ showed variable results regarding EGFR-mutational status., Conclusion: Although each antibody showed relatively high specificity, some EGFR-mutant cases were not detected by the mutation-specific antibodies. Various forms of exon 19 deletions, except E746&#95;A750, were rarely detected by the mutant-specific antibody. Therefore, IHC-negative cases require further molecular analysis to confirm the presence of EGFR mutations., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: MET gene copy number gain (CNG) and protein overexpression have been reported in lung cancer, but the clinical implications in early stage adenocarcinoma remain unclear., Methods: We investigated MET gene copy number and protein expression in 141 cases of surgically resected stage I pulmonary adenocarcinoma. MET gene CNG was determined by silver in situ hybridization, and MET protein expression was assessed by immunohistochemistry. The correlation between MET gene CNG/protein expression and clinicopathologic parameters and prognostic significance was analyzed., Results: MET gene CNG was found in 24.1% (34 of 141) of the cases and was associated with larger tumor size, pleural invasion, and lymphatic vessel invasion. MET gene CNG was inversely correlated with the presence of lepidic subtype (r = -0.17, p = 0.045) and was not associated with EGFR, KRAS mutation, or ALK gene rearrangement. In addition, MET gene CNG was significantly associated with shorter disease-free survival (DFS) (49 vs. 75 months; p < 0.001) and shorter overall survival (OS) (65 vs. 78 months; p = 0.01). Multivariate analysis confirmed that MET gene CNG was significantly associated with poorer DFS [p < 0.001; hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.2-13.9] but was not significantly associated with OS. MET overexpression was observed in 71.3% of cases (97 of 136), but it was not correlated with gene CNG., Conclusions: MET gene CNG is an independent poor prognostic factor in patients with stage I lung adenocarcinoma. It is associated with aggressive pathologic features and is inversely correlated with the presence of lepidic subtype.

Background: Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790 M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50 % of patients, but the remaining mechanisms are unknown., Methods: Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification., Results: Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p = 0.005) and shorter overall survival (p = 0.059). Additionally, β-catenin alteration was associated with a poor ORR (p = 0.012). Of the metastatic tumours, three cases (37.5 %) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss and two cases (25 %) demonstrated MET/EGFR amplification., Conclusions: Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.

Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn't find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p = 0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p = 0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p = 0.837, OS; 61.0 vs. 62.4 months; p = 0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123-2.532; p = 0.012; OS: HR, 1.965; 95 % CI, 1.108-3.486; p = 0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p > 0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.

Background: Activating mutations in the epidermal growth factor receptor (EGFR) in non-small cell lung carcinoma (NSCLC) are associated significantly with responsiveness to EGFR tyrosine kinase inhibitors. The objective of this study was to investigate the suitability of cytologic specimens for assessing EGFR mutations in lung adenocarcinomas., Methods: Sixty paired histologic and cytologic specimens of lung adenocarcinoma were collected. Exons 18 through 21 of the EGFR gene were amplified using polymerase chain reaction, and the mutation status of each sample was analyzed by pyrosequencing. A comparison of EGFR mutation status between histologic specimens and cytologic specimens was performed., Results: The overall EGFR mutation concordance rate between histologic specimens and corresponding cytologic specimens was 91.7%. No significant difference was observed in the concordance rate between cytologic specimens from primary lesions and specimens from metastatic lesions (P = .63). The following parameters were correlated with the most reliable EGFR mutation results using the pyrosequencing method (100% concordance with the corresponding histologic specimens) in cytologic samples: a DNA concentration >25 ng/μL, content of >30 tumor cells, or a tumor percentage >30%., Conclusions: In this study, routinely prepared cytologic specimens were reliable sources for assessing EGFR mutation status. The authors concluded that cytologic specimens from metastatic lesions and primary tumors are suitable for the successful assessment of EGFR mutation status., (Copyright © 2012 American Cancer Society.)

Aims:   The anaplastic lymphoma kinase gene (ALK) has attracted considerable attention as a potential molecular target in non-small-cell lung cancer (NSCLC). However, it is unclear whether ALK alterations are acquired during the metastatic progression of NSCLC., Methods and Results:   ALK status and ALK expression were evaluated in a series of 67 primary NSCLCs and their corresponding metastatic lesions using fluorescence in-situ hybridization and immunohistochemistry. ALK rearrangement was detected in 7.5% (5/67) of the primary tumours and in 9.0% (6/67) of the metastases (P < 0.001). ALK copy number gain (CNG) was detected in 1.5% (1/67) of the primary tumours and in 35.8% (24/67) of the metastases. Whereas ALK rearrangement was detected only in adenocarcinomas, CNG was identified in various histological subtypes of NSCLC. ALK expression was detected in 11.9% (8/67) of the primary tumours and in 25.4% (17/67) of the metastatic lesions., Conclusions:   ALK alteration and ALK expression can be acquired during metastatic progression in NSCLC, and ALK CNG is associated with ALK expression., (© 2012 Blackwell Publishing Limited.)

Introduction: Epidermal growth factor receptor (EGFR) mutation has been known to be associated with adenocarcinoma with bronchioloalveolar carcinoma (BAC; lepidic) feature. This study was aimed to characterize the frequency of EGFR mutations and their association with histologic subtypes in Korean nonsmall cell lung cancer (NSCLC) patients., Methods: Three hundred eighty-two (88 biopsies and 294 resections) NSCLC patients were investigated for EGFR mutations (exons 18-21) by polymerase chain reaction and direct sequencing method. For the resected adenocarcinoma specimens, histologic subtypes were classified according to both 2004 World Health Organization classification and 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification. The results were correlated with EGFR mutation and clinicopathologic features., Results: EGFR mutations were detected in 196 of 382 NSCLCs (51.3%) and were more frequent in women than in men (65.7% versus 34.3%, p < 0.001) and in nonsmokers than in smokers (63.4% versus 32.0%, p < 0.001). Regarding histologic subtypes of adenocarcinoma, mixed acinar and BAC pattern showed the most frequent EGFR mutation (67.6%), followed by mixed papillary and acinar (65.2%), mixed solid and acinar (38.2%), micropapillary and acinar (30.4%), and acinar and mucinous BAC (13.3%). In addition, EGFR mutations were more frequently observed in tumors with BAC or papillary components than those with mucinous BAC or solid components. Identical EGFR mutations were detected in a single tumor showing mixed histological features. EGFR protein expression was seen more frequently in tumors with EGFR mutations than those without EGFR mutations (75.3% versus 24.7%, p=0.003). EGFR mutations were significantly more common in tumors with thyroid transcription factor-1 (TTF-1) expression than those without TTF-1 (p < 0.001), and almost all (92.7%) mutated adenocarcinomas were TTF-1 positive., Conclusions: The incidence of EGFR mutations is variable according to histologic subtypes, gender, and smoking history. The mixed acinar and BAC and papillary and acinar subtypes, the presence of BAC (lepidic) or papillary components, EGFR, and TTF-1 protein expression can predict higher EGFR mutation in lung adenocarcinoma. However, intratumoral heterogeneity of EGFR mutation was not found. In addition, relatively high incidence of EGFR mutations in Korean men who smoked with adenocarcinoma histology suggests that these patients should not be left behind EGFR mutation test.

Introduction: The Wnt signaling pathway plays a major role in cancer development and progression. As a novel anticancer drug can be developed using inhibitors of this pathway, we investigated the clinical significance of the Wnt signaling pathway molecules in non-small cell lung cancer (NSCLC)., Methods: Immunohistochemical analysis of a tissue microarray with 262 resected NSCLC specimens was performed to study the expression and subcellular localization of Wnt1 in relation to downstream molecules, including GSK-3β, β-catenin, c-Myc, cyclin D1, and p53. These results were correlated with other clinicopathologic features., Results: Cytoplasmic Wnt1 overexpression was detected in 36.6% (96 of 262) NSCLCs, and aberrant β-catenin staining was identified in 76% (189 of 262) of NSCLCs. There were significant associations between Wnt1 expression and altered expression of β-catenin (p = 0.034), overexpression of c-Myc (p < 0.001), or overexpression of cyclin D1 (p = 0.018). While there was no significant association between Wnt1 or β-catenin and stage, the 5-year survival was significantly lower in patients with Wnt1- and β-catenin-positive NSCLCs than negative NSCLCs (p < 0.05, respectively). In multivariate analysis, stage and Wnt1+/β-catenin+ expression were independent prognostic factors of overall survival (p < 0.05)., Conclusion: These findings show that Wnt1 expression may be one of the possible mechanisms of the activation of the canonical Wnt/β-catenin signaling pathway in NSCLC, and Wnt1 and altered β-catenin expression are poor prognostic markers, independent of stage.