Objectives. There have been few large single-series investigations of endobronchial leiomyoma. In this study, we set out to determine the clinicopathologic and immunohistochemical characteristics of endobronchial leiomyoma. Methods. We collected the data of 14 patients with histological diagnoses of endobronchial leiomyoma from our institution between 1979 and 2010, and examined the clinicopathologic and immunohistochemical features of these cases. Results. The patients comprised 9 men and 5 women (age range, 31-80 years, mean, 52.7) with main clinical symptoms of cough and sputum. Their chest X-ray findings were obstructive pneumonia in 4 cases and chest computed tomography findings showed a tumor shadow in the bronchus in 3 cases. The tumors were located mainly in the large bronchi (main to lobar bronchi), predominantly on the right side. The size of the tumors ranged from 2 to 20 mm in greatest dimension (mean, 6.5 mm), and a small leiomyoma (size; 2-4 mm) was observed in 8 cases. On bronchoscopic examination, the presence of a polypoid tumor or a small nodular tumor with a smooth surface was revealed in all cases. All cases, except one case with inadequate specimens, were histologically diagnosed as endobronchial leiomyoma using biopsy specimens. Histologically, the tumor in the submucosa of the bronchus was composed of interlacing bundles of spindle cells, but without nuclear atypia or mitosis. Immunohistochemically, the spindle cells were positive for α-SMA, desmin, h-caldesmon, and HHF35 but negative for estrogen and progesterone receptors. The rate of MIB-1 positive cells was 0.3% (0-1.0%). Surgery was performed in 3 patients; pneumonectomy in 1 and lobectomy in 2. Endoscopic Nd-YAG laser therapy was used in 3 patients, and removal of the small tumor by biopsy forceps was performed in 8 patients. The outcome of all patients is good, and no recurrence of tumor has been detected in any. Conclusions. The early detection of endobronchial leiomyoma on bronchoscopic examination is very important to avoid the destruction of peripheral lung tissue due to airway obstruction caused by tumor. The appropriate treatment for tumors depends on the location, size, width of the base of the lesion, and the reversibility of the changes in the distal pulmonary tissue. Immunohistochemical staining is a practical, effective method for the pathological diagnosis of endobronchial leiomyoma.

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Objective. We reviewed the clinical findings and diagnostic methods used in the diagnosis of malignant pleural mesothelioma (MPM) in patients with pleural effusion with low levels of adenosine deaminase (ADA), but without signs of acute inflammation or pleural thickening. Materials and Methods. The hospital records of 40 patients with pleural effusion of unknown origin or pleural thickening were retrospectively investigated. In all of those studies, pleural effusion was exudative, lymphocyte-dominant, no mycobacteria or other bacteria, and low levels of ADA. Results. There were 30 men and 10 women with an average age of 62.8 years old. The diagnosis of MPM was obtained by cytology of the pleural effusion in 3 patients and by core-needle biopsy of the thickened pleura in 3. Thoracoscopic pleural biopsy under general anesthesia was performed for the other 34 patients. The pathologic diagnosis of pleural biopsy was MPM in 20 patients, inflammatory change in 12, and pleural dissemination of cancer in 2. All of the 7 patients with more than 100 μg/ml of hyaluronic acid in their pleural effusion received a diagnosis of MPM. A total of 20 of 23 patients with irregular or nodular pleural thickening on computed tomography findings were confirmed to have MPM. Moreover, 6 of 17 patients with smooth pleural thickening were confirmed to have MPM. In patients with nodular pleural thickening it was easy to make the diagnosis. However, in those with smooth thickening, careful observation was required to select the appropriate biopsy site and resection margins of full-thickness pleura. Conclusion. As the rate of MPM in the patients with pleural effusion with low levels of ADA, but without signs of acute inflammation or pleural thickening is high (65%), an early thoracoscopic pleural biopsy is strongly recommended.

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Objective. Aquaporins (AQPs) are a family of small (-28 kDa/monomer) channel-forming membrane proteins that function as osmotically driven transepithelial and transcellular water transporters. To date, 13 homologous members have been identified in mammals. Recent studies using several varieties of aquaporin-gene knock-out mice have indicated previously unanticipated roles for AQPs, including cell cycle control and migration. In this review, we summarize the recent data on the involvement of AQPs in the progression of adenocarcinoma of the lung. Results. AQP1, 3, 4 and 5 were demonstrated in normal lung tissue with cell type-specific and polarized patterns. AQP1, 3 and 5 were frequently expressed in lung adenocarcinoma tissue subtypes. There were 3 recognized AQP-expression patterns: 1) a polarized expression of AQP1 and 3 in accordance with the differentiation of normal lung cells; 2) a polarized but aberrant expression of AQP5, and 3) the overexpression in the absence of any polarity of AQP1 and 5. Pattern 1) was seen predominantly in bronchioloalveolar carcinoma cells, of either non-mucinous or mucinous type, and decreased according to the progression of the disease. Pattern 2) was detected not only in bronchioloalveolar carcinoma cells, but also in atypical adenomatous hyperplasia cells, which suggested a relationship between AQP5 expression and the tumorigenesis of adenocarcinoma. Pattern 3) has been increasingly observed in the areas with micro-invasion, becoming prominent in the areas with widespread invasion, and correlated significantly with the decreased survival rates observed in adenocarcinoma patients. The oncogenic roles of each pattern were determined by in vitro studies using tumor cells with the AQP cells either knocked-in or knocked-out. Overexpressed AQP1 facilitated lamellipodia formation at the front line of the invasion, and AQP5 activated intracytoplasmic signal molecules, which play critical roles in cellular proliferation and epithelial mesenchymal transition (EMT). The involvement of AQP5 in the secretion of mucin in mucinous tumors and AQP1 in the aggressiveness of micropapillary components were also observed. The level of AQP4 expression was high in lung adenocarcinoma, and correlated significantly with a more favourable prognosis in adenocarcinoma patients. Conclusion. Several studies indicate that AQP1 and 5 are vital activators of the EMT of lung adenocarcinoma, suggesting that AQP can be a novel target molecule for counteracting the aggressiveness of lung adenocarcinoma.

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Background. The development of a foreign body granuloma on the staple-line after pulmonary resection is rare. Case. A 64-year-old man underwent a left nephrectomy for renal cell carcinoma in 1997 and wedge resection of the left lung for metastatic renal cell carcinoma in 2010. In 2011, 8 months after the resection, a computed tomography scan revealed a pulmonary nodule on the staple-line. The nodule was considered to be malignant, and therefore we performed a second wedge resection of the left lung. Histopathologically, this nodule was found to be a foreign body granuloma. Conclusion. Local recurrence or secondary primary lung cancer, and numerous cases of mycobacterial granuloma on the staple-line after pulmonary resection have been reported. However, a foreign body granuloma on the staple-line appears to be very rare.

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Background. Pulmonary carcinosarcoma is rare lung tumor composed of carcinomatous and heterotopic sarcomatous components, but there are few reports on the imaging diagnosis of pulmonary carcinosarcoma. Case. A 66-year-old man was admitted to our hospital with right shoulder pain and dyspnea. A chest X-ray film revealed a large quantity of right pleural effusion and chest computed tomography (CT) showed right pleural effusion and a cavitated giant tumor in the right lung field. Cancer cells were detected in his pleural effusion and we made a diagnosis of lung cancer (cT3N0M1a, stage IV). However, despite chemotherapy (CBDCA+GEM), the tumor progressed and the development of calcification in the tumor was observed on a CT scan 6 months after his first presentation. The patient subsequently died 7 months after presentation. The pathological findings of an autopsy specimen revealed the tumor to be composed of squamous cell carcinomatous components, fibrosarcomatous components, chondrosarcomatous components, osteosarcomatous components and rhabdomyosarcomatous components. We made a final diagnosis of pulmonary carcinosarcoma. We observed an osteosarcomatous component with neoplastic osteoids and ossification which showed as areas of calcification on a CT scan, corresponding to neoplastic bones of osteosarcomatous components. Conclusion. We present a case of a pulmonary carcinosarcoma with development of calcification in the tumor. The osteosarcomatous components in the carcinosarcoma were observed as areas of calcification on CT.

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Background. In the Japanese Lung Cancer guidelines, gefitinib is recommended as a first-line or later chemotherapy drug for patients with epidermal growth factor receptor (EGFR) mutation-positive advanced or recurrent non-small cell lung cancer. However, acquired drug resistance is common. Case. A 65-year-old woman complaining of back pain was admitted to our hospital. She had a metastatic bone tumor in her thoracic spine area and underwent metastasectomy. Chest computed tomography also revealed a lung tumor in the left lower lobe. A pathological examination of the excised spine tumor resulted in a diagnosis of metastatic cancer from lung adenocarcinoma (cT1N0M1, c-stage IV). Gefitinib was administered following 2 courses of carboplatin (CBDCA) + paclitaxel (PTX). The lung tumor shrank following gefitinib administration, but then grew slowly during the subsequent 6 years. Thereafter, bronchofiberscopic examination revealed adenocarcinoma with T790M-tolerant gene expression. As no distant metastasis was observed, we considered that the primary tumor, but not the metastasis, had become resistant to gefitinib, and therefore, we performed a left lower lobectomy and lymph node dissection. The patient was disease-free at 20 months after the second operation. Conclusion. We achieved a good outcome in salvage surgery for stage IV non-small cell lung cancer following long-term control by gefitinib and thoracic spine metastasectomy. Salvage surgery should be considered when acquired resistance is localized in the primary tumor site.

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Background. Thymic carcinoid with a thymic cyst is extremely rare. Case. An abnormal mediastinal shadow was noted in a 35-year-old man on a chest radiograph during a follow-up examination for chronic hepatitis C. Computed tomography (CT) revealed a solid tumor in the anterior mediastinum with a cystic lesion. Positron emission tomography-CT (PET-CT) showed uptake (maximum standardized uptake value: 3.95) in the tumor, which was diagnosed as well-differentiated neuroendocrine carcinoma by CT-guided biopsy. The patient was referred to our hospital for surgery, which consisted of tumor resection and thymectomy through a median sternotomy. The histopathological diagnosis was atypical carcinoid of the thymus with a thymic cyst. Furthermore, metastasis to an anterior mediastinal lymph node was observed. Conclusion. We report a resected case of a thymic carcinoid with a thymic cyst, which is the first case described in the Japanese literature. It is possible that thymic carcinoid can develop from the wall of a thymic cyst.

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Background. Pulmonary carcinosarcoma is a rare and aggressive malignant neoplasm which has been reported to have poor prognosis. Preoperative diagnosis is often difficult, and the optimal therapy has not been established. We report a patient with giant pulmonary carcinosarcoma with good survival after the total resection of the tumor. Case. A 64-year-old man presented to our hospital with a complaint of hemoptysis. A chest computed tomographic (CT) scan on admission demonstrated a 17-cm mass in the right lung. Lymphadenopathy was observed only in the hilar node. Bronchial biopsy and fiberscopy showed non-small cell lung cancer, and we initially diagnosed primary lung cancer, cT3N1M0 stage IIIA. Right pneumonectomy was performed through a median sternotomy with a right anterior thoracotomy, and the tumor was completely resected. The tumor was histologically diagnosed as pulmonary carcinosarcoma, pT3N0M0 stage IIB and was 17 cm in diameter. Although the patient received no adjuvant chemotherapy or radiotherapy, neither tumor recurrence nor systemic metastasis was observed on repeated CT scans during follow-up. He finally died of pneumonia at 24 months postoperatively. Conclusion. We report a rare case of giant pulmonary carcinosarcoma with a satisfactory postoperative course. Although poor prognosis is reported in the literatures, complete resection may provide a long survival period, even in patients with giant carcinosarcoma.

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Background. Aerogenous dissemination commonly occurs in bronchioloalveolar carcinoma, but only rarely occurs in pulmonary adenocarcinoma. Adenocarcinoma with this dissemination pattern has been reported as a pneumonic-type adnocarcinoma. Case. A 65-year-old man was referred to our hospital with bloody sputum and we diagnosed pulmonary adenocarcinoma by sputum cytology. A chest X-ray film showed pneumonia-like consolidation in the right lower lobe. Computed tomography demonstrated an infiltrative shadow with a cyst formation in the right lower lobe, and a slightly abnormal shadow in the right middle lobe. We performed right lower lobectomy and lymphadenectomy, but did not resect the right middle lobe as no evidence of abnormal findings were observed macroscopically at operation. The pathological stage of the lesion was pT2N0M0, stage IB. After 4 months, the indistinct lesion in the middle lobe had enlarged. Furthermore, new lesions appeared in the contralateral lung, although the patient was being given oral uracil-tegafur. Subsequently, he received repeated chemotherapy consisting of various regimens, but he died due to the progression of lung adenocarcinoma 1 year and 5 months after the surgery. Conclusion. Pneumonic-type adenocarcinoma is a rare type of pulmonary adenocarcinoma characterized by aerogenous dissemination which is similar to bronchioloalveolar carcinoma. Chest physicians should recognize that the clinical course is different from that of usually encountered adenocarcinoma, and its prognosis is poor.

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Japanese Joint Committee for Lung Cancer Registration was founded in 1998 and is run by a joint effort of the Japan Lung Cancer Society, Japanese Association for Chest Surgery, and Japanese Respiratory Society. Its main objective is to register cases of lung cancer diagnosed and treated in Japan, and provide the basic data necessary for the prevention, diagnosis, and treatment of lung cancer. Committee members are from each of the three associations mentioned above, member(s) of International Association for the Study of Lung Cancer Staging Committee, a biostatistician, and the general secretary. The office is in the Department of Thoracic Surgery, Osaka University. The committee registered and analyzed lung cancer cases who underwent resection in 1989, 1994, and 1999. It also registered lung cancer cases who were diagnosed in 2002, including those who received only medical treatment. These registrations provided the latest and most reliable data of lung cancer demographics and prognosis which will serve as the reference for the diagnosis and treatment of lung cancer. For example, the data show a very good prognosis of female non-smoker adenocarcinoma, suggesting that this population has a distinct cause of cancer other than smoking. The committee has finished compiling data of lung cancer cases resected in 2004 and its results will be published shortly.

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The new international lymph node map in the seventh edition of the TNM classification for lung cancer is basically appropriate since it was revised taking into account the discrepancies and the problems of 2 pre-existing different maps, the Naruke map and the MD-ATS (Mountain-Dresler, American Thoracic Society) map. The concept of zone has been proposed for groups of several lymph node stations. There are still some lymph nodes which are not designated in the new map. These issues will be tested or designated by future analysis.

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Introduction. Since the publication of the UICC 7^th TNM classification, the Naruke-Japanese Map and MD-ATS Map were united to form the IASLC Map, and the border between the N1 and N2 locations was clarified. However, it is still unknown whether this borderline is associated with the outcome of non-small cell lung cancer (NSCLC). Meanwhile, the total number of involved lymph nodes (LNs) has recently been shown to be a prognostic factor and is one of the parameters of the N factors in the present TNM classification of colorectal cancer, bladder cancer and head and neck cancer. In the present study, we retrospectively investigated whether the total number or anatomical location of involved LNs is superior prognostic factor in NSCLC. Patients and Methods. From 2000 to 2007, 1311 patients received surgical resection for primary lung cancer at Tokyo Medical University. After excluding patients who received induction therapy, incomplete resection, or who had a histological diagnosis of small cell lung cancer, a series of 928 consecutive NSCLC patients who underwent complete lobectomy, bilobectomy or pneumonectomy with LNs dissection were eligible. Log-rank and Cox proportional hazard models were used to estimate survival rates and relative risks. Results. Patients with pN1 with a total number of involved LNs of more than 4 tended to have a worse outcome compared with patients with pN2 and 1-3 LN metastasis. Conclusion. The total number of involved LNs better indicated the outcomes of NSCLC patients compared with the anatomical location of involved LNs only in our series. Further validation studies are warranted.

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In 2009, the "Staging Manual in Thoracic Oncology" was published by International Association for the Study of Lung Cancer, and the "TNM Classification of Malignant Tumours, 7th edition" was also issued by the International Union Against Cancer. "The General Rule for Clinical and Pathological Record of Lung Cancer" in Japan was revised based on the above two hand-books. In the 7th edition, part of the "General Rule for Surgical Record of Lung Cancer" was also altered. The main revised points were as follows: 1) representations and definitions of visceral pleural invasion, 2) recommendation of pleural lavage cytology, 3) representations and definitions of separate tumor nodule(s) , 4) nodal definitions, 5) adoption of residual tumor (R) classification for evaluation of the completeness of surgical therapy. Data recorded based on the revised rules could provide useful information for the future revisions of the TNM classification.

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Quality of care has been recognized as a national issue in Japan, particularly in the area of cancer care. The Cancer Control Act of 2006 states that the government should take action to assure quality of care throughout Japan. The Interim Report on the Cancer Control Plan, published in 2010, reviewed current activities and stated the need for a Quality Benchmarking Center to monitor the quality of cancer care using process-of-care quality indicators derived from clinical practice guidelines. Recognizing this national concern, a research project is under way to develop process-of-care quality indicators for 5 major types of cancer in Japan, including lung cancer. The process involved the identification of potential quality indicators and the examination of their validity using the modified Delphi method by a panel of multidisciplinary clinical experts. For lung cancer, this process produced 35 quality indicators covering a broad range of care, including pre-treatment evaluation, surgical treatment, chemotherapy and radiation therapy. Although these quality indicators are designed to be implemented based on medical records, some quality indicators were apparently scorable using data from the Japanese Lung Cancer Registry operated by the Japanese Joint Committee for Lung Cancer Registry. If such usage is possible, systematic quality monitoring and feedback could be provided to the participating facility in order to improve quality of care. Further, feedback on care quality in an individual hospital, without disclosing the information to a third party can be regarded as a benefit of participation. However, detailed examination revealed that 6 out of 7 quality indicators that appeared to be theoretically scorable using registry data examined the presence/absence of the documentation of necessary clinical information in patient medical records. Therefore, for the scores to validly represent quality, we must assume that the existence of information in the examined data sets means that the pertinent documentation is also present in the medical records. Because we do not know whether this assumption is reasonable, we concluded that the current database is insufficient for quality of care monitoring. The current Lung Cancer Registry primarily aims to provide data to determine the TNM staging system, limiting the extent of available information in order to avoid placing an excessive burden on participating institutions. If we are to expand its scope to include quality improvement of lung cancer care in the future, the linking of data with other systems such as administrative databases and hospital-based cancer registries may be necessary.

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Objective. To show activity of the Japanese lung cancer registry conducted by Japanese Joint Committee for Lung Cancer Registration (JJCLCR). Design. Outcomes and plans provided by JJCLCR were reviewed. Results. The Japan Lung Cancer Society, the Japanese Association for Chest Surgery, and the Japanese Respiratory Society jointly established JJCLCR, which provided information regarding Japanese lung cancer treatment in Japanese or English articles. In addition to publications, the JJCLCR is making an international contribution by transferring data of many lung cancer cases to the International Staging Committee of the International Association for the Study of Lung Cancer (IASLC). The JJCLCR conducted regular registration of surgical cases in 1994, 1999 and 2004. In addition, results from a prospective registry of surgical and non-surgical cases in 2002 were evaluated. Planned registries will be prospective registry for non-surgical cases in 2012 and retrospective registry for surgical cases in 2010. Conclusion. The JJCLCR contributes to the improvement of prevention, diagnosis and treatment of lung cancer patients.

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Purpose. To clarify the details of revisions in the 7^th TNM classification of lung cancer by the Union for International Cancer Control (UICC) and to describe the measures taken to adapt to these revisions by the General Rules for the Clinical and Pathological Classification Committee of the Japan Lung Cancer Society. Methods. We compared the 6^th and 7^th Editions of the UICC classification with the 7^th Edition of the General Rules for the Clinical and Pathological Classification of Lung Cancer of the Japan Lung Cancer Society. Results. The main revisions of the 7^th Edition of the TNM are as follows: 1) T-factors are now subclassified according to tumor diameter; 2) malignant effusion and pleural effusion are defined as M1a (formerly T4); an additional pulmonary nodule in the contralateral lung is now also defined as M1a; 3) pleural invasion (PL1) is now defined as T2; 4)T2bN0 and T2aN1 are defined as stage IIA (formerly IB and IIB, respectively); T4N0 and T4N1 are defined as stage IIIA (formerly IIIB); and 5) the lymph node map has been extensively revised. The General Rules for the Clinical and Pathological Classification Committee of the Japan Lung Cancer Society added several clarifications, revised its classification of surgical procedures and made new classifications for pathologists. Accordingly, the number of cases in each stage increased and the prognostic differentiation among stages has much improved. However, the TNM classification system has become more complex. Conclusion. It is necessary for the TNM classification system to reflect patient prognosis as accurately as possible. However, it remains to be clarified whether this staging system will require further amendment based on the emergence of new therapeutic methods such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for EGFR-mutated lung cancer.

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Objective. To exposit the significance of the anatomic extent of visceral pleural invasion (VPI) in lung cancer. Study Design. We reviewed referenced the data in the articles which reported survival data based on elastic stains to assess VPI and 7^th edition of the tumor, node, metastasis (TNM) classification of the International Union Against Cancer and American Joint Committee on Cancer. Results. To define p0 as lack of pleural invasion beyond the elastic layer, p1 as invasion beyond the elastic layer, p2 as invasion to the surface of the visceral pleura and p3 as invasion of the parietal pleura. Most studies, survival was shown to be significantly worse for VPI defined as p1 or p2 compared with p0. Conclusions. Based on the 7^th TNM classification, define VPI as invasion beyond the elastic layer (PL1 or PL2).

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The classification of intrapulmonary metastasis (PM), and its impact on T and M stages has been substantially modified in the 7th edition of the TNM classification for lung and pleural tumors. A separate tumor nodule(s) in the same lobe as the primary tumor is defined as PM1. When PM1 is observed, the primary tumor is now staged as T3, which was previously T4 in the 6th edition. A separate tumor nodule(s) in a different ipsilateral lobe to that of the primary tumor is defined as PM2. When PM2 is observed, the primary tumor is staged as T4. A separate tumor nodule(s) in a contralateral lobe is defined as PM3. When PM3 is observed, the disease is staged as M1a. In the new classification, T4N0M0 and T4N1M0 are both staged as IIIA, and T4N2M0 as IIIB. These modifications have resulted in a clearer differentiation of outcome between stages, which supports the validity of the new classification of intrapulmonary metastases.

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The 7th Edition of the TNM classification was published by the International Union Against Cancer and the American Joint Committee on Cancer in early 2009. The changes from the 6th Edition were based on proposals from the International Staging Project of the International Association for the Study of Lung Cancer. Accordingly, the General Rules for the Clinical and Pathological Definitions of Lung Cancer (7th Edition) of the Japan Lung Cancer Society were revised. In this paper, we discuss the issues regarding the 7th Edition of the TNM clinical staging for lung cancer based from the standpoint of diagnostic imaging.

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Objective. To discuss the problems of the 7th revision of the TNM classification of lung cancer from the standpoint of radiotherapy. Methods. The following changes have been made in the 7th Edition of the TNM classification of lung cancer: 1) new subclassification by tumor size; 2) the reclassification of pleural dissemination as M1a; 3) and the reclassification of T4 tumors by additional nodule(s) in the lung (primary lobe) as T3. Regarding N factors, the entire subcarinal group of lymph nodes, previously labeled as level 7 on the Mountain Dresler modification of the American Thoracic Society (MD-ATS) map but divided into levels 7 and 10 in the Naruke map, is now defined as level 7. Problems related to these changes in the new revision of the TNM classification are discussed from the standpoint of radiotherapy. Results. There is a possible correlation between tumor size and radiation effect. In the 7th Edition, T1 is subclassified as either T1a (≤2 cm) or T1b (≥2 cm-3 cm). Further analysis of patients with small lung lesions is needed to clarify the impact of reclassifying T1 tumors on the clinical outcomes of stereotactic radiotherapy (SRT) . The new subclassification of T2 as T2a (3 cm-5 cm, or T2 by other factors and 5 cm or more) or T2b (5 cm-7 cm) is useful. Cases of pleural dissemination are not indicated for definitive radiotherapy, and thus, the reclassification of M1a is reasonable. Tumors with an additional nodule in the primary lobe, previously defined as T4, are now classified as T3. The subcarinal group of lymph nodes, including levels 7 and 10 in the previous (MD-ATS) map, was defined as level 7 in the current staging system. These new definitions do not indicate definitive radiotherapy for patients with T3 or N2. Conclusion. Compared with the 6th Edition of the TNM classification of lung cancer, a number of changes in the 7th Edition are considered to be compatible with indications for radiotherapy. On the other hand, careful evaluation of the tumor is necessary, because some patients with T3 or N2 may not be candidates for curative radiotherapy.

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