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Patterns of p53 immunostaining are used as a surrogate marker for tumor protein 53 ( TP53) mutations in the diagnosis of ovarian high-grade serous carcinoma (HGSC). We present a rare case of ovarian HGSC that metastasized to the diaphragm and cardiophrenic lymph nodes and showed the immunostaining pattern of wild-type p53 and aberrant neural cell adhesion molecule (CD56) expression. A 63-year-old woman developed multifocal metastases in the diaphragmatic pleura and cardiophrenic lymph nodes. Because she had a history of ovarian HGSC and pulmonary adenocarcinoma, we considered the possibility that the metastatic carcinoma was of either ovarian or pulmonary origin. Immunostaining revealed that the tumor cells were negative for thyroid transcription factor 1 but positive for Wilms tumor 1. The tumor additionally exhibited strong membranous CD56 expression and patchy p53 expression, both of which were inconsistent with the characteristics of ovarian HGSC. However, targeted sequencing analysis revealed that the tumor harbored a pathogenic mutation at the splice acceptor site of TP53 intron 9 (c.994-1G>C).

The connective tissue diseases (CTDs) demonstrating features of interstitial lung disease (ILD) include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), progressive systemic sclerosis (PSS), dermatomyositis (DM) and polymyositis (PM), ankylosing spondylitis (AS), Sjogren’s syndrome (SS), and mixed connective tissue disease (MCTD). In RA patients in particular, interstitial lung abnormality (ILA) (of varying degrees; severe vs. mild) is reported to occur in approximately 20–60 % of individuals and CT disease progression occurs in approximately 35–45 % of them. The ILAs have been associated with a spectrum of functional and physiologic decrement. The identification of progressive ILA may enable appropriate surveillance and the commencement of treatment with the goal of improving morbidity and mortality rates of established RA-ILD. Subpleural distribution and higher baseline ILA/ILD extent were risk factors associated with disease progression. At histopathologic analysis, connective tissue disease-related interstitial lung diseases (CTD-ILDs) are diverse and include nonspecific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), apical fibrosis, diffuse alveolar damage (DAD), and lymphoid interstitial pneumonia (LIP). Even though proportions of ILDs vary, NSIP pattern accounts for a large proportion, especially in PSS, DM/PM and MCTD, followed by UIP pattern. Evidence has been published that treatment of subclinical CT lung abnormalities showing a tendency to progress to ILD may stabilize the CT alterations. The identification of subclinical lung abnormalities can be appropriate in the management of the disease and CT appears to be the gold standard for the evaluation of lung parenchyma.

Tracheobronchopathia osteochondroplastica (TPO) is an idiopathic disease involving the cartilage rings of the large airway, characterized by submucosal calcified nodules. Localized tracheobronchial amyloidosis (TBA) is another rare disease with localized amyloid deposits in the tracheobronchial tree. The two diseases rarely coincide, and only a few case reports and series have been reported. A patient with dyspnea was referred to our clinic for suspicion of TBA. Chest computed tomography (CT) scan showed marked thickening of the tracheobronchial wall with calcified endobronchial submucosal nodules. The nodules were resected with a Diode Laser under rigid bronchoscopy, and results from the biopsy showed both osteochondroid metaplasia on microscopy in Hematoxylin and Eosin staining and apple-green birefringence on polarized microscopy in Congo red staining. This is a rare case in which microscopic findings of both TPO and TBA were observed on one slide. These findings suggest that localized TBA could be a cause of TPO.

Teratomas show diverse biologic behaviour and prognosis as well as variable histological features. Importantly, post-pubertal testicular teratomas composed of mature components have a potential for malignant behaviour, in contrast to ovarian dermoid cysts and pre-pubertal testicular teratomas which are considered almost always benign. On the other hand, the biological behaviour and histogenesis of extragonadal teratomas are still not fully elucidated. In this study of mediastinal mature teratoma (MT), we investigated clinicopathological features and chromosome 12 short arm (12p) status which constitutes a major genetic aberration in the germ cell tumours (GCT) and is indicative of malignant potential. A total of 123 cases of primary mediastinal MT were included, and clinical data were retrieved regarding demographic information, adjuvant treatment, post-operative clinical course, and level of serum tumour markers. Histopathological features were evaluated in 123 cases and 12p status was studied by FISH in 25 cases. Female predilection was identified in the post-pubertal group (38 males vs 77 females), and paediatric teratoma cases had longer follow-up (mean 62.2 months vs 26.5 months). All patients had excellent prognosis with no tumour-associated death, regardless of age and sex. None of the MT cases had cytological atypia and all 21 cases finally evaluated by fluorescence in situ hybridisation were negative for 12p over-representation. Our results support the benign nature of mediastinal MT and suggest the possibility that it may share a common histogenesis with pre-pubertal type GCTs.

Background We aimed to investigate the clinicopathologic and histopathologic characteristics of colloid adenocarcinoma of the lung. Methods We reviewed the data of 10 patients with colloid adenocarcinoma that met the definition and histopathologic criteria of the current classification of the World Health Organization. The clinicopathologic characteristics were analyzed. Comprehensive histologic review and immunohistochemical staining for TTF-1, ALK, CDX2, and MUC5AC as well as a molecular examination for EGFR and KRAS was performed. Results Among 7 men and 3 women (mean age, 69.6 years), three patients had metastasis of the N2 lymph nodes; of these, two experienced recurrence, and one died of the disease. Remaining patients were all alive without metastasis or recurrence of disease. On gross examination, all tumors were circumscribed mucoid masses. Histologically, we observed the characteristic mucin pools that were distending and destroying the alveolar walls and low cellularity of tumor cells. Most tumor cells were tall columnar cells with basally-located bland-looking nuclei and intracytoplasmic mucin. CDX2 and TTF-1 were partially positive in all and four patients, respectively. MUC5AC was positive in all cases, at least focally. Seven cases showed peribronchiolar metaplasia-like, ciliated tumor cells. Three patients with N2 lymph node metastasis showed mild (N = 2) and moderate (N = 1) cytologic atypia in primary tumors. Presence of stromal invasion and/or micropapillary pattern was common findings of cases with N2 lymph metastasis. Conclusion Colloid adenocarcinoma is a rare variant of lung adenocarcinoma with distinct clinicopathologic characteristics. The frequently seen ciliated tumor cells may suggest that this tumor might originate from a metaplastic process. Majority had indolent clinical course but presence of stromal invasion or micropapillary pattern may reflect aggressive behavior of colloid adenocarcinoma and may indicate poor prognosis.

Purpose The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer. Materials and methods We selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays. Results We identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant-bearing cells. Conclusion Our results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.

Thymic adenocarcinoma is extremely rare. Although its histologic features have been occasionally reported, a lack of description of the cytologic features has hampered the prompt and accurate diagnosis of this condition. Herein, we describe the cytologic findings and histology of four aspiration cytology specimens of thymic adenocarcinoma. The specimens were obtained from primary tumors, metastatic lymph nodes, and pericardial effusions. All four specimens showed three-dimensional glandular clusters with a loss of polarity and nuclear overlapping. One specimen had extensive extracellular mucinous material. Three specimens contained tumor cells with intracytoplasmic vacuoles. While the specimen with extracellular mucin showed relatively mild cytologic atypia, other specimens exhibited more atypical cytologic changes: irregular nuclear membranes, a coarse chromatin pattern, and prominent nucleoli. The cytologic features were correlated with the histologic features in each case of enteric type thymic adenocarcinoma. The differential diagnosis included other thymic carcinomas, yolk sac tumors, and metastatic adenocarcinoma from the lung or colorectum.

We aimed to investigate clinicopathological features and histology of ALK-rearranged adenocarcinomas with extensive mucin production (AEM) that mimic mucinous adenocarcinoma (MA). Retrospectively, 12 cases of AEM and 25 cases of MA harbouring KRAS mutation were retrieved. The clinicopathological profile and detailed histological features were analysed and compared based on the ALK and KRAS status. AEMs occurred in younger patients (p = 0.044) and were characterised by floating tubulopapillary pattern (p < 0.001), prominent nucleolus (p < 0.001), and apical cytoplasmic snouts (p < 0.001). In contrast, KRAS-mutated MAs lacked ALK-specific histological patterns (p < 0.05). Instead, tumour-infiltrating leukocytes (p = 0.018) and smooth cytoplasmic borders (p < 0.001) with vesicular nuclei (p = 0.004) were prominent in KRAS-mutated MAs. AEMs demonstrated characteristic tubulopapillary pattern and apical snouts, which were distinguishing features from MAs with KRAS mutation. Apical snouts can be a useful histological surrogate for ALK rearrangement in the pulmonary adenocarcinomas showing extensive mucin that mimic MA.

// Boram Lee 1, 3 , Taebum Lee 1 , Se-Hoon Lee 2, 3 , Yoon-La Choi 1, 3 , Joungho Han 1 1 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea Correspondance to: Yoon-La Choi, email: ylachoi@skku.edu Joungho Han, email: joungho.han@samsung.com Keywords: lung cancer, EGFR, KRAS, ALK, molecular epidemiology Received: December 19, 2015 Accepted: February 23, 2016 Published: March 14, 2016 ABSTRACT Background: EGFR, KRAS , and ALK alterations are major genetic changes found in non-small cell lung cancers (NSCLCs). Testing advanced lung adenocarcinoma tumors for these three genes is now standard care. The purpose of this study was to investigate the clinicopathologic expression pattern of these three genes in East Asian NSCLC patients. Patients and methods: We conducted a retrospective study of all patients tested for mutations of these three genes at a single institute in Korea between 2006 and 2014. Study data were extracted from electronic medical records. Univariate and multivariate logistic regression analyses were used to measure associations between clinicopathologic features and alterations of EGFR , KRAS , and ALK . Results: We detected 12 EGFR -mutated tumors with additional mutations in KRAS ( N =6, 0.1%) or ALK ( N =6, 0.1%). General clinicopathologic characteristics of tumors with EGFR , KRAS , or ALK mutations were similar to previous reports. Patients having EGFR L858R point mutations were older than patients having EGFR exon 19 deletions. EGFR G719X point mutations were more common in men and smokers than exon 19 deletions or L858R point mutations. Tumors having KRAS G12C mutations were less often of mucinous type than those with G12D or G12V, mutations. Conclusions: This is the largest three gene molecular epidemiology study in East Asian NSCLC patients. Each genetic alteration was associated with distinct clinicopathologic characteristics. Furthermore, different age and sex are associated with different subtypes of EGFR and KRAS mutations.

This review article aims to address mysteries existing between Interstitial Lung Abnormality (ILA) and Nonspecific Interstitial Pneumonia (NSIP). The concept and definition of ILA are based upon CT scans from multiple large-scale cohort studies, whereas the concept and definition of NSIP originally derived from pathology with evolution to multi-disciplinary diagnosis. NSIP is the diagnosis as Interstitial Lung Disease (ILD) with clinical significance, whereas only a part of subjects with ILA have clinically significant ILD. Eventually, both ILA and NSIP must be understood in the context of chronic fibrosing ILD and progressive ILD, which remains to be further investigated.

The objective of our study was to investigate histopathology features, imaging features, and prognoses of surgically resected pure small cell lung carcinomas (SCLCs) and combined SCLCs.Forty-one patients with a pure SCLC or a combined SCLC underwent preoperative chest CT andThe study group was composed of 34 men and seven women with a mean age of 62.0 ± 10.2 (SD) years. Sixteen of 41 (39%) patients had pure SCLC, and the remaining patients had combined SCLC. The most common combined SCLC histologic subgroup was combined SCLC and large cell neuroendocrine carcinoma in 17 (41%) patients. The mean SUVIn our study group of patients with surgically resected SCLC, patients with a peripheral tumor (including a purely endobronchial tumor) or stage I disease showed a better prognosis than those with a central tumor or higher-stage disease.

Two major genetic mutations in non-small cell lung carcinomas (NSCLCs), epidermal growth factor receptor (EGFR) and KRAS, have been well studied. Since 2007 when Soda et al. [1] discovered rearrangements of anaplastic lymphoma kinase (ALK) in NSCLC, the ALK gene has received attention as being responsible for another molecular subtype of lung cancer, accounting for about 3% to 6% of NSCLCs [1,2]. It is important that the presence of ALK gene rearrangement can be an indication for targeted therapy, like EGFR-tyrosine kinase inhibitor (ex. gefitinib) as first-line therapy in patients with advanced pulmonary adenocarcinoma. Moreover, studies have shown that the ALK-targeted inhibitor ‘crizotinib’ produces a notable positive effect in patients harboring the EML4/ALK translocation [3]. For the most effective use of ALK inhibitor, an accurate method to detect ALK gene rearrangement should be performed. To date, fluorescence in situ hybridization (FISH) is the universally accepted standard method for detecting ALK rearrangement, with immunohistochemistry (IHC) used as a screening method for identifying ALK rearrangement [4,5]. However, there is a need for a more rapid method to detect ALK rearrangement due to the highly time-consuming nature of FISH. We encountered a patient who showed a dramatic response to crizotinib treatment before confirming ALK rearrangement by FISH based only IHC-positive results for ALK and suspicious histological findings from a biopsy. Therefore, we were curious whether the combination of IHC and suspicious histological findings can improve upon the shortcomings of FISH. Additionally, limited specimen obtained by biopsy is common and often results in lack of remaining tissue for ALK study after the two major mutation tests (EGFR and KRAS) for lung cancer. If the histologic finding is more suggestive of ALK mutation [6], priority can be given to the ALK mutation test because EGFR, KRAS, and ALK are known to be virtually mutually exclusive. Our study aimed to investigate the characteristic histologic features of ALK-positive pulmonary adenocarcinoma, in order to identify important histologic findings in small biopsied specimens whose architecture is difficult to assess and to evaluate whether the combination of these morphologic features and IHC results can overcome the shortcomings of FISH.

Background This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results Four thousand seven hundred and twenty-six CpGs (P 0.05, Wilcoxon rank-sum test). However, their methylation levels were significantly different between paired bronchial biopsy and washing (P

Background and Aims Pleuroparenchymal fibroelastosis (PPFE) is classified as a rare idiopathic interstitial pneumonia, and its clinicopathologic features remain unclear. We sought to investigate the clinical, radiologic, and pathologic features of patients with histologically proven PPFE. Methods Seven patients who had histologic features of PPFE that were definitive or consistent with PPFE were included. Clinical data and radiologic findings of chest computed tomography were obtained. Histologic evaluation was performed by 2 pathologists. Results Four patients had elevated serum autoantibodies, 3 had a history of organ transplantation, and 1 had acute Aspergillus infection. All patients had various degrees of restrictive patterns on pulmonary function tests. Histologic examination revealed a variable extent of PPFE. Fibroblastic foci, patchy lymphocytic infiltration, and pneumothorax were observed, but these findings were nonspecific. Radiologically, PPFE lesions were distributed diffusely, rather than being limited to the upper lungs. Conclusions PPFE seems to be a histologic finding that may partly overlap with other chronic lung diseases. There can be various underlying clinical states.

Background Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutation in pulmonary adenocarcinoma is clinically important due to its association with resistance to EGFR inhibitors and poor prognosis. To our knowledge, there has not been a comparative study focusing on cytological nuclear features of pulmonary adenocarcinoma harboring KRAS mutation (KRAS-AD). Hence, we compared the cytomorphology of metastatic KRAS-AD and EGFR-positive adenocarcinoma (EGFR-AD) in aspiration specimens from lymph nodes. Methods Forty lymph node aspiration specimens from forty KRAS-AD patients were collected at Samsung Medical Center (Seoul, Korea) from 2009 to 2013. As a control group, 40 EBUS-FNA lymph node specimens from 20 EGFR-AD patients were collected. EGFR-AD specimens were evaluated at Samsung Medical Center (Seoul, Korea) from 2012 to 2013. All 80 specimens were histologically confirmed to metastatic adenocarcinoma. Two pathologists performed a blinded review of all specimens. Results Compared with EGFR-AD, KRAS-AD exhibited more severe nuclear pleomorphism (P

Primary and metastatic non-epithelial tumors of the lung and pleura (NETs-LP) are presumed to represent a small proportion of pulmonary neoplasm, and their epidemiologic characterization is lacking. Moreover, classification of pulmonary mesenchymal tumor according to ‘WHO Classification of Tumors of Lung and Pleura’ (2004) is simple and necessary to give a supplementation like new ‘WHO Classification of Tumors of Soft Tissue and Bone’ (2013). Non-epithelial tumors of the lung and pleura diagnosed from January 1995 to April 2013 were retrospectively reviewed and classified in accordance with ‘WHO Classification of Tumors of Soft Tissue and Bone’ (2013). Of 681 cases represented in the study, smooth muscle tumor (13.1%) was most common, and tumor of uncertain differentiation (10.5%) and fibroblastic/myofibroblastic tumor (5.7%) were followed. Smooth muscle tumor (12.6%) was the common primary tumor, whereas chondrogenic or osteogenic tumor (21.6%) was common in metastatic ones. Pulmonary vascular sarcoma ( n = 15) was the most frequent primary pulmonary sarcoma with following synovial sarcoma ( n = 9) and malignant type of solitary fibrous tumor ( n = 9). This study is the first trial of epidemiologic investigation in Korea about NETs-LP, indirectly representing their incidence in Korea and northeast Asia, and we hope that this presentation offers guidance in further study of NETs-LP.

Background: ROS1 rearrangement accounts for 1%–2% of non-small cell lung cancer (NSCLC) with a remarkable response to crizotinib. Although ROS1-rearranged tumors are known to have characteristic histologic features, only a few studies have investigated the histologic features of advanced-stage ROS1-rearranged tumors. Methods: We analyzed the histopathologic features of ROS1-rearranged tumors in advanced-stage NSCLC patients and assessed the ROS1 immunohistochemistry (IHC) staining patterns of ROS1-rearranged cases. Results: A total of 37 ROS1 fluorescence in situ hybridization (FISH)-positive cases and 64 ROS1 FISH-negative cases were analyzed, and all tumors were EGFR-, ALK-, and RET-negative. Solid pattern, round nuclei with macronucleoli, solid signet-ring cells, extracellular mucin, and a close relation with adjacent bronchioles were significantly associated with ROS1 rearrangement, and the solid signet-ring cell feature was exclusively identified in ROS1-rearranged tumors. ROS1 IHC showed a 97.3% sensitivity when weak to strong protein expression was considered positive. Conclusions: Our findings highlight distinct histologic features of ROS1-rearranged tumors, including their nuclear features. A thorough understanding of ROS1 rearrangement-related histologic features would be helpful to identify ROS1-rearranged tumors in advanced-stage NSCLC.

The majority of previous studies on pulmonary carcinoid tumor have usually focused on clinical behavior or outcome, seldom considering histopathologic features. We retrospectively collected 63 cases of resected pulmonary carcinoid tumors from 1995 to 2011 at Samsung Medical Center, Seoul, Korea. The clinical and pathological features were correlated and survival analyses were performed. Forty cases (63.5%) were classified as typical carcinoid (TC) and 23 cases (36.5%) were classified as atypical carcinoid (AC) according to WHO classification criteria. AC patients showed a higher frequency of current smoking status and a higher stage of the tumor by the American Joint Committee on Cancer than TC patients. The disease was associated with death and recurrence in five and seven patients, respectively, with almost all of the associations found in AC patients. The five-year survival rate of TC and AC were 100% and 83.5%, respectively, with AC showing poorer prognosis than TC in overall survival (OS) and disease free survival (DFS) (p=0.005 and p=0.002). Lung parenchymal invasion was observed more commonly in AC than in TC (39.1% vs 12.5%, p=0.01) and was a poor prognostic factor in OS and DFS. Rosette-like arrangements were found only in six cases of AC, while abundant basophilic cytoplasm mimicking paraganglioma and ossification were found only in TC. Through the comprehensive study of pulmonary carcinoid tumor in Korea, we suggest that lung parenchymal invasion could be a useful histologic feature to suspect the diagnosis of AC in daily practice as well as to predict the prognosis of carcinoid tumor.

Simian virus 40 (SV40) is a polyomavirus that originates from the rhesus macaque and was discovered in 1960 as a contaminant of human polio vaccines produced in monkey cells.1 Recently, there has been considerable interest in the identification of SV40 in human tumors, including malignant mesothelioma (MM) and other rare tumors such as osteosarcoma, ependymoma, and choroid plexus tumors.2-6 Subsequently, it has been found that SV40 may play an important role in the etiology of these tumors.2-6 However, SV40 was not detected in malignant lymphomas in Korean patients.7 Oncogenesis driven by SV40 is mediated by the large tumor antigen (T-Ag) oncoprotein, which is capable of transforming different types of cells in the absence of other viral genes.8,9 T-Ag induces DNA synthesis in host cells and prolongs the onset of the S-phase through the inhibition of tumor suppressor proteins p53 and Rb.8 MM is a rare and extremely aggressive neoplasm that arises from the serosal surfaces of pleural, peritoneal, and pericardial cavities and is very likely associated with amphibole asbestos exposure.10,11 In recent years, the incidence of MM has been gradually increasing in concert with industrial development and increased exposure to asbestos.12 However, only a small number of people who have been exposed to asbestos during their lifetime will develop MM.11 This suggests that SV40 may act as an independent carcinogenic agent or as a cofactor of asbestos to augment the risk of MM.13 Studies investigating the relation of SV40 to MM have been inconsistent and differ by geographical location.6 The incidence of MM varies according to geographic location, and the highest incidence rates are reported from Australia, Belgium, and Great Britain.14 In Korea, the incidence of MM is very low compared with other developed countries, with only about one case per million in the last decade.14,15 However, the incidence is recently increasing. Korea has a higher proportion of females (33.8%) among MM cases compared with other nations such as Canada (15.4%) or Italy (27.6%), and most of the patients are diagnosed when they are in their 50s, which is younger compared to cases in other countries.15 Although the majority of MM patients have had occupational (36.8%) and/or environmental (20.4%) asbestos exposure, the remaining patients (42.8%) had no known asbestos exposure.15 The role of SV40 in the oncogenesis of MM following asbestos exposure has not yet been studied in a Korean population. The purpose of this study is to identify SV40 DNA and protein in tissues extracted from MM from a Korean population using quantitative polymerase chain reaction (PCR) and immunohistochemical staining.

Purpose: This study was aimed at analyzing the recurrence-related prognostic significance of 12 candidate molecular biomarkers in node-negative stage I–II non–small cell lung cancer (NSCLC). Experimental Design: We retrospectively analyzed promoter methylation of eight genes using methylation-specific PCR in formalin-fixed and paraffin-embedded tissues from 328 node-negative stage I–II NSCLCs. The expression of Bcl-2, E-cadherin, p53, and p63 proteins was also assessed by immunohistochemistry. Results: Recurrence was found in 145 (44%) of 328 node-negative stage I–II NSCLCs with a median follow-up period of 6.2 years. No association was found between recurrence and alteration of individual biomarker in univariate analysis. We defined recurrently divergent groups on the basis of recursive partitioning analyses for 12 biomarkers and found a significant association of co-alteration of RASSF1A and p63 with poor recurrence-free survival (RFS). Cox proportional hazards analysis showed that hypermethylation of RASSF1A and negative expression of p63 was associated with poor RFS [HR, 1.93; 95% confidence interval (CI), 1.13–5.47; P = 0.009] compared with those without co-alteration of RASSF1A and p63, after adjusting for age, adjuvant therapy, histology, and tumor size. Random forest classifier including RASSF1A and p63 showed best performance in the prediction of recurrence in node-negative stage I–II NSCLCs: area under receiver operator characteristic curve for random forest was 0.91 and error rate for the model was 17%. Conclusion: The present study suggests that RASSF1A and p63 may be independent prognostic indicators for RFS in node-negative stage I–II NSCLCs. Clin Cancer Res; 19(5); 1204–12. ©2012 AACR.

Lung cancer is the most common solid tumor in critically ill cancer patients admitted to intensive care units and is associated with a poor prognosis. Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is active for advanced non–small cell lung cancer (NSCLC) patients harboring ALK rearrangements. We report three cases of NSCLC patients who required mechanical ventilation for respiratory failure and were successfully weaned from mechanical ventilation after treatment with ALK inhibitors. These responses were accompanied by minimal toxicities and an overt improvement in performance status. These results suggest that ALK inhibitors may be safe and effective in critically ill patients on mechanical ventilation for respiratory failure resulting from EML4-ALK translocated NSCLC progression.

Objective A mutational analysis of tumor tissue samples is an important part of advanced lung cancer treatment strategies. This study evaluated the efficacy of a triple gene analysis using samples obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Methods Either metastatic lymph nodes or primary lung mass samples obtained by EBUS-TBNA were collected between May 2011 and May 2013. We consecutively analyzed epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) fusion genes using remnant tissue samples. Results A total of 109 patients were diagnosed with non-small cell lung cancer (NSCLC). Of these, 70% were adenocarcinoma, 27% squamous cell carcinoma with NSCLC, and 3% were related to other types of lung cancer. EGFR mutations were detected in 23 cases (21.1%), KRAS mutations in 13 cases (11.9%), and ALK fusion genes in 5 cases (4.9%). The ALK fusion genes could not be analyzed in four cases because of insufficient tissue samples remaining after routine histochemistry and an EGFR/KRAS mutation analysis. We found that small biopsy samples from EBUS-TBNA were adequate for performing a triple gene analysis in 97 patients (96%). ALK fusion protein immunohistochemistry (IHC) was 100% consistent with fluorescence in situ hybridization (FISH). Conclusion Small samples obtained by EBUS-TBNA were found to be sufficient for performing a triple gene analysis following routine histology and IHC. ALK IHC showed a very good concordance with FISH for detecting ALK fusion genes.

Primary thymic adenocarcinoma is an extraordinarily rare malignancy; only 49 cases have been reported in the medical literature to date. Because of its rarity, clinical and pathologic characteristics of thymic adenocarcinoma are unclear. We present nine cases of primary thymic adenocarcinoma and discuss clinicopathologic findings in the context of the existing literature. Two-hundred twenty-six thymic carcinoma cases were diagnosed at Samsung Medical Center in Korea, from January, 2001 to July, 2016. Nine of these 226 cases were primary thymic adenocarcinomas. The mean age of primary thymic adenocarcinoma patients was 53.6 years, slightly younger than the mean age of patients with thymic squamous cell carcinomas. The male to female ratio was 2:1. Symptoms, if present, were usually due to compression by the tumor. Tumors showed an extra- or intra-cellular mucin and tubular growth pattern, with CK20- and CDX2-immunoreactivity, similar to adenocarcinomas of the lower intestinal tract. Twenty-five previously reported cases, classified as mucinous adenocarcinoma and adenocarcinoma, not otherwise specified, also had similar characteristics to enteric-type adenocarcinoma and generally expressed CK20, CDX2, CEA, and/or MUC2. Some of these cases had a thymic cyst. These characteristics are different from those of papillary thymic carcinomas, which are morphologically similar to papillary thyroid carcinomas, express CK7 but not CK20, and are often associated with thymoma. The prognosis of thymic adenocarcinoma, enteric type appeared to be worse than the prognosis of papillary thymic carcinoma or carcinoma with adenoid cystic carcinoma-like features. In summary, we demonstrated that common primary thymic adenocarcinomas show enteric-type differentiation with mucin. This tumor type has distinct clinical, pathological, immunohistochemical and prognostic characteristics and is different from other subtypes of thymic adenocarcinoma, papillary thymic carcinoma, and carcinoma with adenoid cystic carcinoma-like features.

Metastatic calcification is rare; it is found during autopsy in patients who underwent hemodialysis. Diffuse calcium precipitation of small and medium-sized cutaneous vessels, known as calciphylaxis, can result in progressive tissue necrosis secondary to vascular calcification. This condition most commonly involves the skin; however, a rare occurrence of visceral calciphylaxis has been reported. Here we report on an autopsy case. Despite a thorough evaluation, and even performing an autopsy, the underlying cause of acute-onset hypercalcemia, resulting in the production of pulmonary calciphylaxis and metastatic renal calcification associated with acute respiratory and renal failure, could not be determined. Metastatic calcification often lacks specific symptoms, and the degree of calcification is a marker of the severity and chronicity of the disease. This unusual autopsy case emphasizes the importance of rapidly progressing visceral calciphylaxis, as well as its early detection.

Background Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. Methods We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. Results It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. Conclusions In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs.

Background The objectives of this study were to examine trends in mesothelioma incidence over a decade and to identify histories of asbestos exposure among cases in Korea. Methods In 2001, The Korea Occupational Safety and Health Agency organized a nationwide cardiopulmonary pathology group and established a malignant mesothelioma surveillance system covering all general hospitals in Korea. Mesothelioma cases were reported to this surveillance system with information about age, gender, location, occupational history, asbestos exposure environment, date of diagnosis, diagnostic method, histopathologic subtype, occurrence site, and other clinical information. Additionally, an epidemiological survey was conducted using a structured verbal questionnaire to allow further evaluation of asbestos exposures. Results A total of 399 cases of malignant mesothelioma were reported in the last decade, translating to approximately 40 annual cases, and an annual average incidence rate of 0.83 cases per million. Of the 152 patients interviewed by occupational physicians, 56 had occupational asbestos exposure histories (36.8%). Their occupations and industries included construction (19.7%), automobile repair (5.9%), asbestos textile, shipbuilding and repair, refinery work, boiler making, and asbestos cement work. Another 31 patients had environmental asbestos exposure histories. Conclusions Surveillance data indicate that malignant mesothelioma incidence in Korea is, thus far, lower than that of other developed countries, and that construction and environmental asbestos exposure were the main identifiable causes of malignant mesothelioma. Am. J. Ind. Med. 55:869–875, 2012. © 2012 Wiley Periodicals, Inc.

We report the dynamic contrast-enhanced CT and histopathologic findings of a rare case of recurrent pulmonary capillary hemangiomas. The findings consisted of peripheral nodular enhancement at the early arterial phase and a subsequent "central filling-in" enhancement pattern on the delayed scans, which was identical to the well-known enhancement pattern of hemangiomas of the liver. Although there was no evidence of histological malignancy, pulmonary capillary hemangiomas manifested as multiple nodular lesions and showed postoperative recurrence.

Metaplastic thymoma (MT), accepted in the World Health Organization 2004 scheme, is a circumscribed tumor of the thymus exhibiting biphasic morphology. We herein describe the clinicopathologic features of four MTs and the differential diagnoses of this unusual tumor. There were three women and one man with mean age of 49.5 years. The patients were found to have mediastinal masses, and underwent surgical excision. One exhibited symptoms of myasthenia gravis, and the serum titer for anti-acetylcholine receptor antibody was positive. Grossly, the tumors were encapsulated, and showed vaguely multinodular, solid, tan-white to yellow cut surfaces. Histologically, they comprised epithelial islands intertwining with bundles of delicate spindle cells. The patients remained well after surgical excision at 5-55 months. Because of the distinctive histological appearance and benign clinical course, MT should be distinguished from other more aggressive mediastinal neoplasms displaying biphasic feature.

To compare prognostic differences between dry pleural dissemination (DPD) and wet pleural dissemination (WPD) in patients with non-small cell lung cancer (NSCLC) andto review the applicability of computed tomographic (CT) findings of DPD for rendering the diagnosis of this disease.The institutional review board approved this retrospective study, and informed patient consent was waived. Of 98 patients (male-to-female ratio, 55:43; mean age, 60 years ± 12) with NSCLC, 20 patients had pathologically proved DPD, and the remaining 78 patients had pathologically proved WPD. Twelve patients, who had been lost to follow-up, were excluded from survival analysis. Observers looked for CT findings of multiple pleural or fissural nodules (more than six in number) and uneven thickening or bandlike thickness. Survival after initial presentation was analyzed and compared between patients with DPD (n = 19) and patients with WPD (n = 67) by using the Kaplan-Meier method and the log-rank test. The sensitivity of CT for depicting DPD was also calculated.Median survival after initial presentation was significantly longer in patients with DPD than in patients with WPD; it was 38 months (95% confidence interval [CI]: 29.9 months, 46.0 months) in patients with DPD and 13 months (95% CI: 9.8 months, 16.2 months) in patients with WPD (P.001). CT helped identify DPD in 90% (18 of 20) of patients with pathologically proved DPD. Multiple pleural or fissural nodules were noted on CT images in 16 (80%) of 20 patients. Uneven or bandlike pleural thickening was recognized in 15 (75%) patients.Patients with DPD show better survival than patients with WPD. CT helps suggest strongly the presence of DPD preoperatively.

Objectives: Sarcomatoid carcinoma of the lung is a very rare and aggressive subtype of non-small cell lung cancer. We explored the clinicopathologic characteristics and surgical outcome of this tumor. Methods: Among 4,212 patients who underwent curative resection for non-small cell lung cancer from September 1994 to December 2009, 99 patients had sarcomatoid carcinoma. Medical records of patients were reviewed retrospectively. Results: The mean follow-up period was 16.07 months. Thirty-six patients had pathologic stage I disease, and 63 had more advanced disease. Surgery included 2 wedge resections, 67 lobectomies, 17 bilobectomies, and 13 pneumonectomies. There were 90 pleomorphic carcinomas, 6 spindle cell carcinomas, 1 giant cell carcinoma, 1 carcinosarcoma, and 1 pulmonary blastoma. Overall 5-year survival was 54.3%. Forty-three patients experienced recurrence and 42 of these died of the cancer. Pathologic T stage as defined by the 7th TNM staging system was significantly associated with survival and recurrence (p = 0.004 and 0.002, respectively). Mean positron emission tomography uptake was significantly higher than in other types of lung cancer (p < 0.0001). Conclusions: Our results implied that surgery for sarcomatoid carcinoma must be carefully planned after extensive preoperative evaluation. Efforts should be made for accurate preoperative histological diagnosis of large peripheral tumor with exceedingly high positron emission tomography uptake.

Pleural mesothelioma is a rare neoplasm and roughly 70% are the epithelioid type, which is characterized by proliferation of epithelioid tumor cells with a tubulopapillary growth pattern [1]. There have been few reports of mesothelioma having a micropapillary pattern [2] and a small cell component [3]. To the best of our knowledge, there has been no previously reported case containing both micropapillary and small cell components. Herein, we report a rare case of mesothelioma with micropapillary component and small cell differentiation exhibiting aggressive behavior in a 59-year-old woman.

Inhaled particulate matter (PM) might influence many adverse health effects in human body, including increased exacerbations of pulmonary and cardiovascular diseases. In this study, we examined the associations between PM and pulmonary adverse effects. Two types of particles, Asian dust (AD) and titanium dioxide (TiO(2)), were administered intratracheally to C57BL/6 mice. The mice were exposed to saline and saline suspensions of 20 mg/kg of AD, TiO(2) particles twice a week for 12 weeks. Following exposure with these particles, the lungs were analyzed histopathologically by hematoxylin and eosin (H&E) and Masson's trichrome (MT) staining. Oxidative injuries were determined by immunohistochemistry (IHC) for 8-oxoguanine in the lungs and Comet assays in peripheral blood mononuclear cells (PBMCs) of C57BL/6 mice. Mice exposed to AD and TiO(2) showed significant inflammatory changes and oxidative damages in the lungs as compared with the control group. DNA damage in PBMCs was also increased significantly in AD and TiO(2)-exposed mice. However, lung fibrosis was minimal and there was no significant difference between PM exposed and control mice. Exposure to AD and TiO(2) particles-induced similar inflammatory damages in the lungs and elicited oxidative DNA damage in the PBMCs.

The presence of pulmonary vasculitis can be suggested by a clinical presentation that includes diffuse pulmonary hemorrhage, acute glomerulonephritis, chronic refractory sinusitis or rhinorrhea, imaging findings of nodules or cavities, mononeuritis multiplex, multisystemic disease, and palpable purpura. Serologic tests, including the use of cytoplasmic antineutrophil cytoplasmic antibody (ANCA) and perinuclear ANCA, are performed for the differential diagnosis of the diseases. A positive cytoplasmic ANCA test result is specific enough to make a diagnosis of ANCA-associated granulomatous vasculitis if the clinical features are typical. Perinuclear ANCA positivity raises the possibility of Churg-Strauss syndrome or microscopic polyangiitis. Imaging findings of pulmonary vasculitis are diverse and often poorly specific. The use of a pattern-based approach to the imaging findings may help narrow the differential diagnosis of various pulmonary vasculitides. Integration of clinical, laboratory, and imaging findings is mandatory for making a reasonably specific diagnosis.

The objective of this study was to describe the PET/CT findings of mucin-producing non-small cell lung cancer (NSCLC) and how those findings are associated with pathology.A review of all patients with FDG-PET/CT identified 11 patients with histopathologically confirmed mucin-producing NSCLC; 3 mucinous bronchioloalveolar carcinoma (mBAC), 5 mixed-type adenocarcinoma with prominent mucinous BAC pattern (ADENO + mBAC), and 3 mixed-type adenocarcinoma with mucin production (ADENO + MUCIN) in our institute.Among 11 patients, only 2 lesions (18%) evidenced positive PET results for standardized uptake value (SUV) of 3.5 (by ROC analysis) whereas all cases were detected correctly at CT. The mean SUV was 2.0 in the 9 lesions not detected and 2.5 in all cases. The mean SUV of pure mBAC was 1.93, that of mucin-producing adenocarcinoma was 2.69 without a significant difference (p = 0.279). No significant correlations between tumor size or stage and SUV were determined.PET/CT for SUV is limited in the detection of mucin-producing NSCLC. Therefore, the CT component of PET/CT may allow for significantly improved sensitivity and help to reduce delayed diagnose. The SUV in mBACs were lower than the other types of mucin-producing adenocarcinoma; however, we determined no significant difference to exist between the SUVs of two groups of lung cancer.