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Here, we report the first cytology findings of the newly characterized entity, palisading adenocarcinoma of the salivary gland, diagnosed in the sublingual gland of a 61-year-old female. The liquid-based cytology showed a moderately cellular aspirate containing three-dimensional clusters and trabeculae of tumor cells of various sizes. The cells had dark ovoid nuclei, finely granular chromatin, inconspicuous to punctate nucleoli, and ample cyanophilic cytoplasm with indistinct cell borders. In conventional smears, the cells displayed frequent crush artifacts and anisonucleosis resembling endocrine-type atypia. The background was clean, devoid of secretions, and contained singly dispersed tumor cells with stripped nuclei. Interestingly, concentrically laminated globules of extracellular matrix surrounded by the tumor cells were identified. Mitotic figures and tumor necrotic debris were absent. The cytologic findings correlated with the histologic findings of the excision specimen. The cytologic differential diagnosis and tumor grading of palisading adenocarcinoma were briefly discussed., (© 2024 The Author(s). Diagnostic Cytopathology published by Wiley Periodicals LLC.)

The tumor microenvironment is important in the initiation and progression of lung adenocarcinoma (LUAD). In this study, we aim to analyze the expression profile of immune-related genes in LUADs, examine the differential expression of immune-related genes in epidermal growth factor receptor (EGFR) wild-type and mutant LUADs, and the clinicopathologic significance of these differentially expressed genes. We used the NanoString PanCancer Immune Profiling Panel to examine 34 cases of LUADs (18 EGFR wild-type, 16 EGFR mutant). In EGFR wild-type LUADs, the macrophage and neutrophil signatures are significantly higher, and significantly higher expression of chemokines, interleukins, leukocyte, macrophage, natural killer cell, pathogen defense, Tumor necrosis factor superfamily, and transporter function signatures are also observed. TNFRSF10B mRNA was preferentially expressed in EGFR wild-type LUADs (P = 6.15e-6, adjusted P = .0244). Immunohistochemical staining for TRAIL-R2 (encoded by TNFRSF10B) on 134 tissue microarray LUAD cases demonstrated strong, moderate, and weak staining in 75 (56.0%), 46 (34.3%), and 13 (9.7%) cases, respectively. Strong TRAIL-R2 expression was significantly associated with poor overall survival (OS) in all stages and EGFR wild-type LUADs, but not in EGFR-mutant tumors. Furthermore, strong TRAIL-R2 expression (P = .004) was an independent risk factor for poor OS. In summary, TNFRSF10B mRNA revealed significantly higher expression in EGFR wild-type LUADs, and strong TRAIL-R2 expression predicts an unfavorable prognosis for these tumors. These patients may benefit from additional treatment with TRAIL-R2-targeted therapies., (Copyright © 2022. Published by Elsevier Inc.)

Background: To evaluate the long-term outcomes after surgical resection for stage I lung adenocarcinoma based on the percentage of lepidic component (LC) and invasive tumor size (IS)., Methods: The clinicopathological characteristics of 1049 patients with stage I lung adenocarcinoma who underwent surgery between 2006 and 2016 were retrospectively reviewed. Tumors were categorized into groups: A (LC ≥ 50%) and B (LC < 50%). Groups A0 and A1 consisted of minimally invasive adenocarcinomas (MIA) and other lepidic-predominant invasive adenocarcinomas, respectively. Group B was categorized into B1 (IS ≤ 1 cm), B2 (1 < IS≤2 cm), and B3 (2 < IS≤3 cm) by invasive tumor size and divided into subgroups (B1[lep+]/[lep-], B2[lep+]/[lep-], and B3[lep+]/[lep-]) according to the presence[lep+] or absence[lep-] of LCs. Cumulative incidence of recurrence (CIR) and cancer-specific survival (CSS) were examined., Results: LC decreased with increasing IS. Only 24 (8.5%) tumors in group A had an IS >1 cm. 10-year CIR and CSS were 15.2% and 86.0%. LC and IS were found to be independent predictors of CSS. Patients in group A had 1.4% 10-year CIR and 100% 10-year CSS. In group B, a significantly higher CIR and worse CSS were observed as IS increased (p < 0.001), but LC was not a predictor for CSS (p = 0.593). No significant differences in CIR or CSS were found in presence of LC or not when LC < 50% (B1[lep+]/[lep-], B2[lep+]/[lep-], and B3[lep+]/[lep-]: p = 0.36/0.48, p = 0.82/0.94, and p = 0.90/0.37, respectively)., Conclusions: LC≥50% tumors demonstrated excellent prognosis regardless of IS. The outcomes of LC < 50% tumors were well predicted by IS, corresponding to the T-staging system. The predictive value of LC for prognosis became insignificant., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate whether preoperative biopsy affects the outcomes of patients undergoing at least lobectomy for stage I lung adenocarcinoma., Methods: We reviewed the medical records of patients who underwent surgery for stage I lung adenocarcinoma between 2006 and 2013. Tumor recurrence and survival were compared between patients who underwent preoperative biopsy, including computed tomographic-guided needle biopsy and transbronchial biopsy, and those who underwent intraoperative frozen section., Results: Among 509 patients, 229 patients (44.9%) underwent preoperative biopsy and 280 patients had lung adenocarcinoma diagnosed by intraoperative frozen section (reference group). Recurrence developed in 65 (12.8%) patients within a median follow-up period of 54.4 months. Multivariate analysis demonstrated that preoperative biopsy (OR 1.97, p = 0.045), radiological solid appearance (OR 5.43, p < 0.001), and angiolymphatic invasion (OR 2.48, p = 0.010) were independent predictors of recurrence. In the overall cohort, preoperative biopsy appeared to worsen 5-year disease-free and overall survival significantly (76.6% vs. 93.0%, p < 0.001; and 83.8% vs. 94.5%, p = 0.002, respectively) compared with the reference group. After propensity matching, multivariable logistic regression still identified preoperative biopsy as an independent predictor of overall recurrence (OR 2.21, p = 0.048) after adjusting for tumor characteristics., Conclusion: Preoperative biopsy might be considered a prognosticator of recurrence of stage I adenocarcinoma of the lungs in patients who undergo at least anatomic lobectomy without postoperative adjuvant chemotherapy.

Precise noncoding RNA (ncRNA)-based network prediction is necessary to reveal ncRNA functions and pathological mechanisms. Here, we established a systemic pipeline to identify prognostic ncRNAs, predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD). After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990 and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortens the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitates tumor growth that leads to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in the TCGA cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that interacts with the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established a systematic strategy to uncover prognostic ncRNAs with functional prediction methods suitable for pan-cancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the PTTG3P/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: The role of adjuvant chemotherapy for patients with stage I NSCLC remains unknown. The prognostic value of histological subtypes in resected node-negative small lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma 3 cm or smaller to find potential candidates for adjuvant chemotherapy., Methods: A total of 726 patients with completely resected node-negative lung adenocarcinoma 3 cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated., Results: During follow-up, recurrence developed in 59 patients (8.1%). Univariate analysis showed that the micropapillary/solid predominant pattern group was associated with a significantly lower probability of FFR (p = 0.001) in node-negative lung adenocarcinoma 3 cm or smaller. Those with greater tumor size (p = 0.001) and the micropapillary/solid predominant pattern group (p = 0.035) had a significantly lower probability of FFR in multivariate analysis. For tumors 2 cm or smaller, the micropapillary/solid predominant pattern group had a trend toward a lower probability of FFR (p = 0.053) in multivariate analysis. Presence of the solid pattern was a prognostic factor for lower probability of FFR (p = 0.001) in multivariate analysis., Conclusions: The new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma 3 cm or smaller. Patients with the micropapillary/solid predominant pattern have a significantly higher risk for recurrence. For tumors 2 cm or smaller, presence of the solid pattern was a prognostic factor for higher probability of recurrence. This information is useful for patient stratification for adjuvant therapy., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Analysis of the targetable driver mutations is now recommended in all patients with advanced lung adenocarcinoma. Molecular-based methods are usually adopted, however, along with the implementation of highly sensitive and/or mutation-specific antibodies, immunohistochemistry (IHC) has been considered an alternative method for identifying driver mutations in lung adenocarcinomas., Materials and Methods: A total of 205 lung adenocarcinomas were examined for EGFR mutations and ALK and ROS1 rearrangements using real-time PCR, fluorescence in situ hybridization (FISH) and IHC in parallel. The performance of different commercially available IHC antibody clones toward targetable driver mutations was evaluated. The association between these driver mutations and clinicopathological characteristics was also analyzed., Results: In 205 cases we studied, 58.5% were found to harbor EGFR mutations, 6.3% ALK rearrangements and 1.0% ROS1 rearrangements. Compared to molecular-based methods, IHC of EGFR mutations showed an excellent specificity but the sensitivity is suboptimal, while IHC of ALK and ROS1 rearrangements demonstrated high sensitivity and specificity. No significant difference regarding the performance of different antibody clones toward these driver mutations was observed, except that clone SP125 showed a higher sensitivity than 43B2 in the detection of p.L858R of EGFR., Conclusion: In circumstances such as poor quality of nucleic acids or low content of tumor cells, IHC of EGFR mutation-specific antibodies could be used as an alternative method. Patients negative for EGFR mutations are subjected to further analysis on ALK and ROS1 rearrangements using IHC methods. Herein, we proposed a lung adenocarcinoma testing algorithm for the application of IHC in therapeutic diagnosis., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The aim of the study is to demonstrate the relationship between clinicopathological variables and occult lymph node metastasis in resected lung adenocarcinoma., Methods: The clinicopathological characteristics of 471 patients with clinical N2-negative status undergoing resection for lung adenocarcinoma of 3 cm or smaller at Taipei Veterans General Hospital between 2004 and 2012 were retrospectively reviewed. The association between clinicopathological variables and lymph node metastasis was analysed by univariate and multivariate logistic regression., Results: Among the 471 patients, there were 386 (82.0%) patients with pathological N0 status, 35 (7.4%) with pathological N1 status and 50 (10.6%) with pathological N2 status. Greater tumour size (P = 0.002), presence of a micropapillary pattern (P < 0.001), presence of a solid pattern (P < 0.001) and predominant pattern group (micropapillary/solid predominant) (P = 0.001) were significantly associated with higher percentage of occult N2 lymph node metastasis. In multivariate analysis, greater tumour size (P = 0.008), presence of micropapillary pattern (P < 0.001) and presence of solid pattern (P = 0.001) were significant predictors of occult N2 lymph node metastasis in tumours of 3 cm or smaller. When histological pattern was entered as the predominant pattern in multivariate analysis, micropapillary/solid predominant pattern (P = 0.005) was also a significant predictor of occult N2 lymph node metastasis., Conclusions: The presence of micropapillary or solid pattern, as well as micropapillary/solid predominant pattern, is significantly associated with occult N2 lymph node metastasis in lung adenocarcinoma. Radical mediastinal lymph node dissection may help to identify occult lymph node metastasis in these patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: The benefit of adjuvant chemotherapy remains controversial for patients with stage IB non-small-cell lung cancer (NSCLC). This study investigated the effect of adjuvant chemotherapy and the predictors of benefit from adjuvant chemotherapy in patients with stage IB lung adenocarcinoma., Methods: A total of 243 patients with completely resected pathologic stage IB lung adenocarcinoma were included in the study. Predictors of the benefits of improved overall survival (OS) or probability of freedom from recurrence (FFR) from platinum-based adjuvant chemotherapy in patients with resected stage IB lung adenocarcinoma were investigated., Results: Among the 243 patients, 70 (28.8%) had received platinum-based doublet adjuvant chemotherapy. A micropapillary/solid-predominant pattern (versus an acinar/papillary-predominant pattern) was a significantly worse prognostic factor for probability of FFR (p = 0.033). Although adjuvant chemotherapy (versus surgical intervention alone) was not a significant prognostic factor for OS (p = 0.303), it was a significant prognostic factor for a better probability of FFR (p = 0.029) on multivariate analysis. In propensity-score-matched pairs, there was no significant difference in OS between patients who received adjuvant chemotherapy and those who did not (p = 0.386). Patients who received adjuvant chemotherapy had a significantly better probability of FFR than those who did not (p = 0.043). For patients with a predominantly micropapillary/solid pattern, adjuvant chemotherapy (p = 0.033) was a significant prognostic factor for a better probability of FFR on multivariate analysis., Conclusions: Adjuvant chemotherapy is a favorable prognostic factor for the probability of FFR in patients with stage IB lung adenocarcinoma, particularly in those with a micropapillary/solid-predominant pattern., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: We investigated the role of the 2011 International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification in predicting occult lymph node metastasis in clinically mediastinal node-negative lung adenocarcinoma., Methods: We reviewed lung adenocarcinoma patients who had clinically N2-negative status, were evaluated by preoperative positron emission tomography combined with computed tomography (PET/CT) and had undergone lobectomy or pneumonectomy at Memorial Sloan Kettering Cancer Center (n = 297). Tumours were classified according to the 2011 IASLC/ATS/ERS classification. The associations between occult lymph node metastasis and clinicopathological variables were analysed using Fisher's exact test and logistic regression analysis., Results: Thirty-two (11%) cN0-1 patients had occult mediastinal lymph node metastasis (pN2) whereas 25% of cN1 patients had pN2 disease. Increased micropapillary pattern was associated with increased risk of pN2 disease (P = 0.001). On univariate analysis, high maximum standard uptake value of the primary tumour on PET/CT (P = 0.019) and the presence of micropapillary (P = 0.014) and solid pattern (P = 0.014) were associated with occult pN2 disease. On multivariable analysis, micropapillary pattern was positively associated with risk of pN2 disease (odds ratio = 3.41; 95% confidence intervals = 1.42-8.19; P = 0.006)., Conclusions: The presence of micropapillary pattern is an independent predictor of occult mediastinal lymph node metastasis. Our observations have potential therapeutic implications for management of early-stage lung adenocarcinoma., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: Recurrence after surgical resection is the most common cause of treatment failure in patients with non-small-cell lung cancer. The aim of the study is to investigate the prognostic factors of postrecurrence survival (PRS) in patients of resected lung adenocarcinoma., Methods: The clinicopathological characteristics of 179 patients with recurrence after complete resection of lung adenocarcinoma at Taipei Veterans General Hospital between 2004 and 2010 were retrospectively reviewed. The prognostic and predictive effects of these clinicopathological variables in PRS were analyzed., Results: The pattern of recurrence included local only in 25 (15.4%), distant only in 56 (34.6%), and both local and distant in 81 (50.0%) of patients. The 2-year and 5-year PRS were 65.2% and 29.8%, respectively. The most common organ sites of metastasis were the contralateral lung (39.1%), followed by the brain (33.5%) and the bone (31.3%). Multivariate analysis revealed that micropapillary/solid predominant pattern group (versus acinar/papillary; hazard ratio = 2.615; 95% confidence interval: 1.395-4.901; p = 0.003) and no treatment for recurrence (p < 0.001) were significant prognostic factors of worse PRS. For patients receiving treatment for recurrence, micropapillary/solid predominant pattern group (versus acinar/papillary; hazard ratio = 2.570; 95% confidence interval: 1.357-4.865; p = 0.004) was a significant predictive factor of worse PRS. Treatment for recurrence with surgery (p = 0.067) tended to be a significant predictive factor of better PRS., Conclusions: In lung adenocarcinoma, micropapillary/solid predominant pattern group (versus acinar/papillary) was a significant poor prognostic factor for PRS.

Background: Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma., Methods: Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method., Results: In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008)., Conclusions: Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.

Background: High-grade malignant mixed adenoneuroendocrine carcinoma (MANEC) is a highly malignant combined neoplasm formed by an adenocarcinomatous component and a poorly differentiated (Grade 3) neuroendocrine (NE) carcinoma., Methods: Tumors from 21 patients with gastrointestinal high-grade malignant MANECs or tumors with varying percentages of Grade 3 NE component were examined, and the NE component was confirmed by morphological analysis and immunohistochemical staining. Patients were divided into high NE (NE component > 50% in the primary tumor) and low NE (NE component ≤ 50% in the primary tumor) component groups., Results: High NE component was a poor prognostic factor for patients with high grade MANEC (p = 0.021). Out of 13 patients with high-grade malignant MANEC, eight had a pure NE component, one had a pure adenocarcinomatous component, and four had mixed-type cancer in the metastatic lymph nodes. We further enrolled eight patients who had a Grade 3 NE component in the primary tumor and found that the pure NE component in tumor emboli and distant liver metastases were more frequent in the high NE than in the low NE component group (p = 0.012 and p = 0.046, respectively)., Conclusion: The predominant tumor component in primary tumors was a prognostic factor and could predict tumor emboli and liver metastases pathology in high-grade malignant MANECs., (Copyright © 2015. Published by Elsevier Taiwan.)

Aims: The IASLC/ATS/ERS classification of lung adenocarcinoma provides a prognostically significant histological subclassification. The aim of this study was to investigate the accuracy, limitations and interobserver agreement of frozen sections for predicting histological subtype., Methods and Results: Frozen section and permanent section slides from 361 resected stage I lung adenocarcinomas ≤ 3 cm in size were reviewed for predominant histological subtype and the presence or absence of lepidic, acinar, papillary, micropapillary and solid patterns. Fifty cases were additionally reviewed by three pathologists to determine interobserver agreement. To test the accuracy of frozen section in judging degree of invasion, five pathologists reviewed frozen section slides from 35 cases with a predominantly lepidic pattern. There was moderate agreement on predominant histological subtype between frozen sections and final diagnosis (κ = 0.565). Frozen sections had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for the acinar pattern)., Conclusions: Frozen section can provide information on the presence of aggressive histological patterns-micropapillary and solid-with high specificity but low sensitivity. It was difficult to predict the predominant pattern on the basis of frozen sections, mostly because of sampling issues., (© 2014 John Wiley & Sons Ltd.)

A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.

Purpose: This study investigated the pattern of recurrence of lung adenocarcinoma and the predictive value of histologic classification in resected lung adenocarcinoma using the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification system., Patients and Methods: Histologic classification of 573 patients undergoing resection for lung adenocarcinoma was determined according to the IASLC/ATS/ERS classification system, and the percentage of each histologic component (lepidic, acinar, papillary, micropapillary, and solid) was recorded. The pattern of recurrence of those components and their predictive value were investigated., Results: The predominant histologic pattern was significantly associated with sex (P < .01), invasive tumor size (P < .01), T status (P < .01), N status (P < .01), TNM stage (P < .01), and visceral pleural invasion (P < .01). The percentage of recurrence was significantly higher in micropapillary- and solid-predominant adenocarcinomas (P < .01). Micropapillary- and solid-predominant adenocarcinomas had a significantly higher possibility of developing initial extrathoracic-only recurrence than other types (P < .01). The predominant pattern group (micropapillary or solid v lepidic, acinar, or papillary) was a significant prognostic factor in overall survival (OS; P < .01), probability of freedom from recurrence (P < .01), and disease-specific survival (P < .01) in multivariable analysis. For patients receiving adjuvant chemotherapy, solid-predominant adenocarcinoma was a significant predictor for poor OS (P = .04)., Conclusion: In lung adenocarcinoma, the IASLC/ATS/ERS classification system has significant prognostic and predictive value regarding death and recurrence. Solid-predominant adenocarcinoma was also a significant predictor in patients undergoing adjuvant chemotherapy. Prognostic and predictive information is important for stratifying patients for aggressive adjuvant chemoradiotherapy., (© 2014 by American Society of Clinical Oncology.)

Multiple reports indicate that epidermal growth factor receptor (EGFR) mutations are associated with lepidic-pattern lung adenocarcinoma and that KRAS mutations are associated with invasive mucinous adenocarcinoma. We sought to investigate the association between EGFR and KRAS mutations and specific morphologic characteristics, such as predominant histologic subtype and mucinous features. Clinical data for 864 patients with resected lung adenocarcinoma that underwent molecular testing for EGFR and KRAS mutations were collected. Histologic subtyping was performed according to the IASLC/ATS/ERS lung adenocarcinoma classification, with attention given to signet-ring cell feature and extracellular mucin. EGFR mutations were detected using a polymerase chain reaction-based sizing assay, KRAS mutations were detected using Sanger sequencing, and ALK expression was detected using immunohistochemistry. Invasive mucinous adenocarcinoma was associated with KRAS mutation (P<0.001). Among invasive mucinous adenocarcinomas with KRAS mutation, a pure mucinous pattern was more common than a mixed mucinous/nonmucinous pattern (P=0.002). Invasive mucinous adenocarcinoma was associated with KRAS transition mutations (G→A) but not transversion mutations (G→T or G→C) compared with nonmucinous tumors (P=0.009). The lepidic-predominant group was associated with EGFR mutation compared with nonlepidic-predominant tumors (P=0.011). Extracellular mucin was associated with KRAS mutation (P<0.001), whereas signet-ring cell feature was not associated with EGFR or KRAS mutation (P=0.517). ALK expression was associated with signet-ring cell feature (P=0.001) but not with extracellular mucin (P=0.089). Our study shows that histologic patterns of mucin in lung adenocarcinoma-including invasive mucinous adenocarcinoma and extracellular mucin-are associated with KRAS mutation.

The 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients (∼40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995-2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n=46) was 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P=0.002) or papillary predominant tumors (83%; P=0.020) but was comparable to that for patients with micropapillary (P=0.34) or solid predominant tumors (P=0.56). The recurrence-free probability for patients with ≥10% cribriform pattern tumors (n=214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with <10% cribriform pattern tumors (n=824; 84%; P<0.001). In multivariate analysis, patients with acinar predominant tumors with ≥10% cribriform pattern remained at significantly increased risk of recurrence compared with those with <10% cribriform pattern (P=0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (≥10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype.

Background: Treatment for synchronous multiple primary lung cancers (SMPLC) remains controversial. Some surgeons treat SMPLC like advanced lung cancer, whereas other surgeons treat SMPLC as separate primary lung cancers. In this study, survival of SMPLC patients and matched-stage solitary primary lung cancer (SPLC) patients after surgical treatment were compared., Methods: Prospective medical records between 2001 and 2011 were retrospectively reviewed., Results: A total of 1,995 patients underwent pulmonary resection for lung cancer in a tertiary referral center. Only 97 patients met the modified criteria of Martini and Melamed for SMPLC. The median follow-up time was 38.3 months. The 3-year and 5-year overall survival rates were 83.1% and 69.6%, respectively. In the univariate analysis, males, smokers, and tumor size greater than 3 cm demonstrated significantly worse survival. After multivariate analysis, only tumor size (p = 0.018; hazard ratio 3.199) was identified as an independent predictor of survival. In addition, there was no significant difference in overall survival between the matched-stage SMPLC and SPLC without mediastinal lymph node involvement. Subgroup analysis in the multiple synchronous adenocarcinoma (n = 78) group demonstrated no significant difference between similar and different comprehensive histologic subtyping with respect to overall survival (61.3% versus 68.8%, p = 0.474)., Conclusions: The surgical results for SMPLC were compatible and acceptable with those for SPLC even with similar histologic subtyping, instead of T4 or M1 stages in the current TNM classification system. Preoperatively, tumor size was the only independent prognostic factor for SMPLC with surgical intervention., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths around the world, and a high recurrence rate after complete resection is an important issue reducing the cure rate and survival of patients with early stage NSCLC. Several pathologic biomarkers are associated with recurrence in early stage lung cancer after complete resection., Methods: We evaluated the expression and prognostic value of the α1 subunit of the nicotinic acetylcholine receptor (CHRNA1) as well as other pathologic features of tumor tissues resected from patients with stage I adenocarcinoma of the lung., Results: A high ratio (173/185) of CHRNA1 expression (93.5 %) was found in stage I lung adenocarcinoma. In the multivariate survival analysis, tumor necrosis, angiolymphatic invasion, perineural invasion, and CHRNA1 expression were independent poor prognostic factors for both recurrence-free and overall survival (OS). Patients expressing CHRNA1 had worse median recurrence-free survival (60.6 vs. 77.9 months, P = 0.03) and OS (65.1 vs. 77.9 months, P = 0.04) compared with CHRNA1-negative patients., Conclusions: CHRNA1 expression could be directly tested from the tumor after complete resection. In early stage NSCLC, it could be a useful prognostic factor for recurrence and survival.

The epidermal growth factor receptor (EGFR), which is up-regulated in lung cancer, involves the activation of mitogenic signals and triggers multiple signaling cascades. To dissect these EGFR cascades, we used 14 different phospho-EGFR antibodies to quantify protein phosphorylation using an in situ proximity ligation assay (in situ PLA). Phosphorylation at EGFR-Thr654 and -Ser1046 was EGF-dependent in the wild-type (WT) receptor but EGF-independent in a cell line carrying the EGFR-L858R mutation. Using a ProtoAarray™ containing ∼5000 recombinant proteins on the protein chip, we found that AURKA interacted with the EGFR-L861Q mutant. Moreover, overexpression of EGFR could form a complex with AURKA, and the inhibitors of AURKA and EGFR decreased EGFR-Thr654 and -Ser1046 phosphorylation. Immunohistochemical staining of stage I lung adenocarcinoma tissues demonstrated a positive correlation between AURKA expression and phosphorylation of EGFR at Thr654 and Ser1046 in EGFR-mutant specimens, but not in EGFR-WT specimens. The interplay between EGFR and AURKA provides an explanation for the difference in EGF dependency between EGFR-WT and EGFR-mutant cells and may provide a new therapeutic strategy for lung cancer patients carrying EGFR mutations.

Background and Aim: It is of importance to search for prognostic indicators supplementing the tumour-node-metastasis stage for surgically resected early-stage lung adenocarcinomas. The roles of stromal invasion and micropapillary pattern in categorising histopathology and predicting the prognosis of stage I lung adenocarcinomas are explored., Methods: We retrospectively examined 212 consecutive surgically resected stage I lung adenocarcinomas to propose a new histopathology-based categorical classification. Category A tumours have pure lepidic growth pattern without stromal invasion (ie, adenocarcinoma in situ). Stromal invasion in the form of central fibrotic focus is absent in category B tumours and present in category C tumours. Category B is subclassified into B1, which has areas of lepidic growth, and B2, which does not. Category C is subclassified into C1, which has invasive tumour cells in the periphery of central fibrotic focus, and C2, which has invasive tumour cells in the centre of central fibrotic focus. Based on the absence or presence of micropapillary pattern, the C2 tumours are further subclassified into C2a and C2b, respectively., Results: The 5-year recurrence-free probabilities for categories B1 (17 cases), B2 (10 cases), C1 (nine cases), C2a (114 cases) and C2b (62 cases) are 100%, 78.8%, 100%, 67.5% and 53.1%, respectively (p<0.001)., Conclusions: Based on stromal invasion and micropapillary pattern, the histopathological categorical classification proposed here provides a concise and precise scheme for outcome prediction in early-stage lung adenocarcinomas.

Tumor recurrence is the most common cause of disease failure after surgical resection in early-stage lung adenocarcinoma. Identification of clinically relevant prognostic markers could help to predict patients with high risk of disease recurrence. A meta-analysis of available lung adenocarcinoma microarray datasets revealed that T-LAK cell-originated protein kinase (TOPK), a serine/threonine protein kinase, is overexpressed in lung cancer. Using stable cell lines with overexpression or knockdown of TOPK, we have shown that TOPK can promote cell migration, invasion, and clonogenic activity in lung cancer cells, suggesting its crucial role in lung tumorigenesis. To evaluate the prognostic value of TOPK expression in resected stage I lung adenocarcinoma, a retrospective analysis of 203 patients diagnosed with pathological stage I lung adenocarcinoma was carried out to examine the expression of TOPK by immunohistochemistry (IHC). The prognostic significance of TOPK overexpression was examined. Overexpression of TOPK (IHC score >3) was detected in 67.0% of patients, and these patients were more frequently characterized with disease recurrence and angiolymphatic invasion. Using multivariate analysis, patient age (>65 years old; P = 0.002) and TOPK overexpression (IHC score >3; P < 0.001) significantly predicted a shortened overall survival. Moreover, TOPK overexpression (IHC score >3; P = 0.005) also significantly predicted a reduced time to recurrence in the patients. Our results indicate that overexpression of TOPK could predetermine the metastatic capability of tumors and could serve as a significant prognostic predictor of shortened overall survival and time to recurrence., (© 2011 Japanese Cancer Association.)

Introduction: Previous studies have shown that lung squamous cell carcinoma has higher ¹⁸F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) than adenocarcinoma. We hypothesized that histological subtypes of lung adenocarcinoma were also different in ¹⁸F-FDG uptake., Methods: Patients who had preoperative PET/computed tomography (CT) scan and had undergone complete resection for lung adenocarcinoma between April 2007 and December 2009 were enrolled in this study. Because of the limitation of spatial resolution on PET/CT, tumors less than 1 cm were excluded for analysis. Two independent classification systems were used to categorize histological subtypes of adenocarcinoma; one was modified from the current World Health Organization classification and the other used the morphological features of the terminal respiratory unit (TRU). The maximal standardized uptake value (SUVmax) on PET/CT and the glucose transporter type 1 (GLUT-1) expression of the tumors were measured and correlated to the histology of lung adenocarcinoma., Results: One hundred fifty-two patients with 153 primary lung adenocarcinomas were included. There was a significant difference in SUVmax among different histological subtypes. Namely, solid predominant adenocarcinomas had significantly higher SUVmax than those with other predominant histology (p < 0.001), and TRU-type adenocarcinomas had significantly lower SUVmax than non-TRU-type adenocarcinomas (p < 0.001). Consistently, GLUT-1 expression was higher in tumors with a solid growth pattern than those without (p < 0.001) and in tumors with non-TRU type than TRU type (p < 0.001)., Conclusions: The histological subtypes of lung adenocarcinomas differ in GLUT-1 expression and ¹⁸F-FDG uptake on the PET/CT scan, suggesting that histological subtyping not only has morphological but also biological implications.

Purpose: Early lung adenocarcinoma may present with ground-glass opacity (GGO) component in computed tomography (CT) scan. Epidermal growth factor receptor (EGFR) mutation had been reported in patients with lung cancer with GGO patterns. Nevertheless, the correlation between clinical characteristics, CT image patterns, and EGFR mutation status was indeterminate., Methods: Patients with stage I lung adenocarcinoma with tumor lesions less than 3 cm were included and classified into pure GGO, part-solid, and solid patterns by CT scan images. All patients had EGFR mutation test from frozen tumors. Available paraffin-embedded archival tissues were microdissected into three different locations similar to CT images with central and peripheral parts of tumor, and adjacent normal part for EGFR mutation tests., Results: Totally, 162 patients were analyzed, 90 women and 72 men, and 128 nonsmokers. The patients included 35 (21.6%) pure GGO, 41 (25.3%) part-solid, and 86 (53.1%) solid lesions. The EGFR mutation rate was 64.2% (n = 104). Analysis of the correlation between CT image patterns and EGFR mutation, the less GGO ratio had more typical mutation, especially L858R (p = 0.037). In 45 microdissected tumors, the central and peripheral parts had the same EGFR mutation status. In adjacent normal parts, 5 of 32 (15.6%) EGFR mutant patients had identical mutation but none in nonmutant patients., Conclusions: In stage I lung adenocarcinoma, typical mutation, especially L858R was detected more frequent in invasive solid pattern and significantly less in pure GGO pattern. EGFR mutation is an early event in the pathogenesis of lung adenocarcinoma and may facilitate the tumor into aggressive behavior.

Aims: To study the clinicopathological features of pulmonary adenocarcinomas with microcystic histology., Materials and Results: Two cases of pulmonary adenocarcinoma exhibiting a unique microcystic growth pattern were analysed. The 20-mm tumour of a 59-year-old woman showed a predominantly complex microcystic architecture with a focal papillary configuration, whereas the 15-mm tumour of another 46-year-old woman displayed a solely microcystic growth pattern. The first tumour was found to have metastasized to lymph nodes at surgery and, 4 years later, to the chest wall. The second tumour did not metastasize or recur over a follow-up period of 12 years. The tumour cells were immunoreactive with thyroid transcription factor-1 (TTF-1), which helped to differentiate them from salivary gland-type tumours. No mutations of epidermal growth factor receptor (EGFR) or K-ras genes were detected. However, facilitated by laser microdissection, a Q787Q polymorphism was found in the microcystic component but not in the papillary component. To our knowledge, this is the first report to illustrate intratumoral heterogeneity of EGFR gene polymorphism among different growth patterns within the same tumour., Conclusions: Pulmonary microcystic adenocarcinoma has a variable clinical outcome. The microcystic tumour cells are immunoreactive with TTF-1 and may harbour polymorphisms of the EGFR gene.

The prognostic role of histological patterns of dominant tumor (DT) and second dominant tumor (sDT) in synchronous multiple adenocarcinoma (SMADC) of lung remains unclear. SMADC patients diagnosed between 2003 and 2015 were retrospectively reviewed. DT and sDT were defined as two maximum diameters of consolidation among multiple tumors. Histological pattern was determined using IASLC/ATS/ERS classification system. DTs were divided into low- (lepidic), intermediate- (acinar, papillary) and high-grade (micropapillary, solid) subtypes, and sDTs into non-invasive predominant (lepidic) and invasive predominant (acinar, papillary, micropapillary, solid) subtypes. During mean 74-month follow-up among 149 nodal-negative patients having SMADC resected, recurrence was noted in 44 (29.5%), with significantly higher percentage in high-grade DT (p < 0.001). Five-year overall (OS) and disease-free (DFS) survivals in low-, intermediate- and high-grade DT were 96.9%, 94.3%, 63.3% (p < 0.001) and 100%, 87.2%, 30.0%, respectively (p < 0.001). Cox-regression multivariate analysis demonstrated high-grade DT as a significant predictor for DFS (Hazard ratio [HR] 5.324; 95% CI 2.570–11.462, p < 0.001) and OS (HR 3.287; 95% CI 1.323–8.168, p = 0.010). Analyzing DT and sDT together, we found no significant differences in DFS, either in intermediate- or high-grade DT plus invasive or non-invasive sDT. DT was histologically an independent risk factor of DFS and OS in completely resected nodal-negative SMADCs. [ABSTRACT FROM AUTHOR]

Background: Although the lower lobes of the lungs occupy half of the chest on both sides, the prognostic value of tumor location in lung cancer in the lower lobe has not been well demonstrated. This study investigated the prognostic value of tumor location (basal vs. superior) in patients with resected lung adenocarcinoma in the lower lobe. Methods: A total of 207 patients undergoing lobectomy for lung adenocarcinoma in the lower lobe were included in the study. The association between tumor location and mediastinal lymph node metastasis was analyzed. Prognostic factors of overall survival and probability of freedom from recurrence (FFR) were also investigated. Results: During follow‐up, 71 (34.3%) patients developed recurrence. Patients with basal segment tumors had a significantly higher possibility of developing N2 lymph node metastasis than those with superior segment tumors (P = 0.025). Univariate analysis showed that location in the basal (vs. superior) segment was a significant prognostic factor for a lower probability of FFR (P = 0.013). Basal (vs. superior) segment remained a significant prognostic factor for a lower probability of FFR (P = 0.010) in multivariate analysis. Conclusions: Basal segment tumors have a significantly higher possibility of developing N2 lymph node metastasis than superior segment tumors in resected lung adenocarcinoma in the lower lobe. Tumor location at the basal segment was a significant prognostic factor for a lower probability of FFR. This information is useful for patient stratification of risk of postoperative recurrence. [ABSTRACT FROM AUTHOR]

Background: Aldo‐keto reductases (AKRs) modify carbonyl groups on aldehyde or ketones to form primary or secondary alcohols, which are then conjugated with sulfates or glucuronide for excretion. The AKR1B10 gene encodes a member of the AKR superfamily. Overexpression of AKR1B10 plays an important role in the tumorigenesis of lung cancer cells; however, the prognostic value of AKR1B10 expression in patients with lung adenocarcinoma has not been well demonstrated. Methods: A total of 96 patients with resected lung adenocarcinoma were included in the study. AKR1B10 expression was determined by immunohistochemistry in tumor specimens. The prognostic value of AKR1B10 overexpression and its relationship with clinicopathological variables were investigated. Results: AKR1B10 overexpression was identified in 22 (22.9%) of the 96 patients and tended to be significantly associated with N1 or N2 status (P = 0.055). AKR1B10 overexpression was not a significant prognostic factor for overall survival (P = 0.301) but was a significant prognostic factor for poor recurrence‐free survival (P = 0.015). T status (T3 or T4 vs. T1 or T2; P = 0.020), N1 or N2 (vs. N0; P = 0.019), predominant pattern group (lepidic/acinar/papillary vs. micropapillary/solid; P = 0.023), and AKR1B10 overexpression (P = 0.013) were significant prognostic factors for poor recurrence‐free survival in multivariate analysis. Conclusions: AKR1B10 overexpression was a significant prognostic factor for poor recurrence‐free survival in patients with resected lung adenocarcinoma. This information is useful to stratify patients at high‐risk of recurrence after lung adenocarcinoma resection. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma has a strong propensity to metastasize to the brain. The brain metastases are difficult to treat and can cause significant morbidity and mortality. Identifying patients with increased risk of developing brain metastasis can assist medical decision-making, facilitating a closer surveillance or justifying a preventive treatment. We analyzed 27 lung adenocarcinoma patients who received a primary lung tumor resection and developed metastases within 5 years after the surgery. Among these patients, 16 developed brain metastases and 11 developed non-brain metastases only. We performed targeted DNA sequencing, RNA sequencing and immunohistochemistry to characterize the difference between the primary tumors. We also compared our findings to the published data of brain-tropic and non-brain-tropic lung adenocarcinoma cell lines. The results demonstrated that the targeted tumor DNA sequencing did not reveal a significant difference between the groups, but the RNA sequencing identified 390 differentially expressed genes. A gene expression signature including CDKN2A could identify 100% of brain-metastasizing tumors with a 91% specificity. However, when compared to the differentially expressed genes between brain-tropic and non-brain-tropic lung cancer cell lines, a different set of genes was shared between the patient data and the cell line data, which include many genes implicated in the cancer-glia/neuron interaction. Our findings indicate that it is possible to identify lung adenocarcinoma patients at the highest risk for brain metastasis by analyzing the primary tumor. Further investigation is required to elucidate the mechanism behind these associations and to identify potential treatment targets. [ABSTRACT FROM AUTHOR]