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OBJECTIVE Several clinical studies have demonstrated the efficacy and safety of adjuvant chemotherapy in patients with completely resected small cell lung cancer for a selected limited stage. However, it is unclear whether adjuvant chemotherapy is feasible in clinical practice. The objective of this study was to analyze the efficacy and safety of adjuvant chemotherapy for small cell lung cancer patients retrospectively in clinical practice. METHODS From January 2002 to March 2012, 56 small cell lung cancer patients underwent surgery as initial therapy in our institute. Of these, 26 patients received adjuvant chemotherapy. The clinical data of patients who received adjuvant chemotherapy were retrospectively analyzed. RESULTS The chemotherapy regimens were cisplatin and irinotecan in 16 patients, cisplatin and etoposide in 1 and carboplatin and etoposide in 9. Median follow-up time was 44.8 months. Nineteen (73%) patients received the full course of chemotherapy. Median recurrence-free survival was 21.4 months. Median survival time was not reached. There was no treatment-related death. CONCLUSION Adjuvant chemotherapy may be generally safe and efficacious in selected small cell lung cancer patients.

Introduction Indications for surgical resection for small cell lung cancer (SCLC) have been very limited. Because early-stage SCLC is a rare presentation of lung cancer, studies comparing surgical resection among a large number of patients are unlikely to be conducted. This study reports the most recent surgical outcomes of a large number of SCLC patients who underwent surgery in 2004. Methods: In 2010, the Japanese Joint Committee of Lung Cancer Registry performed a nationwide retrospective registry study regarding the prognosis and clinicopathologic profiles of 11,663 patients who underwent resection for primary lung cancer in 2004. Of the 11,663 patients, 243 patients with SCLC (2.1%) were included in this study. The registry data of the patients with SCLC were analyzed, and the clinicopathologic profiles and surgical outcomes of the patients were evaluated. Results: The 5-year survival rate for all cases ( n = 243, 213 males, mean age 68.2 years) was 52.6%. The 5-year survival rates by c-stage and p-stage were as follows: IA, 64.3% ( n = 132) and 72.3% ( n = 93); IB, 45.7% ( n = 36) and 61.1% ( n = 51); IIA, 50.5% ( n =25); and 44.8% ( n = 27); IIB, 33.3% ( n = 10) and 40.3% ( n = 17); IIIA, 30.5% ( n = 30) and 23.4% ( n = 45); and IV, 0% ( n = 7) and 0% ( n = 9), respectively. A multivariate analysis showed that the significant prognostic factors were age, gender, c-stage, and surgical curability. A kappa value was moderate conformity between c-stage and p-stage in all cases. Conclusions: Surgical resection in selected patients with early-stage SCLC, especially stage I, had favorable results.

Large-cell neuroendocrine carcinoma (LCNEC) of the lung is an uncommon aggressive neoplasm with a poor prognosis compared with non-small-cell lung carcinoma (NSCLC). Because of its rarity, the treatment recommendations are not based on clinical trials, but are extrapolated from the approach to patients with NSCLC and small-cell lung carcinoma and the established literature for LCNEC, which is primarily retrospective in nature. Further studies should clarify the histology-specific characteristic and optimal therapeutic approach to establish the entity of LCNEC.

Background Lung adenocarcinoma with morule-like components is an unusual variant of lung adenocarcinoma, comprising uniform, tightly packed spindle-shaped cells, which fill the lumen of the glandular structures of the carcinoma. The aim of the study was to outline the clinicopathologic features of this variant. Patients and methods We examined a series of 904 surgically resected adenocarcinomas. We defined morule-like components as small buds of spindle-cell proliferation in the tumor lumen of the glandular structures of the carcinoma and calculated their proportion of total tumor mass. Targeted genotyping was performed for KRAS , EGFR , HER2 , and BRAF . ALK rearrangements were analyzed immunohistochemically. Immunopositive cases were confirmed using RT-PCR and/or FISH. Results We detected 17 cases of adenocarcinoma with morule-like components. This variant, representing only 1.9% was associated with unfavorable outcomes and a mutation in the EGFR . Histologic examination revealed adenocarcinoma with morule-like components accounting for 5−50% of tumors. Among the morule-like components, 10 (58.8%) of the 17 samples showed intracytoplasmic lumina formation containing eosinophilic mucinous material. The presence of micropapillary components in adenocarcinoma with morule-like components suggests that morule-like components could be merely excessive growth of the micropapillary pattern. However, our results indicated no statistical differences in the MIB-1 indices of the morule-like components and the adjacent tumor components or the micropapillary components. The univariate and multivariate analyses revealed a correlation between the presence of a morule-like components and an unfavorable outcome. Conclusions Our study clearly indicated that adenocarcinoma with morule-like components is distinct unfavorable prognostic and predictor for EGFR mutation.

Lobectomy and systematic nodal dissection are still the standard for small-size (

Solitary fibrous tumor (SFT) is an uncommon fibroblastic neoplasm. Although histologic characteristics and frequent CD34 expression allow for an accurate diagnosis in the majority of SFT cases, a wide histologic spectrum and an occasional unexpected immunophenotype may pose diagnostic challenges. Molecular analyses have discovered that almost all SFTs harbor an NAB2-STAT6 fusion gene, which is considered specific to this tumor type. Recent studies have suggested that STAT6 immunohistochemistry is a reliable surrogate for detection of the fusion gene. Our aim was to validate these findings by examining a large number of SFT cases and a broad array of 30 different types of non-SFT tumors. A total of 49 SFTs with a range of histologic characteristics and 159 benign or malignant tumors that can mimic SFTs were retrieved and stained for STAT6. All 49 SFTs (100%) showed STAT6 expression that was restricted in the nucleus, mostly in a diffuse and strong manner, irrespective of the tumor sites and histologic patterns. The staining was uniform in most cases but was heterogenous in about 20% of the cases in which zonal staining attenuation was observed, likely reflecting variability in fixation or tissue ischemia. In contrast, only 4 non-SFT tumors (2.5%) exhibited weak nuclear STAT6 expression, whereas the remaining 155 cases showed no staining or often weak reactivity in both the cytoplasm and the nucleus. Therefore, nuclear STAT6 immunoreactivity is a highly sensitive and specific marker of SFTs and can be helpful when diagnosis is inconclusive by conventional methods.

Background: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors. Methods: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription–PCR (RT–PCR) were performed to detect RET gene rearrangement. Results: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B–RET fusion genes, whereas 3 possessed CCDC6–RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P

Background Even if detected at an early stage, a substantial number of lung cancers relapse after curative surgery. However, no method for distinguishing such tumors has yet been established. Patients and methods The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridization on tissue microarrays comprising 543 surgically resected adenocarcinomas of the lung. Results Amplification (an increase in the copy number by ≥2.0 fold) of the ACTN4 gene was detected in two of seven lung adenocarcinoma cell lines and 79 (15%) of 543 cases of pathological stage I–IV lung adenocarcinoma. Multivariate analysis revealed that ACTN4 gene amplification was the most significant independent factor associated with an extremely high risk of death (hazard ratio, 6.78; P = 9.48 × 10-5, Cox regression analysis) among 290 patients with stage I lung adenocarcinoma. The prognostic significance of ACTN gene amplification was further validated in three independent cohorts totaling 1033 patients. Conclusions Amplification of the ACTN4 gene defines a small but substantial subset of patients with stage I lung adenocarcinoma showing a distinct outcome. Such patients require intensive medical attention and might benefit from postoperative adjuvant chemotherapy.

Nuclear inclusion or pseudoinclusion is a peculiar cytological feature, and its recognition in appropriate clinicopathological settings can aid in the diagnosis of several disease entities. To the best of our knowledge, only 1 case of pulmonary neuroendocrine tumor (NET) with nuclear pseudoinclusion has been reported. A review of 227 patients who had undergone surgical resection for pulmonary NETs revealed 2 tumors with different mechanisms of nuclear inclusion. To explore the cause of nuclear inclusion, NET with nuclear inclusion was characterized immunohistochemically and ultrastructurally. Nuclear inclusions were observed in 2 of the 227 (0.9%) patients with pulmonary NETs. The first patient was a 46-year-old woman with small cell carcinoma. Tumor cells with nuclear inclusions were distributed focally. Ultrastructural analysis showed that these inclusions were pseudoinclusions. The second patient was a 62-year-old man with large-cell neuroendocrine carcinoma. Nuclear inclusions were observed in the focal area of the tumor. Immunohistochemical analysis revealed that the intra-nuclear materials consisted of biotin and aberrant cytoplasmic and nuclear accumulation of β-catenin. Mutational analysis revealed a CTNNB1 gene mutation. Although very rare, diagnostic errors may be observed in cases of pulmonary NETs with nuclear inclusions. The mechanisms of nuclear inclusion differed, with one due to herniation of the cytoplasm into the nucleus (pseudoinclusion) and the other due to accumulation of biotin resulting from a CTNNB1 gene mutation.

Background The present study aimed to determine the ability of the revised International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification of lung adenocarcinoma to predict patient survivals and driver gene alterations. Patients and Methods A reclassification of 904 surgically resected adenocarcinomas was performed. The results were statistically analyzed to examine the correlation between the classification and overall survival (OS) using Cox regression analyses, and integrated discrimination improvement (IDI) analyses. Results The 5-year OS rates for adenocarcinomas in situ (AIS) or minimally invasive adenocarcinoma (MIA) were 98%. Five-year OS rates of Lepidic-, acinar-, papillary-, micropapillary-, and solid-predominant adenocarcinomas was 93%, 67%, 74%, 62%, and 58%, respectively. The IDI estimates revealed that classification of ADC into the 7 subgroups had a higher estimated (0.0175) than did the combined histological grouping (AIS + MIA, lepidic + acinar + papillary, micropapillary + solid + others) (0.0111). Epidermal growth factor receptor mutations, KRAS gene mutations, and anaplastic lymphoma kinase gene alterations were statistically prevalent in papillary-predominant ( P = 0.00001), invasive mucinous ( P = 0.00001), and micropapillary- and acinar-predominant ( P = 0.00001) adenocarcinomas, respectively. Conclusions The new classification reflects disease prognosis, and was also associated with driver gene alterations.

Recent clinical trials have revealed that accurate histologic typing of non-small cell lung cancer is essential. Until now, squamous cell carcinoma (SQC) and adenocarcinoma (ADC) markers have not been thoroughly analyzed for pulmonary neuroendocrine carcinomas (NECs). We analyzed the expression of 8 markers [p63, cytokeratin (CK) 5/6, SOX2, CK7, desmocollin 3, thyroid transcription factor-1 (8G7G3/1 and SPT24), and napsin A] in 224 NECs. SOX2 (76.2%) had the greatest expression for NECs. CK5/6 (1.4%), desmocollin 3 (0.5%), and napsin A (0%) were expressed less or not at all in NECs. Although our investigated markers have been reported useful for differentiating between SQC and ADC, some of them were also present in a portion of pulmonary NECs. In our study, CK5/6 and desmocollin 3 were highly specific markers for SQC, and napsin A was highly specific for ADC. These markers are recommended for diagnosis of poorly differentiated non-small cell lung cancer.

Low-grade lung adenocarcinoma of fetal lung type, which is well characterized by its unique clinicopathologic and molecular features, is recognized as a distinct variant of lung cancer. In contrast, high-grade lung adenocarcinoma with fetal lung-like morphology (HG-LAFM) has not been studied widely. To characterize this subset better, we analyzed 17 high-grade adenocarcinomas with at least focal component resembling a developing epithelium in the pseudoglandular phase of the fetal lung. These rare (ca. 0.4%) carcinomas occurred predominantly in elderly men with a heavy smoking history, who showed elevated serum α-fetoprotein in 4 of 5 cases tested. Histologic examination revealed a fetal lung-like component as a focal finding accounting for 5% to 60% of the total tumor volume. It was invariably admixed with tissues having a morphology not resembling that of a fetal lung. A coexisting non-fetal lung-like element was quite heterogenous in appearance, showing various growth patterns. However, clear-cell (88%), hepatoid (29%), and large cell neuroendocrine carcinoma (24%) histology seemed overrepresented. HG-LAFM was characterized immunohistochemically by frequent expression of α-fetoprotein (41%), glypican-3 (88%), SALL-4 (59%), neuroendocrine markers (82%), CDX-2 (35%), and p53 (65%). HG-LAFM was molecularly heterogenous in that EGFR or KRAS mutation was observed in 22% of cases tested for both. Our data indicate that HG-LAFMs might form a coherent subgroup of lung adenocarcinomas. However, the uniformly focal nature of the fetal lung-like element, widely diverse coexisting non-fetal lung-like histology, and inhomogenous molecular profiles lead us to believe that HG-LAFM is best regarded as a morphologic pattern showing characteristic association with several clinicopathologic parameters rather than a specific tumor entity.

Recent discovery of ROS1 gene fusion in a subset of lung cancers has raised clinical interest, because ROS1 fusion-positive cancers are reportedly sensitive to kinase inhibitors. To better understand these tumors, we examined 799 surgically resected non-small cell lung cancers by reverse transcriptase polymerase chain reaction and identified 15 tumors harboring ROS1 fusion transcripts (2.5% of adenocarcinomas). The most frequent fusion partner was CD74 followed by EZR. The affected patients were often younger nonsmoking female individuals, and they had overall survival rates similar to those of the ROS1 fusion-negative cancer patients. All the ROS1 fusion-positive tumors were adenocarcinomas except 1, which was an adenosquamous carcinoma. Histologic examination identified an at least focal presence of either solid growth with signet-ring cells or cribriform architecture with abundant extracellular mucus in 53% of the cases. These 2 patterns are reportedly also characteristic of anaplastic lymphoma kinase (ALK)-rearranged lung cancers, and our data suggest a phenotypic resemblance between the ROS1-rearranged and ALK-rearranged tumors. All tumors except 1 were immunoreactive to thyroid transcription factor-1. Fluorescence in situ hybridization using ROS1 break-apart probes revealed positive rearrangement signals in 23% to 93% of the tumor cells in ROS1 fusion-positive cancers, which were readily distinguished using a 15% cutoff value from 50 ROS1 fusion-negative tumors tested, which showed 0% to 6% rearrangement signals. However, this perfect test performance was achieved only when isolated 3' signals were included along with classic split signals in the definition of rearrangement positivity. Fluorescence in situ hybridization signal patterns were unrelated to 5' fusion partner genes. All ROS1 fusion-positive tumors lacked alteration of EGFR, KRAS, HER2, ALK, and RET genes.

OBJECTIVE: This study aimed to verify the prognostic impact of pleural invasion according to the revised TNM classification, seventh edition. METHODS: The study consisted of 1488 patients with surgically resected non-small cell carcinoma. The degree (pl0-3) and location of pleural invasion were examined using hematoxylin and eosin- and elastica van Gieson-stained slides, and outcome was compared with stratification by several clinicopathological factors. RESULTS: The 5-year overall survival rates of 1008, 260, 85 and 135 patients with pl0, pl1, pl2 and pl3 tumours were 80, 60, 55 and 52%, respectively. Overall survival differed significantly between patients with pl0 tumours and those with pl1 tumours (P < 0.0001). The difference was significant for patients with 1

Background High-grade neuroendocrine tumours (HGNTs) of the lung manifest a wide spectrum of clinical behaviour, but no method for predicting their outcome has been established. Materials and methods We newly established a monoclonal antibody specifically recognizing the product of the alternatively spliced ACTN4 transcript (namely, variant actinin-4), and used it to examine the expression of variant actinin-4 immunohistochemically in a total of 609 surgical specimens of various histological subtypes of lung cancer. Results Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 0.8% (3/378) of non-neuroendocrine (NE) lung cancers. The expression of variant actinin-4 was significantly associated with poorer overall survival in HGNT patients (P = 0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards model showed that the expression of variant actinin-4 was the most significant independent negative predictor of survival in HGNT patients (hazard ratio (HR), 2.15; P = 0.00113) after the presence of lymph node metastasis (HR, 2.25; P = 0.00023). Conclusions The expression of variant actinin-4 is an independent prognostic factor for patients with HGNTs. This protein has a high affinity for filamentous actin polymers and likely promotes aggressive behaviour of cancer cells. The present clinical findings clearly support this notion.

Nodal categories for malignant pleural mesothelioma are derived from the lung cancer staging system and have not been adequately validated. The International Association for the Study of Lung Cancer developed a multinational database to generate evidence-based recommendations to inform the eighth edition of the TNM classification of malignant pleural mesothelioma.Data from 29 centers were entered prospectively (n = 1566) or by transfer of retrospective data (n = 1953). Survival according to the seventh edition N categories was evaluated using Kaplan-Meier survival curves and Cox proportional hazards regression analysis. Survival was measured from the date of diagnosis.There were 2432 analyzable cases: 1603 had clinical (c) staging, 1614 had pathologic (p) staging, and 785 had both. For clinically staged tumors there was no separation in Kaplan-Meier curves between cN0, cN1 or cN2 (cN1 versus cN0 hazard ratio [HR] = 1.06, p = 0.77 and cN2 versus cN1 HR = 1.04, p = 0.85). For pathologically staged tumors, patients with pN1 or pN2 tumors had worse survival than those with pN0 tumors (HR = 1.51, p 0.0001) but no survival difference was noted between those with pN1 and pN2 tumors (HR = 0.99, p = 0.99). Patients with both pN1 and pN2 nodal involvement had poorer survival than those with pN2 tumors only (HR = 1.60, p = 0.007) or pN0 tumors (HR = 1.62, p0.0001).A recommendation to collapse both clinical and pN1 and pN2 categories into a single N category comprising ipsilateral, intrathoracic nodal metastases (N1) will be made for the eighth edition staging system. Nodes previously categorized as N3 will be reclassified as N2.

Introduction: The M component and TNM stage groupings for malignant pleural mesothelioma (MPM) have been empirical. The International Association for the Study of Lung Cancer developed a multinational database to propose evidence-based revisions for the eighth edition of the TNM classification of MPM. Methods: Data from 29 centers were submitted either electronically or by transfer of existing institutional databases. The M component as it currently stands was validated by confirming sufficient discrimination (by Kaplan-Meier analysis) with respect to overall survival (OS) between the clinical MO (cM0) and cM1 categories. Candidate stage groups were developed by using a recursive partitioning and amalgamation algorithm applied to all cM0 cases. Results: Of 3519 submitted cases, 2414 were analyzable and 84 were cM1 cases. Median OS for cM1 cases was 9.7 months versus 13.4 months (p = 0.0013) for the locally advanced (T4 or N3) cM0 cases, supporting inclusion of only cM1 in the stage IV group. Exploratory analyses suggest a possible difference in OS for single- versus multiple-site cM1 cases. A recursive partitioning and amalgamation generated survival tree on the OS outcomes restricted to cM0 cases with the newly proposed (eighth edition) T and N components indicates that optimal stage groupings for the eighth edition will be as follows: stage IA (T1N0), stage IB (T2-3N0), stage II (T1-2N1), stage IIIA (T3N1), stage IIIB (T1-3N2 or any T4), and stage IV (any M1). Conclusions: This first evidence-based revision of the TNM classification for MPM leads to substantial changes in the T and N components and the stage groupings. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Giant lamellar bodies (GLBs) are intra-alveolar eosinophilic concentric lamellar structures that typically have a diameter of 20–30 μm. GLBs are most commonly associated with sclerosing pneumocytoma, which was formerly known as sclerosing haemangioma.1, 2 In addition, GLBs have frequently been observed in mucosa-associated lymphoid tissue (MALT)-type lymphomas, and Perry et al.3 have suggested that GLBs may favour a diagnosis of lymphoma over follicular bronchiolitis. Other conditions that reportedly contain GLBs include alveolar adenoma,4 plasma cell granuloma,4 pulmonary alveolar proteinosis5, and Mycobacterium avium complex lung disease.6 Thus, GLBs have typically been associated with benign or low-grade lung lesions, and, to the best of our knowledge, there have been no reports regarding GLBs in lung carcinoma. Here, we describe 8 lung adenocarcinomas that harboured GLBs. This article is protected by copyright. All rights reserved.

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group was organized in 1986. Initially, 26 collaborative institutions participated. In the early period, the Lung Cancer Surgical Study Group focused on combined modality therapies and conducted nine trials, including JCOG9101: adjuvant chemotherapy for resected small-cell lung cancer, and JCOG9806: induction chemoradiotherapy followed by surgery for superior sulcus tumor, which greatly impacted the treatment strategies for some special kinds of lung cancer. Since the 2000s, the Lung Cancer Surgical Study Group has defined radiologically noninvasive adenocarcinoma: JCOG0201 and investigated adequate modes of surgical resection for small-sized non-small cell lung cancer: JCOG0802, JCOG0804 and JCOG1211. The accrual of these trials is now complete and we are waiting for the maturation of follow-up data. In addition, two adjuvant trials have been conducted: JCOG0707; a Phase III study of adjuvant chemotherapy for resected pathological stage I (T1 > 2 cm) non-small cell lung cancer, and JCOG1205; a Phase III study of adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine tumor. The accrual of JCOG0707 is complete and we are waiting for the maturation of follow-up data. At present, 44 institutions are active members of the Lung Cancer Surgical Study Group. In addition to thoracic surgeons, medical oncologists, pathologists and radiotherapists are participating in the Lung Cancer Surgical Study Group. The Lung Cancer Surgical Study Group continues to conduct various clinical trials in an effort to improve survival in patients with lung cancer. In this review, we provide an overview of the past 30 years, as well as the present status and future direction of the Lung Cancer Surgical Study Group.

Introduction Stage classification provides a consistent language to describe the anatomic extent of disease and is therefore a critical tool in caring for patients. The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer developed proposals for revision of the classification of lung cancer for the eighth edition of the tumor, node, and metastasis (TNM) classification, which takes effect in 2017. Methods An international database of 94,708 patients with lung cancer diagnosed in 1999–2010 was assembled. This article describes the process and statistical methods used to refine the lung cancer stage classification. Results Extensive analysis allowed definition of tumor, node, and metastasis categories and stage groupings that demonstrated consistent discrimination overall and within multiple different patient cohorts (e.g., clinical or pathologic stage, R0 or R-any resection status, geographic region). Additional analyses provided evidence of applicability over time, across a spectrum of geographic regions, histologic types, evaluative approaches, and follow-up intervals. Conclusions An extensive analysis has produced stage classification proposals for lung cancer with a robust degree of discriminatory consistency and general applicability. Nevertheless, external validation is encouraged to identify areas of strength and weakness; a sound validation should have discriminatory ability and be based on an independent data set of adequate size and sufficient follow-up with enough patients for each subgroup.

Background T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. Patients and methods We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. Results In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P Conclusions A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC.

Background Insulin-like growth factor-1 receptor (IGF-1R), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-type 2 (HER2), and c-Met are members of the receptor tyrosine kinases (RTKs). The associations between the RTK status [protein expression and gene copy number (GCN)] and patient characteristics and between the RTK status and prognosis remain undetermined. Materials and methods The study included 140 patients who underwent surgery for thymic tumors. Protein expression was evaluated by immunohistochemistry (IHC) and GCN was evaluated by bright-field in situ hybridization (BISH). The correlations between the RTK status and clinicopathological findings were examined. Results IGF-1R protein was frequently detected in thymic carcinoma (83.8%) and EGFR in thymic tumors (91.4%). Thirty-six and 39 tumors were BISH high for IGF-1R and EGFR, respectively: 28 and 25 exhibited high polysomy; 8 and 14 exhibited gene amplification. No tumor was positive for HER2 or c-Met by IHC and BISH. Multivariate analysis revealed that IGF-1R gene amplification (P = 0.027), thymic carcinoma histology, and higher tumor stage were significantly correlated with an adverse prognosis. Conclusions Thymic epithelial tumors frequently express IGF-1R and/or EGFR proteins. IGF-1R gene amplification is suggested to define an unfavorable subset for thymic epithelial tumors.

Background The current staging system for malignant pleural mesothelioma (MPM) is controversial. To plan revisions of this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. Initial analyses focus on patients managed surgically. Methods Participation was solicited from centers known to have MPM registries. Common data elements were analyzed by the International Association for the Study of Lung Cancer Staging Committee Statistical Center. Survival was analyzed by the Kaplan–Meier method, prognostic factors by log rank and Cox regression model. p Value less than 0.05 was significant. Results Data included 3101 patients (15 centers, 4 continents). Demographics: median age 63 years, 79% men, 62.3% epithelioid tumor. Best tumor, node, metastasis (bTNM) stages were: I (11%), II, (21%), III (48%), and IV (20%). Curative-intent surgery was performed in 1494 patients (64.5%). Median survivals by clinical TNM and pathological TNM were similar: stage I, 21 months; stage II, 19 months; stage III, 16 months; and stage IV, 12 months. Median survival by histology: epithelioid 19 months, biphasic 13 months, and sarcomatoid 8 months. By multivariable analyses, significant differences in overall survival were seen for: T4 versus T3 and T3 versus T2 but not T2 versus T1; N0 versus N1 and N2 but not N1 versus N2; stages III and IV versus I but not II versus I; epithelioid histology versus other; age of female versus age of male; and palliative versus curative-intent surgery. Conclusions This is the largest international database examining outcomes in surgically managed MPM patients. Survival differences reported from smaller databases are confirmed but suggest the need to revise tumor and node staging.

Secondary cancers developing after allogeneic hematopoietic stem cell transplantation generally originate from recipient-derived cells. In this study, we analyzed the tumor cell origin of 5 epithelial malignant tumors (esophageal squamous cell carcinoma, lung adenocarcinoma, gastric adenocarcinoma, pharyngeal squamous cell carcinoma, and thyroid papillary carcinoma) that developed after allogeneic peripheral blood stem cell transplantation using anti-AE1/3 immunofluorescence with fluorescence in situ hybridization analysis for sex chromosomes and/or short-tandem repeat microsatellite analysis of laser-microdissected tumor cells. The results revealed that 1 of these 5 cancers was derived from donor cells. In this case, transfused pluripotent cells, which include both mesenchymal stem cells and hematopoietic stem cells, might have given rise to epithelial malignant cells. Our observations suggest that transfused peripheral blood cells may be involved in the development of cancers after allogeneic peripheral blood stem cell transplantation.

BACKGROUND: In patients with nonsmall cell lung carcinoma (NSCLC) who have with pathologic N1 (pN1) lymph node status, the prognostic significance of segmental lymph node (level 13) metastasis and/or subsegmental lymph node (level 14) metastasis is unknown. METHODS: Lymph node metastasis patterns were analyzed in 230 patients with NSCLC who had pN1 status. Clinical outcomes were examined for 230 patients with pN1 status and 700 patients with pN0 status. The pN1 group was stratified into 4 subgroups according to the highest level of lymph node involvement. RESULTS: The 5-year disease-free survival (5DFS) rates for pN1 and pN0 patients were 50.1% and 90.5%, respectively. The highest level of lymph node involvement was a significant prognostic indicator; the 5DFS rates for patients with pN1 status who had level 13/14, lobar (level 12), interlobar (level 11), and hilar (level 10) lymph node metastasis were 69.4%, 46.4%, 46.7%, and 37%, respectively. Patient outcomes were significantly worse for those with pN1 status who had only level 13/14 lymph node metastasis than for patients with pN0 status (P = .0034), and outcomes were significantly worse for patients with pN1 status who had level 11/12 lymph node metastasis than for patients who had only level 13/14 lymph node metastasis (P = .021). The median number of level 13/14 lymph nodes examined was 3 (range, 0-22 level 13/14 lymph nodes), and metastases to these lymph nodes were detected in 61% of patients who had pN1 status. A single lymph node pN1 disease, single-level pN1 status, and squamous cell carcinoma histopathology also were indicators of a better patient outcome. CONCLUSIONS: The current results indicated that the highest level of lymph node involvement may be used to stratify the outcome of patients who have NSCLC with pN1 status. Patients with pN1 status who had only level 13/14 lymph node metastasis had an intermediate 5DFS rate between that of patients with pN0 status and other patients with pN1 status. Routine examination of level 13/14 lymph nodes is important for accurate pathologic staging and for the predicting clinical outcome of patients with NSCLC. Cancer 2012. © 2012 American Cancer Society.

To investigate the proteomic background of malignancies of the pleura, we examined and compared the proteomic profile of malignant pleural mesothelioma (MPM)(10 cases), lung adenocarcinoma (11 cases), squamous cell carcinoma of the lung (13 cases), pleomorphic carcinoma of the lung (3 cases) and synovial sarcoma (6 cases). Cellular proteins were extracted from specific populations of tumor cells recovered by laser microdissection. The extracted proteins were labeled with CyDye DIGE Fluor saturation dyes and subjected to two-dimensional difference gel electrophoresis (2D-DIGE) using a large format electrophoresis device. Among 3875 protein spots observed, the intensity of 332 was significantly different (Wilcoxon p value less than 0.05) and with more than two-fold inter-sample-group average difference between the different histology groups. Among these 332, 282 were annotated by LC-MS/MS and included known biomarker proteins for MPM, such as calretinin, as well as proteins previously uncharacterized in MPM. Tissue microarray immunohistochemistry revealed that the expression of cathepsin D was lower in MPM than in lung adenocarcinoma (15% vs. 44% of cases respectively in immunohistochemistry). In conclusion, we examined the protein expression profile of MPM and other lung malignancies, and identified cathepsin D to distinguish MPM from most popular lung cancer such as lung adenocarcinoma.

がん医療の均てん化が唱われたがん対策基本法が施行され医療の質への関心が高まっている．医療の質を評価測定するためには，効果についてエビデンス/コンセンサスのある標準診療を診療の質指標（Quality Indicator，QI）として実際に患者の受けた診療を検討し，対象患者のうちどの程度の割合で標準診療が行われているかを検証する方法がある．そこで肺癌診療ガイドラインのグレードの高い推奨を元に，関連専門家パネルによるデルファイ変法という国際的に標準的方法とされる手法を用いて35項目の指標を決定した．現在，他のがん種とともに協力病院を募って診療録から情報収集して調査を行っているところであるが，各学会の収集する臓器がん登録においても一部のQIは適用可能であり，またQI集計のフィードバックが施設への参加動機を作り出す情報サービスになるとも期待できる．しかし，肺癌登録の項目を検討した結果，7項目のQIが算定可能と考えられるも，そのうち6項目は必要事項の診療録記載を吟味するQIであり，現状では適用する意義は薄いと考えられた．今後臓器がん登録の発展的な運用を考える上で施設負担も考慮しながらQIフィードバックの仕組みなど，検討の価値はあると考えられる．

A new adenocarcinoma classification was recently introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS). A distinction is made between pre-invasive lesions, and minimally invasive and invasive adenocarcinoma. The confusing term "bronchioloalveolar carcinoma" is not used any more and new subcategories include adenocarcinoma in situ and minimally invasive adenocarcinoma. Due to a renewed interest in screen-detected nodules and early-stage lung cancers of

Introduction Among the mutations of epidermal growth factor receptor ( EGFR ), deletions in exon 19 (DEL), and point mutations in exon 21 (L858R) predict the response to EGFR-tyrosine kinase inhibitors (TKIs) in primary lung adenocarcinoma. The ability to detecting such mutations using immunohistochemistry (IHC) would be advantageous. Methods The molecular-based and IHC-based EGFR mutations were analyzed in 577 lung adenocarcinomas using high resolution melting analysis (HRMA) and 2 mutation-specific antibodies, respectively. Results In the molecular-based analyses, DEL was detected in 135 cases (23%), and L858R was detected in 172 cases (30%). In the IHC-based analyses, a positive reaction was detected in 59 cases (10%) for the DEL-specific antibody, and in 139 cases (24%) for the L858R-specific antibody. With the molecular-based results set as the gold standard, the sensitivity and specificity of the DEL-specific antibody were 42.2% and 99.5%, respectively, while the sensitivity and specificity of the L858R-specific antibody were 75.6% and 97.8%, respectively. The antibody specificities improved when the threshold for the mutation-positive reactions was set as >50% of immunopositive tumor cells. The significant predictors of the clinical response to EGFR-TKI were molecular-based EGFR mutations ( p EGFR mutations ( p = 0.001). However, a multivariate analysis revealed that only molecular-based EGFR mutations were significantly correlated with the clinical response ( p Conclusions Mutation-specific antibodies demonstrated extremely high specificities, but their sensitivities were not higher than those of molecular-based analyses. However, IHC should be performed before a molecular-based analysis, because it is more cost-effective and can effectively select candidates for EGFR-TKI therapy.

Introduction Recent clinical trials revealed that accurate histologic typing of non-small cell lung cancer, especially squamous cell carcinoma (SCC), is essential. Patients and Methods We analyzed 10 antibodies expression in 150 SCC cases (53 well-, 51 moderately, and 46 poorly differentiated cases) and 159 adenocarcinoma (AC) cases (49 well-, 52 moderately, and 58 poorly differentiated cases). Results In all SCC and AC cases, p63 was the most sensitive marker for SCC (98.7%), followed by high-molecular-weight (HM) cytokeratin (CK) (97.3%), CK5/6 (93.3%), Sox2 (80%), thrombomodulin (79.3%), desmocollin-3 (72.7%), S100A7 (70.7%), S100A2 (63.3%), and glypican-3 (46.7%). Desmocollin-3 was the most specific marker for SCC (100%), followed by CK5/6 (98%), Sox2 (95.5%), glypican-3 (92.4%), S100A7 (86.8%), thrombomodulin (79.9%), S100A2 (64.6%), p63 (51.6%), and HMCK (33.3%). Thyroid transcription factor-1 (TTF-1) expression was observed in 87.4% of AC cases and 2.0% of SCC cases. When analyzing only poorly differentiated tumors, HMCK was the most sensitive marker for SCC (100%), followed by p63 (97.8%), CK5/6 (87.0%), Sox2 (71.7%), thrombomodulin (58.7%), desmocollin-3 (52.2%), S100A2 (50%), glypican-3 (45.7%), and S100A7 (45.7%). Desmocollin-3 was the most specific marker for poorly differentiated SCC (100%), followed by CK5/6 (98.3%), glypican-3 (94.8%), Sox2 (94.8%), S100A2 (81%), S100A7 (75.9%), thrombomodulin (72.4%), p63 (48.3%), and HMCK (36.8%). The 10-fold crossvalidated classification and regression tree analysis revealed that the combination of CK5/6 and TTF-1 was the best immunohistochemical marker panel for the differentiation between SCC and AC. Conclusion CK5/6 is the best marker for differentiating SCC and AC, irrespective of the histological grade of the tumor. Thus, the combination of CK5/6 and TTF-1 is the most recommended combination of immunohistochemical markers.

Few cases each of malignant pulmonary epithelioid hemangioendothelioma (PEH) and PEH with lymph node metastasis have been reported. Here we report a case of PEH with lymph node metastasis. A Japanese woman was found to have a 2-cm–diameter mass with small satellite nodules in the right upper lobe of the lung. Microscopic examination revealed solid destructive growth of the main tumor, with epithelioid cells showing cytologic atypia and 3 mitotic figures per 10 high-power fields. Some of the tumor cells had intracytoplasmic lumina that appeared as vacuoles. These lumina were negative for alcian blue and periodic acid Schiff, and contained erythrocytes. However, erythrocytes were seen more frequently within small but distinct vascular channels that were arranged diffusely in the periphery of the main tumor. Other satellite nodules showed conventional PEH morphology. In hilar lymph nodes, the tumor cells resembled those of the main tumor. The vascular origin of the main tumor and satellite nodules was demonstrated by positive immunoreactivity for some endothelial markers. Although the diagnostic features of malignant PEH are not clear, those for PEH in other organs have included nuclear atypia, many mitoses, presence of necrosis, large tumor size, and spindle cell proliferation. The present case met these criteria, except for large tumor size and spindle cell proliferation. In conclusion, atypical cytologic features, the presence of necrosis, a high Ki-67 labeling index, and accompanying nodules of conventional PEH in the same pulmonary lobe suggest that this case was a malignant PEH with hilar lymph node metastasis.

Purpose: Pathological noninvasiveness needs to be precisely predicted in preoperative radiological examinations of patients with early lung cancer for the application of limited surgery. Patients and Methods: Patients with clinical T1N0M0 peripheral lung cancer were recruited. Radiological findings of the main tumor were evaluated as to ground-glass opacity with thin-section computed tomography. The primary end point was specificity, i.e., the proportion of patients with radiologically diagnosed invasive lung cancer to patients with pathologically diagnosed invasive lung cancer. The precision-based planned sample size was 450. We expected that the lower limit of the 95% confidence interval (CI) for specificity should be satisfied in ≥97% of patients. Results: We enrolled 811 patients from 31 institutions between December 2002 and May 2004. The primary end point was evaluated in 545 patients. The specificity and sensitivity for the diagnosis of pathologically diagnosed invasive cancer were 96.4% (161/167, 95% CI: 92.3–98.7%) and 30.4% (115/378, 95% CI: 25.8–35.3%), respectively, i.e., a negative result. Nevertheless, the specificity for lung adenocarcinoma ≤2.0 cm with ≤0.25 consolidation to the maximum tumor diameter was 98.7% (95% CI: 93.2–100.0%), and this criterion could be used to radiologically define early adenocarcinoma of the lung. Conclusions: Although our predetermined criterion for specificity was not statistically confirmed, radiological diagnosis of noninvasive lung cancer with a thin-section computed tomography scan corresponded well with pathological invasiveness. Radiological noninvasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma ≤2.0 cm with ≤0.25 consolidation.

Introduction:This retrospective study was conducted to evaluate the prognostic significance of the number of metastatic lymph nodes (nN) in resected non-small cell lung cancer (NSCLC) in comparison with the currently used pathologic nodal (pN) category in the staging system.Methods:A total of 1659 patients who underwent potentially curative resection for NSCLC from 2000 to 2006 were included in this study. The association between the nN and survival was explored, and the results were compared with those using the location-based pN stage classification.Results:The patients were divided into four categories according to the number of metastatic nodes: nN0, absence of metastatic nodes; nN1, metastasis in one to two nodes; nN2, metastasis in three to six nodes; and nN3, metastasis in seven or more nodes. The 5-year overall survival for nN0, nN1, nN2, and nN3 was 89.2%, 65.1%, 42.1%, and 22.4%, respectively (p < 0.001). The nN category could be used to subdivide pN1 and pN2 patients into two (nN1 and nN2) and three (nN1, nN2, and nN3) prognostically distinct subgroups, respectively. Multivariate analysis showed the nN category was an independent prognostic factor for resected NSCLC. The difference in overall survival between pN1 and pN2 was not significant (55.4% versus 47.8%, p = 0.245). Patients in each nN category could not be subdivided into different prognostic subgroups according to the pN classification.Conclusions:The nN category in this study was shown to be a better prognostic determinant than the location-based pN stage classification.

日本肺癌学会，日本呼吸器外科学会および日本呼吸器学会は，肺癌登録合同委員会を共同で運営し，2004年に切除された肺癌症例についての全国集計を2010年に行った．1例以上登録をした参加施設数は呼吸器外科認定修練施設605施設中253（41.8％）施設で，症例数は11,663例，全体の5年生存率は69.6％であった．男性（7,369例）の5年生存率は63.0％，女性（4,294例）では80.9％であった．臨床病期別の5年生存率はUICC ver.6（1999），UICC ver.7（2009）でそれぞれIA期（n＝6,295，6,295）：82.0％，82.0％，IB期（n＝2,788，2,398）：63.4％，66.1％，IIA期（n＝203，819）：55.4％，54.5％，IIB期（n＝899，648）：48.6％，46.4％，IIIA期（n＝940，1,216）：43.3％，42.8％，IIIB期（n＝407，90）：41.6％，40.3％，IV期（n＝131，256）：29.1％，31.4％であった．病理病期別の5年生存率はUICC ver.6（1999），UICC ver.7（2009）でそれぞれIA期（n＝5,611，4,978）：85.9％，86.8％，IB期（n＝2,389，2,552）：69.3％，73.9％，IIA期（n＝336，941）：60.9％，61.6％，IIB期（n＝977，848）：51.1％，49.8％，IIIA期（n＝1,354，1,804）：41.0％，40.9％，IIIB期（n＝799，106）：36.7％，27.8％，IV期（n＝188,434）：27.8％，27.9％であった．組織型別5年生存率は腺癌74.9％，扁平上皮癌59.1％，大細胞癌53.3％，小細胞癌52.6％，腺扁平上皮癌50.8％であった．術死は48例（0.4％），在院死は46例（0.4％）に認められた．

Lung cancer shows diverse histological subtypes. Large-cell neuroendocrine cell carcinoma and small-cell lung carcinoma show similar histological features and clinical behaviors, and can be classified as high-grade neuroendocrine carcinoma (HGNEC) of the lung. Here we elucidated the molecular classification of pulmonary endocrine tumors by copy-number profiling. We compared alterations of copy number with the clinical outcome of HGNEC and identified a chromosomal gain of the DEK oncogene locus (6p22.3) that was significantly associated with poor prognosis. We further confirmed that DEK overexpression was associated with poor prognosis in a larger set of HGNEC. Downregulation of DEK by small hairpin RNA led to a marked reduction of in vitro colony formation, in vivo tumorigenicity and chemo-resistance, and was associated with loss of lung cancer stem cell markers. Gene expression profiling revealed that DEK downregulation was associated with altered expression of transcriptional regulators, which specifically include known targets of interchromosomal translocations in hematopoietic tumors, and knockdown of these epigenetic modifiers affected colony formation activity. Our study showed that DEK overexpression, partly through an increase in its gene dose, mediates the activity of global transcriptional regulators and is associated with tumor initiation activity and poor prognosis in HGNEC.