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Objectives: Lung adenocarcinomas are a heterogeneous set of diseases with distinct genetic and histologic characteristics. Besides the discovery of oncogenic mutations and introduction of the histologic classifications (2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society and 2015 WHO), increasing evidence has linked this intertumor heterogeneity to the lung lineage-specific pathways and lineage genes. Therefore, in this study, we assessed the gene expression of identified lung lineage genes to study their role in distinguishing lung adenocarcinoma diversities., Methods: A total of 278 surgically resected lung adenocarcinomas were included. Each case was evaluated for genetic mutations and histologic classification. Lineage genes associated with respiratory tract differentiation (NK2 homeobox 1 gene [NKX2-1], GATA protein binding 6 gene [GATA6], foxhead box J1 gene [FOXJ1], and SAM pointed domain containing ETS transcription factor gene [SPDEF]) and stem/basal-like status (inhibitor of DNA binding 2, HLH protein gene [ID2], POU class 5 homeobox 1 gene [POU5F1], SRY-box 2 gene [SOX2], and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC]) were selected. mRNA expression of these genes in each tumor sample was assessed by quantitative real-time polymerase chain reaction and normalized to paired normal lung tissue., Results: Distinct lineage gene expressions were found on the basis of genetic and histologic diversities. Expression of NKX2-1, GATA6, FOXJ1, and POU5F1 exhibited a significant linear relationship across histologic subgroups that was independent of genetic mutation status. Expression levels of NKX2-1 and POU5F1 were also associated with EGFR mutation status, independent of histologic subtypes. Further analysis revealed that the overexpression of SPDEF defined longer relapse-free survivals, especially in stage I disease., Conclusions: For the first time, we showed the unique lineage backgrounds of different histologic subtypes and oncogenic mutations. Assessing this added parameter might be beneficial in discriminating intertumor heterogeneity, advancing target exploration, developing theranostic/prognostic biomarkers, and designing clinical trials., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Lung adenocarcinoma with micropapillary and solid predominant subtypes was reported to be associated with poor prognosis; however, whether minor components (non-predominant) of micropapillary and solid subtypes predict poor prognosis remains unknown. In this study, we investigated the predictive and prognostic value of lymph node metastasis of minor micropapillary and solid components., Methods: Specimens of resected tumors of 1244 patients were reclassified to determine the predominant subtype and minor components (>5 %, but not predominant). Of these specimens, 105 contained a micropapillary component and 210 contained a solid component. The correlation between each subtype and lymph node metastasis was analyzed, and survival analyses were used to determine the association between each subtype and patient survival., Results: Adenocarcinomas harboring micropapillary and/or solid components held higher rates of metastatic lymph node stations (25.2 % vs. 15.6 %, p = 0.002; and 24.0 % vs. 14.9 %, p < 0.001, respectively) and lymph nodes (17.3 % vs. 10.1 %, p = 0.004; and 15.5 % vs. 9.7 %, p = 0.001, respectively). Patients with micropapillary and solid components in their tumors showed a shorter median recurrence-free survival (15.8 vs. 62.8 months, p < 0.001; and 20.8 months vs. not reached, p < 0.001) and overall survival (47.0 months vs. not reached, p < 0.001; and 69.0 months vs. not reached, p < 0.001)., Conclusions: Minor components of micropapillary and/or solid subtypes of lung adenocarcinoma are correlated with lymph node metastasis and poor prognosis. Thus, it is beneficial to focus not only on predominant subtypes but also minor components to predict prognoses and make therapeutic strategies more comprehensively.

Background: The patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. The clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC., Methods: From 2005 to 2012, consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection at our institution were reviewed. For each case, full-face hematoxylin and eosin-stained sections from surgical specimens were evaluated for the TIL density. A published, recommended TIL scoring scale was followed. The patients were stratified into the TIL- or TIL+ group based on pathologic evaluation., Results: Data from 320 patients were included in the analysis. Based on a median follow-up duration of 30.8 months, a higher density of TILs was associated with an improved postoperative survival time (P = 0.06). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; P = 0.03). Among those with SCC, the TIL+ patients experienced a significantly increased 3-year distant metastasis-free survival (DMFS) compared to the TIL- patients (60.6% versus 42.7%, P = 0.02). Multivariate analyses of the 93 patients with SCC tumors confirmed that TIL+ was an independent prognostic factor for an increased DMFS (HR = 0.39, 95%CI 0.17-0.87, P = 0.02) and a prolonged overall survival (OS; HR = 0.47, 95%CI 0.22-1.00, P = 0.05)., Conclusions: Our data suggest a potential role of TILs in predicting the survival of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced in the prediction of the DMFS and the OS in patients with SCC. This parameter should be considered for prospective inclusion in clinical trials.

Introduction: Thyroid transcription factor 1 (TTF1) is a master regulator of pulmonary differentiation that is downregulated in a subset of lung adenocarcinoma, of which the clinicopathologic characteristics were not fully clarified., Methods: One thousand forty-two lung adenocarcinoma patients who underwent surgery were investigated for clinic characteristics, histologic subtyping, and spectrum of well-identified driver mutations. TTF1 expression was correlated with these clinicopathologic factors and survival., Results: Compared with TTF1 positive (TTF1+) patients, the 133 negative individuals (12.8%, TTF1-) were more likely to be male (p = 0.006) and heavy smokers (p = 0.002) who had larger tumor size (p < 0.001) and more advanced disease stage (p < 0.001). TTF1- presented more in solid and invasive mucinous-predominant carcinomas (both p < 0.001), whereas TTF1+ was identified in 100% patients with adenocarcinoma in situ, minimally invasive and lepidic-predominant adenocarcinomas. The TTF1- tumors harbored the known driver mutations in significantly low frequency compared with TTF1+ adenocarcinomas (57.8% versus 78.1%, p < 0.001), especially in epidermal growth factor receptor (EGFR) mutations (37.6% versus 60.7%, p < 0.001). There was no significant difference in recurrence-free survival between the TTF1- and TTF1+ patients, either for the whole cohort or stratified by pathologic stage, or among the driver mutation-defined subsets. However, recurrence of multiple metastases was more likely to occur in patients with TTF1- adenocarcinomas (88.1% versus 32.4%, p < 0.001). Multivariate analysis revealed that TTF1- independently predicted both poor postrecurrence survival (hazard ratio = 1.664; 95% confidence interval , 1.097-2.524; p = 0.017) and unfavorable overall survival (hazard ratio = 1.553; 95% confidence interval , 1.013-2.381; p = 0.043)., Conclusions: TTF1- correlated with solid and invasive mucinous subtypes of lung adenocarcinoma and lower frequency of EGFR mutations. It defines a subgroup of lung adenocarcinomas with unfavorable outcomes.

Objective: This study investigated the association between clinical pathologic features, especially adenocarcinoma subtypes and prognosis, and skip N2 metastasis in patients with lung adenocarcinoma., Methods: In this study, 177 patients with lung adenocarcinoma and N2 metastasis were enrolled. Patients who had N2 lymph node metastases without N1 lymph node involvement were defined as skip N2 and otherwise as non-skip N2. We investigated the difference of clinicopathologic characteristics, recurrence-free survival, overall survival, and spectrum of well-identified molecular alterations in EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET genes in the 2 groups., Results: Skip N2 metastasis was found in 45 patients, in whom a remarkably lower incidence of lymphovascular invasion was revealed (P = .01). Skip N2 metastasis was also associated with acinar subtype, good differentiation, and right lung cancer. The recurrence-free survival and overall survival were significantly better in the skip N2 group (5-year recurrence-free survival 37.4% vs 5.7%; log-rank P = .005; 5-year overall survival 60.7% vs 32.1%; log-rank P = .024). The predictive value of skip N2 was more significant in patients with lesions in the right lung (5-year recurrence-free survival 36.6% vs 0.0%; log-rank P = .002; 5-year overall survival 57.2% vs 27.9%; log-rank P = .016) and in patients whose tumor diameter was no more than 3 cm (5-year recurrence-free survival 43.1% vs 6.7%; log-rank P = .01; 5-year overall survival 74.6 vs 27.6%; log-rank P = .04)., Conclusions: There are distinct differences in clinicopathologic features and prognosis in patients with or without skip N2 metastasis. Considering the results of our study, subclassifications of mediastinal lymph node metastases could have clinical significance for patients with lung adenocarcinoma., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Lung cancer is the leading cause of cancer-related death in the world. Previous report has identified ribosomal protein s15a (RPS15A) as a TGF-β-responsible gene in the lung adenocarcinoma cell line A549. In this study, we used specific si-RNA to downregulate RPS15A expression in A549 cells and found that decreased RPS15A expression significantly inhibited cell proliferation and survival, as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assays. Moreover, A549 cells were obviously accumulated in the G0/G1 phase in response to RPS15A knockdown, suggesting that RPS15A inhibition could induce a diminution of proliferation through cell cycle arrest. In addition, immunohistochemistry analysis further revealed that RPS15A was overexpressed in surgically resected lung cancer tissues. In conclusion, we identify RPS15A as a novel potential oncogenic gene involved in lung carcinogenesis. This study may provide a preliminary experimental basis for a gene therapy approach for treating lung cancer.

Introduction: Both micropapillary predominant lung adenocarcinoma according to the IASLC/ATS/ERS classification and lung adenocarcinoma with a micropapillary component have been reported to be associated with poor prognosis. However, whether they have different prognosis remains undetermined., Methods: Out of 1302 lung adenocarcinoma patients, 21 patients with micropapillary predominant lung adenocarcinoma (MPP) and 100 patients with nonmicropapillary predominant tumors harboring a micropapillary component of at least 5% (MPC) were investigated for clinicopathologic characteristics, recurrence-free survival (RFS), overall survival (OS), and spectrum of well-identified driver mutations including EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET., Results: Twenty out of 21 (95.2%) micropapillary predominant lung adenocarcinoma harbored driver mutations in EGFR (85.7%), HER2 (4.8%), or RET (4.8%). MPP had significantly worse RFS than MPC in stage I patients (p = 0.003), but not in stages II-III patients. The overall survival was comparable between MPP and MPC regardless of disease stages. Objective response was achieved in 13 out of the 18 MPP or MPC patients with EGFR mutations who received EGFR tyrosine kinase inhibitors (TKIs) after disease recurrence. The postrecurrence survival was significantly better in EGFR-mutated patients who were treated with EGFR TKIs compared to those who did not receive TKIs (p = 0.003)., Conclusions: Micropapillary predominant lung adenocarcinoma is a disease that could be largely defined by targetable driver mutations. For stage I lung adenocarcinoma, MPP was even more likely to recur than MPC. EGFR TKIs might help to control the recurrent disease for MPP or MPC patients harboring EGFR mutations.

Purpose: To define the prevalence, clinicopathologic characteristics and molecular associations of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in East Asian lung adenocarcinoma patients., Methods: A total of 1,086 lung adenocarcinomas were sequenced for EGFR mutations. EGFR and HER2 copy number variations; total and phosphorylated (p) protein expression of ErbB family members including EGFR, HER2, and HER3; phosphorylated protein expression of downstream signaling molecules including Akt and Erk; and clinicopathologic features in lung adenocarcinomas with EGFR exon 20 insertion mutations were all investigated., Results: EGFR exon 20 insertion mutations were present in 2.9 % of lung adenocarcinomas and 4.7 % of all the EGFR mutations. Compared to those with classic activating EGFR mutations, lung adenocarcinomas with exon 20 insertion mutations were characterized by significantly younger age at diagnosis (P = 0.032 for exon 20 insertions vs. L858R) and shorter relapse-free survival [P = 0.045 for exon 20 insertions versus (vs) exon 19 deletions]. Molecularly, samples harboring exon 20 insertion mutations had lower expression of phosphorylated (p)-EGFR (P < 0.001) and HER3 (P = 0.016). In addition, higher expression of p-Akt (P = 0.007) and lower expression of p-Erk (P = 0.009) were observed in tumors with exon 20 insertion mutations., Conclusions: Lung adenocarcinomas with EGFR exon 20 insertion mutations were present in a substantial proportion. This subset showed distinct clinicopathologic features, less dependence on EGFR molecularly, and different pathway activation patterns compared to those with classic EGFR activating mutations.

A total of 1039 stage I-III invasive lung adenocarcinoma including 186 solid subtype patients who have undergone radical resection were assessed for clinicopathologic characteristics, status of common driver mutations, pattern of recurrence, recurrence-free survival (RFS), overall survival (OS), post-recurrence survival (PRS) and predictive value for adjuvant chemotherapy and EGFR tyrosine kinase inhibitors (TKIs). Solid predominant adenocarcinomas were more likely to have initial distant recurrences than non-solid subtype invasive adenocarcinomas (P = 0.018). In univariate analysis, solid predominant adenocarcinoma patients had significantly worse RFS (P < 0.001), OS (P < 0.001) and PRS (P = 0.010). Multivariate analysis adjusting for clinicopathologic variables and mutational status showed that solid subtype was an independent poor prognostic factor (odds ratio = 1.876, 95% confidence interval: 1.291-3.158; P = 0.003) and an independent negative predictor for stage II-III patients undergoing adjuvant chemotherapy (odds ratio = 2.020, 95% confidence interval: 1.291-3.158; P = 0.002). In EGFR-mutated solid predominant lung adenocarcinoma patients who experienced disease recurrence, the response rate to EGFR TKIs was only 37.5%. In radically resected invasive lung adenocarcinoma, solid subtype was an independent poor prognostic factor and negative predictor for adjuvant chemotherapy.

Introduction: Genotyping for driver mutations is now routinely used to guide clinical care of patients with lung cancer. Adenosquamous lung carcinoma (AdSqLC) is a subtype of cancer that contains both adenocarcinoma and squamous cell carcinoma. However, the incidence, clinicopathologic characteristics, and prognostic implications of major driver mutations in AdSqLCs are not well established., Methods: Seventy-six resected AdSqLCs and 646 lung adenocarcinomas were screened for known genetic alterations involving EGFR, ERBB2, KRAS, BRAF, PIK3CA, AKT1, RET, and ALK. Tumors showing acinar, lepidic, micropapillary, or papillary growth in glandular component were classified as classical AdSqLC., Results: Of the 76 AdSqLCs, 43 (56.6%) harbored known mutant kinases, including 24 (31.6%) with EGFR mutations, eight (10.5%) with KRAS mutations, two (2.6%) with AKT1 (2.6%) mutations, one (1.3%) with ERBB2 insertion mutation, one (1.3%) with PIK3CA mutation, four (5.3%) with ALK fusions, and three (4%) with KIF5B-RET fusions. No mutation was found in BRAF. The mutational profiles and clinicopathologic characteristics of classical AdSqLC were strikingly similar to that of poorly differentiated adenocarcinoma. However, AdSqLCs with solid growth pattern in glandular component had high frequency of ALK or RET fusions and low EGFR mutation rate., Conclusions: To our knowledge, this is the first comprehensive study investigating major oncogenic driver mutations in a large cohort of AdSqLC patients in a Chinese population. The findings suggest that it will be clinically valuable to investigate the growth pattern of glandular component in AdSqLCs.

Background and Purpose: Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed malignancies in the world. Small-molecule inhibitors of the EGF receptor's tyrosine kinase domain (TKIs), including gefitinib and erlotinib, have been widely used for treating NSCLC. Unfortunately, nearly all patients after initially experiencing a marked improvement while on these drugs, eventually progress to acquire resistance to TKIs. Because there is no effective therapeutic strategy to treat TKI-resistant NSCLC, we evaluated the effects of luteolin, a naturally occurring flavanoid, on T790M mutant NSCLC cells., Experimental Approach: The effect of luteolin on the viability of NSCLC and normal cell lines was investigated using the Cell Counting Kit-8 (CCK-8) assay. Luteolin-induced apoptosis was assessed by bivariate FITC-annexin V/PI assay, and Western blots were used to measured apoptotic proteins. Co-immunoprecipitation was used to determine the effect of luteolin on the interaction between Hsp90 and mutant EGF receptors. The effect of luteolin on the Akt/mTOR pathway was studied using Western blotting analysis. Its anti-tumour efficacy in vivo was examined in a mouse xenograft model., Key Results: Luteolin exerted significant anti-tumourigenic effects on the EGF receptor L858R/T790M mutation and erlotinib-resistant NSCLC both at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association of Hsp90 with the mutant EGF receptor, and, therefore, prevented PI3K/Akt/mTOR signalling, which resulted in NSCLC cell apoptosis., Conclusion and Implications: Luteolin may be a potential candidate for NSCLC therapy, especially for treatment of patients with acquired erlotinib-resistant NSCLC., (© 2014 The British Pharmacological Society.)

Background: To have a comprehensive investigation of the clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas., Methods: Quantitative real-time reverse transcriptase PCR (qRT-PCR) and reverse transcriptase PCR (RT-PCR) were simultaneously performed to screen ALK, ROS1 and RET fusions in resected tumor samples from 1139 Chinese lung adenocarcinoma patients, with validation of positive results using fluorescent in situ hybridization. Clinicopathologic characteristics, predominant histologic subtype and cytomorphology were assessed in fusion-positive lung adenocarcinomas and compared to those harboring EGFR, KRAS, HER2 or BRAF mutations., Results: There were 58 (5.1%) ALK fusions, 11 (1.0%) ROS1 fusions and 15 (1.3%) RET fusions. Tumors with ROS1 fusions had significantly larger diameter than ROS1 fusion-negative tumors (P = 0.007), whereas all the 15 tumors harboring RET fusions were ≤ 3 cm in diameter (P = 0.001). The three fusion genes were all more prevalent in solid-predominant adenocarcinoma. Compared to fusion-negative lung adenocarcinomas, tumors harboring a fusion gene had significantly higher prevalence of extracellular mucin (P < 0.001), cribriform pattern (P < 0.001), signet ring cells (P < 0.001) and hepatoid cytology (P < 0.001). No significant difference in relapse-free survival (P = 0.147) and overall survival (P = 0.444) was observed between fusion-positive and fusion-negative patients., Conclusions: This study showed fusion-positive lung adenocarcinomas had identifiable common and fusion-pattern specific clinicopathologic, histologic and cytologic features, offering implications for fusion genes screening., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: During the past two decades, many studies have sought to find reliable predictors of N0 status in small-sized lung cancers. However, the way of tumor size measurement was usually not clearly stated, and controversy remains as to whether systematic lymph node dissection should be performed in patients with subcentimeter tumors., Methods: We reviewed correlations between lymph node involvement and clinicopathological variables in 243 small peripheral non-small cell lung cancers with their size measured in fresh specimens before formalin fixation. Histologic subtypes of adenocarcinomas were classified in line with the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification., Results: Incidence of N1 and N2 nodal involvement was 5.3 and 6.6 %, respectively. N2 disease was present in a proportion of subcentimeter tumors (2/53, 3.8 %). No lymph node metastasis was revealed in squamous cell carcinomas, adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma. Collectively, the five cell types accounted for 34.6 % of all the small peripheral cases., Conclusions: Precise measurement of tumor size in fresh tissues revealed that tumor size was not a reliable predictor of N0 status. However, through histologic classification, systematic lymph node dissection might be avoided in more than one third of small peripheral NSCLC.

Demarcation of early gastric cancers is sometimes unclear. Indigo carmine chromoendoscopy has usually been used as a diagnostic method for tumor margins as it enhances mucosal irregularities and differences in color. Fuji Intelligent Color Enhancement (FICE), a recently developed virtual chromoendoscopic system, can explore the entire mucosal surface (of structures and vessels). Here we report a case of a patient with early gastric cancer who underwent a successful endoscopic submucosal dissection (ESD) using endoscopy with FICE. A 58-year-old man with early gastric cancer underwent an ESD. Demarcation of the lesion was not clear through normal endoscopy. Therefore, an endoscopy was performed with FICE, which clearly revealed the demarcation. An ESD was carried out after spots were marked circumferentially. We identified the positional relationship between the demarcation and all markings on the magnifying model. A resection of the lesion was performed on the area outside the markings. Finally, the lesion was Histopathologically diagnosed as a well-differentiated adeno-carcinoma confined in the mucosal region, and the margins were free from carcinoma. FICE, especially combined with the magnifying model, is useful in the identification of the demarcation of early gastric cancer. This method may be useful in increasing the rate of complete resection by ESD for early gastric cancer.

Purpose: We performed this analysis to reveal the association between six well-identified oncogenic driver mutations and clinical and pathological features in lung adenocarcinomas from smokers. It may have the potentiality to optimize existing treatment strategies and clinical trial design., Methods: In this series, 230 resected lung adenocarcinomas from smoker (>100 cigarettes in lifetime) at single center (Shanghai Cancer Center, Shanghai, China) were tested for mutation in EGFR, KRAS, BRAF, HER2, EML4-ALK and PIK3CA. Further we compared the mutation frequency with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype., Results: Among 230 smokers, we detected 100 (43.5%) EGFR mutations, 38 (16.5%) KRAS mutations, 8 (3.5%) PIK3CA mutations, 7 (3.0%) BRAF mutations and 7 (3.0%) EML4-ALK fusions. No HER2 mutation was found. EGFR mutations occurred at a significantly higher frequency in patients with smoking dose ≤20 pack-years (p < 0.001) or age ≥60 years old at diagnosis (p = 0.018). Smoking dose >20 pack-years and age <60 years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation frequency, EGFR mutation had positive correlation with histological subtype micropapillary (p = 0.003), lepidic (p = 0.011), as well as papillary (p = 0.05) predominant adenocarcinoma. Negative correlation was found between EGFR mutation and solid predominant (p < 0.001), as well as invasive mucinous adenocarcinoma (IMA) (p = 0.006). Besides, KRAS mutation had positive correlation with IMA (p = 0.043). The frequency of EGFR mutation decreased with increasing tobacco dose. In contrast, higher frequency of KRAS mutations was observed with increasing tobacco dose. Generally, the frequency of these driver mutations tested in our study decreased with increasing smoking dose., Conclusions: This study represents the first comprehensive and concurrent analysis of these six well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Our previous study revealed that 90% [47 of 52; 95% confidence interval (CI), 0.79-0.96] of Chinese never-smokers with lung adenocarcinoma harbor known oncogenic driver mutations in just four genes EGFR, ALK, HER2, and KRAS. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma., Experimental Design: Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, and molecular alterations were recorded from 349 resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathologic parameters according to mutational status of these genes., Results: Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAF mutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations were significantly younger (P = 0.036). Higher prevalence of KRAS (P = 0.028) and HER2 (P = 0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P = 0.002). Multivariate analysis revealed that older age at diagnosis (P = 0.013) and acinar predominant subtype (P = 0.005) were independent predictors of EGFR mutations. Independent predictors of HER2 mutations included younger age (P = 0.030) and IMA (P = 0.017). IMA (P = 0.006) and poor differentiation (P = 0.028) were independently associated with KRAS mutations., Conclusions: The frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histologic subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies., (©2012 AACR.)

Introduction: A fraction of lung adenocarcinomas harbor activating mutations in the HER2 kinase domain. HER2-targeted therapies have shown minimal benefit in molecularly unselected patients. We investigated clinical and potential molecular factors associated with HER2-mutant lung adenocarcinoma., Methods: A total of 224 lung adenocarcinoma samples were examined for activating mutations in epidermal growth factor receptor (EGFR; exons 18-22), V-Ki-ras2 Kirsten rat sarcoma (KRAS; exons 2 and 3), and HER2 (exons 18-21) by direct sequencing. Gene copy number and protein expression of both EGFR and HER2 were further explored in samples harboring HER2 mutations using fluorescence in situ hybridization and immunohistochemistry, respectively., Results: The mutation rates of EGFR, KRAS, HER2 were 63.39% (142/224), 4.46% (10/224), and 3.57% (8/224), respectively. All mutations were mutually exclusive. All eight HER2 mutations occurred in never smokers and seven were in women. The HER2 mutation rate in samples without EGFR and KRAS mutations was 11.11% (8/72). Seven of eight HER2-mutated tumors showed HER2 copy number gains (CNGs) and five showed EGFR CNGs. All of the HER2-mutated samples showed either HER2 or EGFR CNGs. Gene amplification of HER2 and EGFR was mutually exclusive in HER2-mutated samples., Conclusion: HER2 mutations in lung adenocarcinoma predominantly occurred in women and never smokers. Most HER2-mutated tumors showed HER2 CNGs. As all of the samples with HER2 mutation showed either HER2 or EGFR CNGs, these patients could potentially benefit from novel EGFR/HER2 dual or pan-erythroblastic leukemia viral oncogene homolog tyrosine kinase inhibitors.

Objective: To evaluate the role of cytopathology in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for lung tumor diagnosis and staging., Methods: Two-hundred consecutive cases of lung tumor with EBUS-TBNA performed during the period from April, 2009 to September, 2010 in Shanghai Cancer Hospital were retrospectively reviewed. The cytologic diagnoses were categorized as non-diagnostic, negative, suspicious and malignant. When available, cell block preparation and immunohistochemistry were performed. On the 22 positive cases diagnosed by on-site evaluation, epidermal growth factor receptor (EGFR) mutation study was carried out., Results: In the 200 cases of cytology specimens, 122 cases (69.3%) were diagnosed as malignant, 42 cases (23.9%) as benign and 12 cases (6.8%) as suspicious for malignancy. The non-diagnostic rate was 12.0% (24/200). Amongst the 200 cases studied, 140 cases (70.0%) had histologic correlation available (via core biopsy, mediastinoscopic biopsy or surgical excision). The sensitivity and specificity of EBUS-TBNA cytologic diagnoses were 94.4% and 100%, when using histopathologic findings and clinical follow-up data as gold standard. The cell block preparation and immunohistochemistry were useful in subtyping and diagnosis of extrathoracic malignancy. EGFR mutations were detected in 8 cytology samples (36.4%)., Conclusions: EBUS-TBNA is a sensitive and specific tool for diagnosis and staging of lung cancer. The cytology samples can be used for further ancillary investigations including cell block preparation, immunohistochemistry and molecular studies.

Introduction: Somatic LKB1 mutations are found in lung adenocarcinomas at different frequencies in Caucasian and East Asian (Japanese and Korean) populations. This study was designed to characterize the frequency of LKB1 mutations, their relationship to EGFR and KRAS mutations, and their associated clinicopathologic characteristics in Chinese patients., Methods: Two hundred thirty-nine lung adenocarcinomas consecutively collected from October 2007 to July 2009 were dissected into 3 to 4 small (3 mm) pieces for histopathological analyses of tumor content. Genomic DNA and/or cDNA from 86 samples with more than 70% tumor content were used for sequencing of LKB1 (exons 1-9), EGFR (exons 18-21), and KRAS (exon 2). LKB1 germline mutation status was determined by sequencing of genomic DNA from matched histologically distant lung tissues that are histologically normal., Results: 6.9% of lung adenocarcinomas harbored LKB1 somatic mutations. A total of 10.5% of patients had an LKB1 germline polymorphism, F354L. Interestingly, in two of these patients, tumors displayed loss of heterozygosity at this allele. EGFR kinase domain and KRAS mutations were found in 66.3% and 2.3% of Chinese lung adenocarcinomas, respectively. Concurrent LKB1 and EGFR somatic mutations were observed in one patient. Both KRAS-mutant tumors harbored LKB1 mutations., Conclusions: These data provide important clinical and molecular characteristics of lung adenocarcinomas from Chinese patients.

Objective: To evaluate the effectiveness and safety of fertility-sparing treatment with progestins in patients with well-differentiated endometrial adenocarcinoma in women 40 years old or younger., Methods: Six patients before the age of 40 diagnosed with grade I endometrial adenocarcinoma, who had undergone primary progestin treatment, were retrospectively studied. The clinical records and pathologic slides and the follow-up information were reviewed. Relevant articles describing patients with endometrial adenocarcinoma who were treated with hormonal therapy were searched. A total of 56 cases were found and used in integrated analysis., Results: Four of six cases responded to treatment with normal pathology on follow-up endometrial samplings. Two patients had a recurrence within a period between 10 and 12 months. No response was noted in the other two cases, who were offered surgery. Therefore, a total of 4 patients ultimately underwent hysterectomy. None of these four patients had extrauterine metastasis on postoperation pathologic examination. All these six patients were alive without evidence of disease at last follow-up. According to literatures, 46 of 56 cases responded to hormonal treatment and 11 cases had a recurrence. Seven of the 11 patients who recurred were re-treated with progesterone. Five patients had a second complete response. Sixteen of the 56 patients underwent hysterectomy. One of the patients had a pelvic recurrence after operation. The others remained without evidence of disease. Six patients in author's group had neither pregnancy nor delivery. Among 56 patients described in literatures, there were 41 person-times pregnancies and 40 infants were delivered, including 4 twins and 2 triples., Conclusions: Progestin treatment is proved a safe and feasible therapy in well-differentiated endometrial adenocarcinoma in women 40 years old or younger. This approach may provide the possibility of conceiving and carrying a pregnancy with the aid of assisted reproduction technology.

Aim: To investigate the expression of leptin and leptin receptor (ob-R) in intestinal-type gastric cancer and precancerous lesions, and to explore the possible mechanism and role of the leptin system in developing intestinal-type gastric adenocarcinoma., Methods: Immunohistochemistry was performed to examine the expression of leptin and leptin receptor in archival samples of gastric adenocarcinoma and preneoplastic lesions, including intestinal metaplasia and mild to severe gastric epithelial dysplasia. Positive staining was identified and percentage of positive staining was graded., Results: Dual expression of leptin and leptin receptor were detected in 80% (16/20) intestinal metaplasia, 86.3% (25/30) mild gastric epithelial dysplasia, 86.7% (26/30) moderate gastric epithelial dysplasia, 93.3% (28/30) severe gastric epithelial dysplasia, 91.3% (55/60) intestinal-type gastric adenocarcinoma and 30.0% (9/30) diffuse-type gastric carcinoma. The percentage of dual expression of leptin and leptin receptor in intestinal-type gastric adenocarcinoma was significantly higher than that in diffuse-type gastric adenocarcinoma (c2 = 37.022, P<0.01)., Conclusion: Our results indicate the presence of an autocrine loop of leptin system in the development of intestinal-type gastric adenocarcinoma.

The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy. [ABSTRACT FROM AUTHOR]

Approximately 3–7% of non-small cell lung cancers harbor an anaplastic lymphoma kinase (ALK) gene fusion, constituting a new molecular subtype of lung cancer that responds to crizotinib, an ALK inhibitor. Although previous studies have evaluated ALK-rearranged lung cancers, the comprehensive analysis of lung cancer in Chinese has not well assessed. Herein, we identified 44 cases of ALK-rearranged samples by fluorescent in-situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcription polymerase chain reaction (RT-PCR) in a large number of surgically resected lung cancers. All 44 ALK-rearranged lung cancers were adenocarcinomas, with 2 cases having additional focal squamous components. The goal was to analyse the clinicopathological features of ALK-rearranged lung adenocarcinomas. Our data showed that a cribriform structure, prominent extracellular mucus and any type of mucous cell pattern may be either sensitive or specific to predict an ALK rearrangement. We used FISH as the standard detection method. We compared the ALK rearrangement accuracy of FISH, RT-PCR and IHC. RT-PCR could define both the ALK fusion partner and the fusion variant, but seemed unable to detect all translocations involving the ALK gene. It is noteworthy that IHC using the D5F3 antibody (Cell Signaling Technology) showed higher sensitivity and specificity than the ALK1 antibody (Dako). Therefore, we conclude that IHC remains a cost-effective and efficient technique for diagnosing ALK rearrangements and that D5F3 can be the optimal screening antibody in clinical practice. [ABSTRACT FROM AUTHOR]

An abstract of the case report "Collision Tumor of Metastatic Rectal Cancer and Primary Lung Adenocarcinoma Presented as an Isolated Pulmonary Nodule," by Yiliang Zhang et al. is presented.