Keigo Sekihara

Aggressive tumor microenvironment of solid predominant lung adenocarcinoma subtype harboring with epidermal growth factor receptor mutations

INTRODUCTION Tumor microenvironment critically affects cancer progression. This study aimed to identify differences in microenvironments of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations by histological subtypes. METHODS The study cohort included 214 lung adenocarcinomas harboring EGFR mutations. We analyzed clinicopathological characteristics of lepidic (LPA), papillary (PPA), acinar (APA), and solid-predominant adenocarcinoma (SPA) subtypes, and examined expression levels of EGFR, E-cadherin, ezrin, laminin-5, ALDH1, and PD-L1 in cancer cells, and of CD34, CD204, podoplanin (PDPN), and FoxP3 in stromal cells in 4 subtypes (n=20 each). RESULTS SPA displayed significantly more frequent lymph node metastasis, lymphovascular invasion, and worse prognosis than the other subtypes. Ezrin expression levels in SPA were also significantly higher than in LPA, PPA, or APA (P<0.05, all). Laminin-5 and PD-L1 expression levels in SPA were significantly higher than in LPA (P<0.01 for both) and PPA (P<0.01 for both) and tended to be higher than in APA (laminin-5: P=0.096, PD-L1: P=0.081). Furthermore, SPA displayed higher levels of PDPN (+) cancer-associated fibroblasts (P<0.01) and CD204 (+) tumor-associated macrophages (P<0.05) than the other subtypes. CONCLUSION Compared with other predominant subtypes with EGFR mutations, the microenvironment of SPA with EGFR mutations is characterized by cancer cells with higher invasive and immune evasion potential and more abundant stromal cells with tumor-promoting functions, which would contribute to the more aggressive behavior of SPA.

Visualization of phosphatidylcholine (16:0/16:0) in type II alveolar epithelial cells in the human lung using imaging mass spectrometry

Imaging mass spectrometry (MS) is an emerging technique that can detect numerous biomolecular distributions in a non‐targeting manner. In the present study, we applied a mass imaging modality, mass microscopy, to human lung tissue and identified several molecules including surfactant constituents in a specific structure of the lung alveoli. Four peaks were identified using imaging MS, and the ion at m/z 772.5, in particular, was localized at some spots in the alveolar walls. Using an MS/MS analysis, the ion was identified as phosphatidylcholine (PC)(16:0/16:0), which is the main component of lung surfactant. In a larger magnification of the lung specimen, PC (16:0/16:0) was distributed in a mottled fashion in a section of the lung. Importantly, the distribution of PC (16:0/16:0) was identical to that of anti‐SLC34A2 antibody immunoreactivity, which is known to be a specific marker of type II alveolar epithelial cells, in the same section. Our experience suggests that imaging MS has excellent potential in human pathology research.

Clinical and Pathological Staging Validation in the Eighth Edition of the TNM Classification for Lung Cancer: Correlation between Solid Size on Thin-Section Computed Tomography and Invasive Size in Pathological Findings in the New T Classification

Introduction: The aim of this study was to validate the new eighth edition of the TNM classification and to elucidate whether radiological solid size corresponds to pathological invasive size incorporated in this T factor. Methods: We analyzed the data on 1792 patients who underwent complete resection from 2003 to 2011 at the National Cancer Center Hospital East, Japan. We reevaluated preoperative thin‐section computed tomography (TSCT) to determine solid size and pathological invasive size using the fourth edition of the WHO classification and reclassified them according to the new TNM classification. The discriminative power of survival curves by the seventh edition was compared with that by the eighth edition by using concordance probability estimates and Akaikes information criteria calculated using a univariable Cox regression model. Pearsons correlation coefficient was calculated to elucidate the correlation between radiological solid size using TSCT and pathological invasive size. Results: The overall survival curves in the eighth edition were well distinct at each clinical and pathological stage. The 5‐year survival rates of patients with clinical and pathological stage 0 newly defined were both 100%. The concordance probability estimate and Akaikes information criterion values of the eighth edition were higher than those of the seventh edition in discriminatory power for overall survival. Solid size on TSCT scan and pathological invasive size showed a positive linear relationship, and Pearsons correlation coefficient was calculated as 0.83, which indicated strong correlation. Conclusions: This TNM classification will be feasible regarding patient survival, and radiological solid size correlates significantly with pathological invasive size as a new T factor.

D2‐40‐positive lymphatic vessel invasion is not a poor prognostic factor in stage I lung adenocarcinoma

The present study investigates whether lymphatic vessel invasion (LVI) detected by D2‐40 staining is a prognostic factor for stage I adenocarcinoma of the lung. We retrospectively reviewed 124 patients who underwent complete resection for stage I adenocarcinoma of the lung from January 1983 to June 2003. LVI was microscopically evaluated using D2‐40 immunostaining. The median follow‐up was 71 months. The LVI positive rate was 37%. The 5‐year cancer‐specific survival rates of the D2‐40 positive LVI and negative groups were 88.8% and 84.3%, respectively (P = 0.630). The stage I lung adenocarcinoma patients who were determined to be LVI positive based on D2‐40 immunostaining did not have a significantly poorer prognosis than the LVI negative cases. Thus, lymphatic microinvasion may not be a prognostic indicator in early lung cancer, although advanced LVI does appear to correlate with survival. It is therefore unnecessary to use D2‐40 immunostaining to diagnose LVI in practical settings, and Hematoxylin‐Eosin and Elastica van Gieson staining should continue to be used to predict the prognosis of patients with stage I lung adenocarcinoma.

Long-term survival after complete resection of non-small-cell lung cancer in patients with interstitial lung disease

OBJECTIVES Patients with lung cancer and interstitial lung disease (ILD), usual interstitial pneumonia in particular, are known to have a poor outcome. The aim of this study was to evaluate the prognostic impact of ILD in patients with non-small-cell lung cancer. METHODS A total of 2054 consecutive patients underwent complete resection of Stage IA-IIIA non-small-cell lung cancer in our institution between January 2002 and March 2013. The presence of ILD was diagnosed and categorized based on high-resolution computed tomography images. Multivariate analysis was performed to identify the prognostic factors. RESULTS There were 106 (5%) patients with ILD. There were significantly more patients who developed severe complications (P < 0.01) in the ILD group, with 4 (4%) patients developing acute exacerbation. Although the difference in postoperative mortality rate was marginal between the groups (P = 0.07), the 5-year overall survival and cancer-specific survival rates of the ILD patients were significantly worse than those of the non-ILD group (overall survival: 40.4% vs 72.0%, P < 0.01; cancer-specific survival 55.4% vs 78.6%, P < 0.01). The results of multivariate analysis showed that coexistence of ILD (hazard ratio 1.45; P = 0.01) was an independent, unfavourable prognostic factor. CONCLUSIONS The presence of ILD led to a much poorer survival after complete resection of non-small-cell lung cancer.

Long-term survival outcome after postoperative recurrence of non-small-cell lung cancer: who is 'cured' from postoperative recurrence?

OBJECTIVES Since survival after postoperative non‐small‐cell lung cancer (NSCLC) recurrence is extremely poor, the long‐term post‐recurrence outcomes are not well understood. The purpose of this study was to evaluate the long‐term post‐recurrence outcomes and clarify who are possibly ‘cured’ in recent clinical practice. METHODS We reviewed the medical records of 635 patients who developed postoperative recurrence until 2012 after R0 resection for pathological Stage IA‐IIIA NSCLC between 1993 and 2006. Factors associated with post‐recurrence survival (PRS) and the characteristics of the long‐term (≥5 years) survivors were analysed retrospectively. RESULTS The 5‐year PRS rate of all 635 patients was 13%. Multivariable analysis revealed that female [hazard ratio (HR) = 0.78], adenocarcinoma (HR = 0.77), locoregional (only) recurrence (HR = 0.59) and longer recurrence‐free survival (HR = 0.99) were favourably associated with PRS. A total of 51 patients achieved 5‐year PRS; however, 32 (63%) were cancer‐bearing patients in their fifth post‐recurrent year who were mainly treated by epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI). Subsequent PRS curves for cancer‐controlled and cancer‐bearing groups were different (8‐year PRS: 94% vs 31%, P = 0.003). Among 19 cancer‐controlled patients in their fifth post‐recurrent year, 17 (89%) patients initially received radical local therapy for their recurrence. CONCLUSIONS Two‐thirds of 5‐year survivors after postoperative NSCLC recurrence had a cancer‐bearing status and showed deteriorated subsequent survival. Curability of postoperative NSCLC recurrence should be evaluated in terms of the ‘cancer‐controlled’ status, and ‘cured’ population is included in the patients who are ‘cancer controlled’ at the fifth post‐recurrent year.

P31: Salvage surgery for PMGCT: beneficial for persistent positive-marker patients?

Background Primary mediastinal germ cell tumors (PMGCT) are rare and high-grade malignant tumors. Mainstay treatment for PMGCT is systemic chemotherapy, and salvage surgery for residual tumor is considered in patients with normalized tumor makers. However, survival benefit of salvage surgery for persistent positive-marker patients remains unclear. The purpose is to clarify the outcome of salvage surgery for PMGCT.