Yuki Matsumura

Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung

Tumor budding is morphologically defined as infiltration by small clusters of cancer cells. While the biological properties of budding cells in adenocarcinoma (decreased expression of adhesion molecules and of differentiation markers) have been elucidated, those of the cells in squamous cell carcinoma (SqCC) of the lung still remain to be clarified. We examined the clinicopathological data of 217 patients with SqCC of the lung. Furthermore we evaluated the immunohistochemical properties of the budding cells. Tumor budding was observed in 83 (38.2%) patients. A statistically significant difference was observed in overall 5-year survival rates between the cases showing tumor budding and the cases not showing budding (45.6% vs. 64.0%, p<0.001). As compared with cancer cells forming solid nests, budding cells (BCs) exhibited reduced expression levels of the cellular adhesion molecules (E-cadherin; p=0.004, β-catenin; p=0.002) and increased expression levels of laminin-5γ2 (p=0.001). On the other hand, no significant differences in the staining scores for differentiation markers (p63 and podoplanin) were found between BCs and cancer cells forming nests. Multivariate analysis revealed that tumor budding was a significant independent prognostic factor in patients with SqCC of the lung (p=0.022). Tumor budding is an independent adverse prognostic factor in patients with SqCC of the lung. Although budding cells in SqCC exhibited reduced expression levels of the cellular adhesion molecules, the expression levels of specific differentiation markers were retained, suggesting that the budding mechanism in SqCC may differ, at least in part, from that in adenocarcinoma.

Prognostic impact of microscopic vessel invasion and visceral pleural invasion in non-small cell lung cancer: a retrospective analysis of 2657 patients.

Objective:We aimed to assess the prognostic significance of microscopic vessel invasion (MVI) and visceral pleural invasion (VPI) in non–small cell lung cancer (NSCLC). Background:VPI is included in the current tumor-node-metastasis (TNM) classification in NSCLC; however, MVI is not incorporated in TNM classification. Methods:From August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection. In addition to conventional staging factors, we evaluated MVI histologically and analyzed its significance in NSCLC recurrence prognosis. The recurrence-free period in several NSCLC subgroups was analyzed using the Kaplan-Meier method and Cox regression analysis. Results:The proportion of patients with a 5-year recurrence-free period was 52.6% and 87.5%, respectively, in those with and without MVI (P < 0.001). Multivariate analysis showed that MVI, similarly to VPI, was found to be an independently significant predictor of recurrence [hazard ratio (HR): 2.78]. In particular, MVI and VPI were the 2 strongest significant independent predictors of recurrence in 1601 patients with pathological stage I disease treated without adjuvant chemotherapy (HR: 2.74 and 1.84, respectively). In each T subgroup analysis, evident and significant separation of the recurrence-free proportion curves were observed among the 3 groups (VPI and MVI absent, VPI or MVI present, and VPI and MVI present). Conclusions:This study demonstrated that MVI was a significant independent risk factor for recurrence in patients with a resected T1-4N0-2M0 NSCLC. Further data on MVI prognostic impact should be collected for the next revision of the TNM staging system.

Prognostic Impact of Hypoxia-Inducible miRNA-210 in Patients with Lung Adenocarcinoma

Objective. The aim of this study was to investigate the prognostic value of MicroRNA-210 (miR-210) expression in patients with non-small-cell lung cancer (NSCLC). Methods. We examined the miR-210 expression of samples of 80 patients, who underwent surgical resection at Fukushima Medical University from 2004 to 2007, by using quantitative RT-PCR. The relationship between miR-210 expression and clinicopathological factors as well as histological subtype was statistically analyzed. Results. miR-210 expression showed an inverse correlation with disease-free and overall survival in patients with NSCLC. Significant correlations were found between miR-210 expression and lymph node metastasis, late disease stages, and poor prognosis in patients with adenocarcinoma. Multivariate Cox analysis indicated that miR-210 expression was an independent prognostic factor for disease-free survival in patients with adenocarcinoma. Conclusions. We showed that miR-210 may be a prognostic biomarker for patients with NSCLC, especially for those with lung adenocarcinoma.

Prognostic impact of the combination of glucose transporter 1 and ATP citrate lyase in node-negative patients with non-small lung cancer

OBJECTIVE Metabolic alternations are deemed a hallmark of cancer cells. Among many metabolic pathways, glycolysis and lipogenesis are essential metabolic processes in cancer cells. In this study, we examined the prognostic impact of the combined expression of glycolysis-related glucose transporter 1 (GLUT1) and ATP-citrate lyase (ACLY), which are important molecules in lipogenesis, in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS GLUT1 and ACLY expression in 134 NSCLC specimens were determined by immunohistochemistry using a tissue microarray (TMA). We examined the overall survival of patients with GLUT1-, ACLY- or GLUT+ACLY-positive expression using Kaplan-Meier analysis. We analyzed the prognostic impact of combined GLUT1 and ACLY expression according to lymph node status using multivariate Cox analysis. RESULTS Patients with GLUT1- or ACLY-positive expression exhibited poorer overall survival compared with GLUT1- or ACLY-negative patients. GLUT1-positive/ACLY-positive expression status was associated with the worst overall survival, in contrast with GLUT1 negative/ACLY-negative expression status, which was correlated with the best overall survival (P=0.003). GLUT1-positive/ACLY-positive expression was significantly correlated with poor prognosis in node-negative but not in node-positive patients. Multivariate Cox analysis indicated combined expression of GLUT1 and ACLY was an independent prognostic factor for overall survival in node-negative patients with NSCLC (P=0.049). CONCLUSION These results suggest that the combined expression of GLUT1 and ACLY could be a more valuable prognostic factor than their individual expression in node-negative patients with NSCLC.

Identification of Early T1b Lung Adenocarcinoma Based on Thin-Section Computed Tomography Findings

Introduction: The aim of this study was to radiologically identify early lung adenocarcinoma in clinical T1bN0M0 lung cancer, based on pathological findings and long-term prognosis. Methods: In this study, we reviewed lung nodules findings on thin-section computed tomography in 173 patients with clinical T1bN0M0 lung adenocarcinoma who underwent surgery between 2003 and 2007. The ratio of the size of solid attenuation to the maximum tumor dimension (consolidation/tumor [C/T] ratio) was calculated. We defined two groups of patients by C/T ratio cutoff levels of 0.00, 0.25, 0.50, 0.75, and 1.00 and compared the rates of pathological nonaggressive lung adenocarcinoma, overall survival, and recurrence rates between the groups. The percentages of predominant histological subtypes were compared between two groups divided by the optimal cutoff level. Various clinical factors were analyzed by univariate and multivariate analyses to predict pathological lymph node involvement. Results: The median follow-up period was 62 months. All patients with C/T ratios of 0.5 or less were diagnosed as having pathological nonaggressive adenocarcinomas, and there was no recurrence; their 5-year overall survival rate was 97.4%, which was significantly better than that for patients with C/T ratios of greater than 0.5 (76.2%). None of the ground-glass opacity–predominant tumors were predominantly solid adenocarcinoma with mucin. The C/T ratio of 0.5 or more was an independent predictor of lymph node involvement. Conclusion: In patients with clinical T1bN0M0 disease, the C/T ratio of 0.5 or less identified early lung adenocarcinoma. In patients with the identified early disease, a feasibility study of limited surgery may be warranted.

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non–small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%–100%). Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757–65. ©2016 AACR.

Pulmonary artery pseudoaneurysm after lung resection successfully treated by coil embolization

A 60-year-old man complaining of pyrexia and hemoptysis was diagnosed with a squamous cell carcinoma in his right lung. He underwent a right lower lobectomy with lymph node dissection. Following chest tube removal, he suffered from pyrexia and hemoptysis necessitating CT-scans which detected a pulmonary artery pseudoaneurysm (PAP). An emergent pulmonary arteriography was performed and the PAP was embolized with microcoils. After six years of follow-up, he has been free from recurrence of both the PAP and lung cancer. PAPs represent a rare, but life-threatening condition. Because of their risk of rupture, emergent intervention is necessary. In the past, PAPs were treated with open repair, but recent advances in endovascular surgery have allowed for a less invasive treatment. In this report, we describe an extremely rare case of PAP after lobectomy for lung cancer that was successfully treated by coil embolization.

Impact of Extratumoral Lymphatic Permeation on Postoperative Survival of Non–Small-Cell Lung Cancer Patients

Introduction: Lymphatic permeation has been reported as a prognostic factor for patients with resected non–small-cell lung cancer (NSCLC). Lymphatic canals are located in both intratumoral and extratumoral areas. Since 2001, we have prospectively evaluated lymphatic permeation based on its location. The purpose of this study was to determine the survival impact of extratumoral lymphatic permeation in patients with resected NSCLC by analyzing the long-term follow-up data. Methods: We reviewed 1069 consecutive patients with NSCLC who underwent complete resection between 2001 and 2006. Lymphatic permeation was classified as follows: ly0, absence of lymphatic permeation; ly1, intratumoral; and ly2, extratumoral. Results: There were 845 patients (79%) with ly0, 134 (12%) with ly1, and 90 (9%) with ly2. Ly2 was more frequently observed in patients with advanced disease and intrapulmonary metastases than ly0–1. The 5-year overall survival (OS) rates of the ly0, ly1, and ly2 groups were 75%, 63%, and 34%, respectively. The OS rate was significantly worse in the ly2 group compared with OS rate in the ly0 (p < 0.01) and ly1 groups (p < 0.01). In multivariate analyses, ly2 proved to be an independent poor prognostic factor (hazard ratio, 1.73; p < 0.01). OS and recurrence-free survival of patients with T1 and T2 tumors with ly2 were not statistically different from that of the patients with T3 tumor (OS, p = 0.43 and p = 0.77; recurrence-free survival, p = 0.94 and p = 0.94, respectively). Conclusions: The adverse prognostic impact of lymphatic permeation was remarkably different whether it is detected in intratumoral or extratumoral lymphatic canals. We recommend that lymphatic permeation in resected NSCLC should be evaluated by considering its location.

Prognostic impact of the high-sensitivity modified Glasgow prognostic score in patients with resectable non-small cell lung cancer

OBJECTIVE The present study compared the prognostic value of the Glasgow prognostic score (GPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) in patients with resectable non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This retrospective study included 327 consecutive patients with resectable NSCLC with a follow.-up period. >5. years. Initially, the HS-mGPS was directly compared with the GPS and mGPS in terms of their ability to predict survival in patients with resectable NSCLC. Second, inflammation.-based scores, including the HS-mGPS, NLR, PLR, PI, and PNI, were analyzed preoperatively using multivariate Cox analysis. Clinical characteristics reflecting cancer progression were also analyzed. RESULTS Elevated GPS (P < 0.001), mGPS (P < 0.001), and HS-mGPS (P < 0.001) levels were associated with reduced overall survival. The HS-mGPS (P < 0.001) was superior to the GPS and mGPS (P = 0.884) as a prognostic marker of postoperative outcomes. On multivariate Cox analysis, age (P = 0.026), p-T status (P < 0.001), p-N status (P < 0.001), lymphatic vessel invasion (P = 0.008), and the HS-mGPS (P = 0.016) were independent prognostic factors for survival. CONCLUSION These results suggest that the HS-mGPS might have a greater prognostic impact than the GPS, mGPS, NLR, PLR, PI, or PNI in patients with resectable NSCLC.

Reasonable Extent of Lymph Node Dissection in Intentional Segmentectomy for Small-Sized Peripheral Non-Small-Cell Lung Cancer From the Clinicopathological Findings of Patients Who Underwent Lobectomy with Systematic Lymph Node Dissection

Introduction: Currently, randomized clinical trials to evaluate segmentectomy compared with lobectomy for peripheral cT1aN0M0 non–small-cell lung cancer (NSCLC) are ongoing. During segmentectomy, some lobar-segmental lymph nodes (LSNs) can be difficult to resect for anatomical reasons. The purpose of this study was to clarify the reasonable extent of dissection during intentional segmentectomy for peripheral cT1aN0M0 NSCLC. Methods: We reviewed the records of patients who underwent lobectomies and systematic lymph node dissections for cT1aN0M0 NSCLC from 1992 to 2009. Among them, a total of 307 patients whose primary nodule was located in the outer third peripheral lung field on thin-section computed tomography (TSCT), and who could be candidates for intentional segmentectomy were enrolled in this study. We analyzed the clinical and radiological factors, which may predict nodal metastasis, and the distribution patterns of lymph node metastases. In particular, we set out to evaluate the specific LSNs, which are difficult to resect on segmentectomy (isolated LSNs [iLSNs]). Results: Of all patients, 34 (11%) had lymph node metastases (pN1: 9, pN2: 25). The median tumor sizes and tumor disappearance rates (TDRs) on TSCT were significantly larger and lower, respectively, compared with those of the remaining 273 node-negative patients. All 34 node-positive patients had a solid-dominant component on TSCT (TDR < 0.25). Of these, nine patients (n = 5, station 11, n = 4, station 13) were iLSN positive, but all of them also had metastases to station 12 or mediastinal lymph nodes. No patients had solitary metastasis in iLSNs. Conclusions: The reasonable extent of dissection for intentional segmentectomy for small (⩽ 2 cm) peripheral NSCLC includes LSNs in the segments with tumors, and the hilar and mediastinal nodes. It may not be necessary to examine iLSNs. Systematic lymph node dissection might not be necessary for tumors with ground grass opacity on TSCT (TDR ≥ 0.25).