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Background: Solute carrier family 5 member A8 (SLC5A8) is a sodium-coupled transporter for several chemicals. The SLC5A8 gene has been reported to function as a tumor suppressor gene that contributes to carcinogenesis and tumor progression. The expression of SLC5A8 is silenced in colon neoplasia by hypermethylation of CpG-rich islands located in exon 1. In this study, we assessed the significance of aberrant methylation of the SLC5A8 gene as a prognostic factor for lung adenocarcinoma (AD)., Methods: We analyzed the methylation levels of a consecutive series of 143 node-negative stage I and II lung AD samples using pyrosequencing., Results: The methylation level of exon 1 in the SLC5A8 gene was significantly associated with poor prognosis in cases of node-negative stage I and II lung AD., Conclusions: Gene silencing of SLC5A8 by hypermethylation was associated with poor prognosis in cases of node-negative stage I and II lung AD., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Genome-wide DNA hypomethylation is known to play important roles in genomic instability and carcinogenesis. Methylation in long interspersed nucleotide element 1 (LINE-1) is a good indicator of the global DNA methylation level within a cell. The aim of this study was to evaluate prognostic significance of LINE-1 hypomethylation in lung adenocarcinoma., Methods: A consecutive series of 211 lung adenocarcinoma patients who underwent curative resections without any preoperative chemotherapy or radiotherapy at Kumamoto University Hospital between April 2010 and December 2012 were included. The LINE-1 methylation levels were quantified in tumor and noncancerous tissue by Pyrosequencing assay., Results: Higher histologic grade and positive findings for vascular invasion were significantly associated with lower methylation levels. The disease-free survival in the hypomethylation group was significantly shorter than that of the non-hypomethylation group. The prognostic difference was more obvious in advanced cases (stage II, III) than in stage I cases., Conclusions: The LINE-1 methylation level is associated with histologic grade and vascular invasion of lung adenocarcinoma. Additionally, LINE-1 hypomethylation is a useful biomarker to predict early recurrence of lung adenocarcinoma., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The mechanisms of generation and progression of multicentric lung adenocarcinoma (AD), bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) in the peripheral lung is not well known. In this study, we analyzed epidermal growth factor receptor (EGFR) mutations in the cases of multicentric AD, BAC, and AAH to reveal the role of EGFR mutation in their generations and progressions., Method: Ninety-seven AAH, BAC, or AD lesions less than 3 cm in size in 26 patients were surgically resected. Of these, EGFR mutations of the nodules with the highest and the second highest grade of histologic malignancy were examined in each patient by using the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PNA-LNA PCR) clamp method., Results: EGFR mutations could be examined in 48 nodules in the 26 patients. The EGFR mutations were found more frequently in lesions with higher histologic malignancy, ie, 9 of 10 ADs (90%), 16 of 28 BACs (57%), and one of 10 AAHs (10%). In 22 patients who could be examined of EGFR mutations for the two lesions in each patient, only two patients (9%) had the same mutation patterns between the two lesions, whereas 15 patients (68%) had the different statuses and the remaining five (23%) had no mutations., Conclusion: Our data demonstrated that EGFR mutations seem to contribute to the acquisition of malignant potential in the AAH-AD sequence and occur independently in each lesion and in the cases of multicentric AD, BAC, and AAH.

A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported. The proband was a 70-year-old woman with multiple adenocarcinomas who exhibited secondary EGFR mutations, either L858R or L861Q, in the specimens of resected tumors, in addition to a germline EGFR V843I mutation. These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family.

Introduction: Recent developments of diffusion-weighted magnetic resonance imaging (DWI) make it possible to image malignant tumors to provide tissue contrast based on difference in the diffusion of water molecules among tissues, which can be measured by apparent diffusion coefficient (ADC) value. The aim of this study is to examine the usefulness of DWI for benign/malignant discrimination of pulmonary nodules/masses compared with F-fluorodeoxyglucose (FDG) positron emission tomography (PET)., Methods: PET and DWI were carried out prospectively in 104 patients with 140 pulmonary nodules/masses before surgery. FDG uptake of each lesion was quantitatively measured by a contrast ratio of standard uptake value (SUV-CR) between the lesions and contralateral lung. Diffusion of water molecule in each lesion was quantitatively measured by a minimum ADC (ADC-min). The diagnostic results were compared between the two modalities., Results: The receiver operating characteristics curve showed cutoff values of the ADC-min and the SUV-CR for benign/malignant discrimination to be 1.1 x 10 mm/s and 0.37, respectively. DWI and PET showed sensitivities of 0.70 and 0.72 and specificities of 0.97 and 0.79, respectively. Although there was no significant difference in sensitivity between the two methods, DWI showed a significantly higher specificity than PET because of fewer false-positives for active inflammatory lesions (p = 0.03). The ADC-min and SUV-CR values showed a significant reverse correlation (r = -0.504, p < 0.001)., Conclusions: DWI may be able to be used in place of FDG-PET to distinguish malignant from benign pulmonary nodules/masses with fewer false-positive results compared with FDG-PET.

Objectives: To differentiate among atypical adenomatous hyperplasia (AAH), bronchioloalveolar carcinoma (BAC), and adenocarcinoma showing ground-glass opacity (GGO) on CT scans, we conducted a study to determine the optimal parameter on CT number analysis using three-dimensional (3D) computerized quantification., Methods: From the CT numbers of GGO lesions obtained by 3D computerized quantification, CT number histogram pattern, peak CT number on the histogram, mean CT number, and the 5th to 95th percentile CT numbers were analyzed to determine the optimal parameter for differentiation among AAH (n = 10), BAC (n = 21), and adenocarcinoma (n = 12)., Results: While the CT number histogram showed one peak in all 10 of the AAH lesions (100%), it showed two peaks in 8 of 21 BAC lesions (38%), and in 5 of 12 adenocarcinoma lesions (42%). For differentiation between AAH and BAC, the 75th percentile CT number with a cutoff value of -584 Hounsfield units (HU) was optimal, with a sensitivity of 0.90 and a specificity of 0.81. For differentiation between BAC and adenocarcinoma, a mean CT number with a cutoff value of -472 HU was optimal, with a sensitivity of 0.75 and a specificity of 0.81., Conclusions: From the analysis of CT numbers of GGO lesions obtained by 3D computerized quantification, we conclude the following: (1) two peaks on the CT number histogram can rule out AAH; (2) the 75th percentile is the optimal CT number for differentiating between AAH and BAC; and (3) the mean CT number is the optimal CT number for differentiating between BAC and adenocarcinoma.

The use of steroids to successfully treat a 75-year-old woman with fibrosing mediastinitis and sclerosing cervicitis causing a stricture of the left common carotid artery is reported. Biopsy specimens showed collagenous fibers and fibroblasts with moderate infiltration of lymphocytes. The mediastinal and neck lesions were significantly reduced, with almost complete resolution of arterial stricture, 3 months after initiating administration of prednisolone at 20 mg/d.

Background: In 2005, Cheuk et al reported two patients with microscopic-sized thymomas and proposed the term microthymoma to distinguish it from the nodular hyperplasia of thymic epithelium, so-called microscopic thymoma. Here, we present microthymomas that were found in 196 patients with myasthenia gravis (MG) who had undergone thymectomy., Materials and Methods: Thymic tissues in 196 patients with MG who underwent thymectomy or thymothymomectomy were examined. Of these patients, 73 patients had thymoma indicated by CT before surgery, and the other 123 patients had no mediastinal tumors. From the resected thymic tissues, an average of 14 hematoxylin-eosin-stained sections (range, 4 to 55 sections) were prepared for microscopic examination. The histologic type of the thymoma was classified according to the World Health Organization (WHO) classification., Results: From the 196 patients, we found three microthymomas in 3 patients (1.5%). While these three tumors could not be seen grossly in pathology section, they were found microscopically (range, 2 to 4 mm). The histologic subtype according to the WHO classification system was B1 in one patient and B2 in two patients., Conclusion: Microthymoma was found in 3 of 196 patients (1.5%) with MG. Microthymoma might exist in thymus of patients with MG, even in patients who have no thymoma indicated by CT.

Background: The developments in high-resolution CT scanning have increased the chance of detecting small bronchioloalveolar carcinoma (BAC) or atypical adenomatous hyperplasia (AAH) that appears as a ground-glass opacity (GGO). However, these lesions are not only difficult to localize during surgery, but they are also hard to make pathologic sections of because they are usually impalpable. Here, we report a method of making pathologic sections for impalpable GGO lesions., Methods: Twenty-nine impalpable GGO lesions < 1 cm in size were marked by 0.4 to 0.5 mL of lipiodol under CT scan before surgery. The lesions were resected under C-arm fluoroscopy. The radiopaque areas marked by lipiodol within the formalin-fixed specimens were cut serially under conventional fluoroscopy for pathologic examinations., Results: The mean (+/- SD) size of the lesions was 0.5 +/- 0.2 cm (range, 0.2 to 1 cm), and the mean depth from the pleural surface was 1.6 +/- 1.4 cm (range, 0.2 to 6 cm). The mean number of sections submitted for pathologic examinations was 2.3 +/- 1.7 per lesion (range, 1 to 7 per lesion). While 11 of the 29 lesions (38%) were invisible even on the cut surface of the specimens, all were demonstrated in hematoxylin-eosin sections. The pathologic diagnosis was BAC in 17 lesions, AAH in 10 lesions, and organized pneumonia in 2 lesions. The use of lipiodol did not affect the pathologic findings., Conclusions: The use of fluoroscopy to cut sections from resected specimens after preoperative marking with lipiodol was useful for making pathologic sections of impalpable GGOs < 1 cm in size.

Objective: To determine the optimum selection of mediastinal lymph nodes for biopsy in non-small cell lung cancer (NSCLC), lymph nodes with or without metastasis at each mediastinal station were ranked in size in patients with pathological N2 disease., Methods: Twenty-five NSCLC patients with pathological N2 disease who underwent pulmonary resection with complete mediastinal lymph node clearance were examined. Of 114 mediastinal lymph node stations dissected, 47 had metastases and 67 did not. The sizes of 259 nodes in the 47 positive lymph node stations were measured. Of these 259 nodes, 137 had metastases and 122 did not. The short- and long-axis diameters of the 259 lymph nodes were ranked in each lymph node station., Results: Mean short- and long-axis diameters of lymph nodes with metastases were significantly greater than those without (p < 0.001). In 47 metastatic lymph node stations, the short- and long-axis diameters were greatest in a metastatic node in 44 (94%) and 42 (89%) respectively, whereas in the remaining 3 (6%) and 5 (11%), the second largest but not the largest node was positive. None of the largest lymph nodes with metastasis were smaller than the second largest lymph node at each station. Four of the 10 patients with adenocarcinoma (40%) had metastasis in the second largest but not in the largest node measured by long-axis diameter, a significant difference from one in eight (12.5%) among the squamous cell carcinoma cases (p = 0.04)., Conclusion: For mediastinal lymph node biopsy, both the largest and the second largest node at each station should be sampled, especially in adenocarcinoma. If only the largest lymph node is selected, false-negative results will occur at a rate of about 10%.

Type IV collagen, a major component of the basement membrane (BM), is composed of six genetically distinct alpha(IV) chains, alpha1(IV) to alpha6(IV). Their genes are paired on three different chromosomes in a head-to-head arrangement. The alpha5(IV) gene (COL4A5) and the alpha6(IV) gene (COL4A6) are on chromosome Xq22 and are regulated by a bidirectional promoter. Loss of the alpha5(IV)/alpha6(IV) chains in epithelial BM occur in the early stage of cancer invasion. However, the regulatory mechanism of the specific loss of the alpha5(IV)/alpha6(IV) chains during cancer cell invasion is still undetermined. In the present study, we examined the expression of the alpha5(IV)/alpha6(IV) chains and the methylation profiles of the bidirectional promoter region of COL4A5/COL4A6 in colon cancer cell lines and colorectal tumor tissues. The expression of the alpha5(IV)/alpha6(IV) chains was down-regulated in colorectal cancer, and the loss of expression of the alpha5(IV)/alpha6(IV) chains was associated with the hypermethylation of their promoter region. In conclusion, the hypermethylation of the bidirectional promoter region of COL4A5/COL4A6 is one of the events that is responsible for the loss of expression of the alpha5(IV)/alpha6(IV) chains and the remodeling of the epithelial BM during cancer cell invasion.