Haruhiko Nakamura

A worldwide trend of increasing primary adenocarcinoma of the lung

The four major histological types of lung cancer are adenocarcinoma, squamous cell carcinoma (SQ), large cell carcinoma and small cell carcinoma. Over the past few decades, the incidence of lung adenocarcinoma has increased gradually in most countries as the most frequently occurring histological type, displacing SQ. Adenocarcinoma is the predominant type of lung cancer among lifelong non-smokers and among females. Especially in East Asian countries, the cause(s) of the increase in adenocarcinomas are not clear. Several genetic mutations specific to lung adenocarcinomas have been found, representing attractive targets for molecular therapy. Recently, the pathological classification of lung adenocarcinoma was revised by integrating the newer clinical and biological knowledge concerning this prevailing type. Additional epidemiological, pathological and genetic studies are required to better understand this type of lung cancer.

Close association of IASLC/ATS/ERS lung adenocarcinoma subtypes with glucose-uptake in positron emission tomography

OBJECTIVES Correlations between maximum standardized uptake value (SUVmax) in fluorodeoxyglucose positron emission tomography (FDG-PET) and IASLC/ATS/ERS histopathologic subtypes of lung adenocarcinoma remain unclear. Therefore, the aim of this study was to retrospectively clarify associations between SUVmax and adenocarcinoma subtypes with postoperative outcomes. MATERIALS AND METHODS Associations of SUVmax measured in preoperative FDG-PET/CT and histologic subtypes of lung adenocarcinoma resected in our hospital were analyzed retrospectively. Overall and disease-free survival rates after surgery were calculated by the Kaplan-Meier method, and survival differences between patient groups were tested by the log-rank test. Multivariate analysis for survival was performed using the Cox regression model. RESULTS A total of 255 patients (130 men and 125 women; mean age, 69 years; range, 22-88 years) were included in the study. Clinical stages included IA in 151 patients, IB in 79, IIA in 9, IIB in 10, and IIIA in 6. SUVmax was closely associated with histologic subtype in resected specimens (p<0.0001). Values were highest in micropapillary predominant invasive adenocarcinoma (MPA) followed by solid predominant (SPA), invasive mucinous (IMA), acinar predominant (APA), papillary predominant (PPA), lepidic predominant (LPA), minimally invasive adenocarcinoma (MIA), and adenocarcinoma in situ (AIS). When the subtypes were classified into three subgroups [group A, AIS+MIA+LPA (low risk); group B, APA+PPA+IMA (intermediate risk); and group C, SPA+MPP (high risk)] by expected postoperative prognoses, there were significant differences in SUVmax among the subgroups corresponding to recurrence risk (p=0.0001). CONCLUSION Preoperative SUVmax was closely associated with both adenocarcinoma subtype and aggregated subgroups, reflecting malignant grade of the tumor and prognosis.

Recent mass spectrometry-based proteomics for biomarker discovery in lung cancer, COPD, and asthma

ABSTRACT Introduction: Lung cancer and related diseases have been one of the most common causes of deaths worldwide. Genomic-based biomarkers may hardly reflect the underlying dynamic molecular mechanism of functional protein interactions, which is the center of a disease. Recent developments in mass spectrometry (MS) have made it possible to analyze disease-relevant proteins expressed in clinical specimens by proteomic challenges. Areas covered: To understand the molecular mechanisms of lung cancer and its subtypes, chronic obstructive pulmonary disease (COPD), asthma and others, great efforts have been taken to identify numerous relevant proteins by MS-based clinical proteomic approaches. Since lung cancer is a multifactorial disease that is biologically associated with asthma and COPD among various lung diseases, this study focused on proteomic studies on biomarker discovery using various clinical specimens for lung cancer, COPD, and asthma. Expert commentary: MS-based exploratory proteomics utilizing clinical specimens, which can incorporate both experimental and bioinformatic analysis of protein-protein interaction and also can adopt proteogenomic approaches, makes it possible to reveal molecular networks that are relevant to a disease subgroup and that could differentiate between drug responders and non-responders, good and poor prognoses, drug resistance, and so on.

Clinical impact of the new IASLC/ATS/ERS lung adenocarcinoma classification for chest surgeons

In 2011, a new pathological classification of lung adenocarcinoma was proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society. The new criteria classify adenocarcinomas into eight subtypes according to their histological features. The criteria introduce a new concept of early stage lung cancer, consisting of adenocarcinoma in situ and minimally invasive adenocarcinoma, and categorize invasive adenocarcinomas by the predominant histological pattern. In addition to morphological differences among subtypes, the classification also considers the tumor behavior based on the genetic background within each subtype. We herein review the clinical impact of this new classification for chest surgeons based on the data from several recent validation studies from various institutions.

Malignant pleural mesothelioma presenting as a spontaneous pneumothorax.

Malignant pleural mesothelioma (MPM) is thought to arise from the mesothelial cells that line the pleural cavities. Most patients initially experience the insidious onset of chest pain or shortness of breath and have a history of asbestos exposure. MPM rarely presents as spontaneous pneumothorax. We report two male patients who presented with a spontaneous hydropneumothorax. One was exposed to asbestos and the other was not. Computed tomography showed tiny nodules with pleural thickness. They both underwent pleural effusion cytology and/or pleural biopsy. Therefore, the pathological diagnosis of MPM was obtained in both cases. We also reviewed 16 Japanese MPM cases with pneumothorax including our two patients. More than half of the patients suffered from pneumothorax repeatedly. We emphasize the need to obtain a pathological diagnosis of pleural effusion cytology and/or pleural biopsy in older patients presenting with a spontaneous hydropneumothorax.

Impact of intraoperative blood loss on long-term survival after lung cancer resection.

PURPOSE The purpose of this study was to clarify relationships between intraoperative blood loss (IBL) and long-term postsurgical survival in lung cancer patients. METHODS We retrospectively analyzed 1336 patients undergoing surgery: lobectomy in 1016, sublobar resection in 174, pneumonectomy in 106, and combined resection with adjacent organs in 40. The lobectomy group was stratified further by pathologic stages; overall survival difference was examined according to amount of IBL. RESULTS Volume of IBL differed significantly according to surgical procedure when all patients were included. Within the lobectomy group, IBL differed significantly between gender, pathologic stage, histologic type (adenocarcinoma vs. non-adenocarcinoma), and year of operation (1983 to 2002 vs. 2003 to 2012). After stratification by pathologic stage, survival differed with IBL for stages IB to IIIB. Multivariate analysis identified gender, patients age (<69 vs. ≥69), pathologic stage (IA to IIB vs. IIIA to IV), year of operation, histologic type, and IBL as significant predictors of survival. CONCLUSION Since degree of IBL is an independent predictor of overall survival after lung cancer resection, IBL should be minimized carefully during surgery.

Survival significance of coexisting chronic obstructive pulmonary disease in patients with early lung cancer after curative surgery

The impact of chronic obstructive pulmonary disease (COPD) severity on survival after curative resection of early‐stage lung cancer (NSCLC) has not been sufficiently elucidated.

History, molecular features, and clinical importance of conventional serum biomarkers in lung cancer

Serum biomarkers provide valuable information about the diagnosis and prognosis of a wide variety of malignant tumors. Despite the identification of several useful serum biomarkers in lung cancer, consensus on their utility has not yet been reached. Furthermore, guidelines and standard protocols to implement their use for patients with lung cancer are lacking, despite the accumulation of much data on the efficacy of several serum biomarkers over recent decades. In this review, we discuss the molecular features, functions, and clinical relevance of the conventional serum biomarkers for lung cancer, including carcinoembryonic antigen (CEA), cytokeratin 19 fragment 21-1 (CYFRA 21-1), tissue polypeptide antigen (TPA), carbohydrate antigen 19-9 (CA19-9), sialyl Lewisx (sLex), carbohydrate antigen 125 (CA-125), squamous cell carcinoma-related antigen (SCC-Ag), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (proGRP), aiming to provide a snapshot of the current landscape and their potential combined utility in the diagnosis and prognosis of lung cancer.

Epidermal growth factor receptor mutations in adenocarcinoma in situ and minimally invasive adenocarcinoma detected using mutation-specific monoclonal antibodies.

OBJECTIVES Epidermal growth factor receptor (EGFR) mutation rates in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were studied using both DNA analysis and mutation-specific immunohistochemistry. MATERIALS AND METHODS The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method was used to detect mutations in exons 18, 19, 20, and 21 of the EGFR gene in DNA samples extracted from paraffin-embedded tissue sections. Simultaneously, immunohistochemical analysis with two EGFR mutation-specific monoclonal antibodies was used to identify proteins resulting from an in-frame deletion in exon 19 (E746_A750del) and a point mutation replacing leucine with arginine at codon 858 of exon 21 (L858R). RESULTS Forty-three tumors (22 AIS and 21 MIA) were examined. The EGFR mutation rate in AIS detected by DNA analysis was 27.3% (L858R, 5/22; exon 19 deletion,1/22), whereas that detected in MIA was 42.9% (L858R,4/21; exon 19 deletion,5/21). Mutations detected by immunohistochemical analysis included 22.7% (L858R, 4/22; exon 19 deletion, 1/22) in AIS and 42.9% (L858R, 4/21; exon 19 deletion, 5/21) in MIA. Although some results were contradictory, concordant results were obtained using both assays in 38 of 43 cases (88.4%). CONCLUSION DNA and immunohistochemical analyses revealed similar EGFR mutation rates in both MIA and AIS, suggesting that mutation-specific monoclonal antibodies are useful to confirm DNA assay results.

A Resected Melanoma of the Lung Metastasized from an Occult Skin Lesion: A Case Report

An 86-year-old woman with a history of right breast cancer resected seven years ago had a small pulmonary nodule located in left S5. Diagnosis was made by bronchoscopy using the endobronchial ultrasonography-guided sheath (EBUS-GS) method, but a histological diagnosis was not obtained. Wedge resection was performed due to suspicion of a metastatic lesion from breast cancer based on radiological findings. The tumor was subsequently found to be malignant melanoma of the lung. An initial diagnosis of primary melanoma of the lung was made because a melanoma lesion at another site was not seen despite a detailed work up. However, 8 months after surgery, a malignant melanoma appeared at the tip of the right index finger. We rediagnosed the lung lesion as a metastatic malignant melanoma based on the low incidence of primary melanoma of the lung and on the pathological features.