Thymic Adenocarcinoma with Positivity for Thyroid Transcription Factor-1 and a BRAF V600E Mutation.

Thymic adenocarcinomas are rare. We herein report for the first time a case of thymic adenocarcinoma with positivity for thyroid transcription factor-1 (TTF-1) and a BRAF V600E mutation. A 50-year-old woman had persistent suffocation and chest pain. Computed tomography revealed a 42×28-mm tumor in the anterior mediastinum. The patient underwent tumor resection using video-assisted thoracoscopic surgery. Histopathological findings showed thymic papillary adenocarcinoma, Masaoka stage II. Immunohistochemically, the tumor was positive for TTF-1. A sequencing analysis revealed a BRAF V600E mutation. The patient underwent postoperative radiotherapy and was in good health without recurrence at five months after resection.

Primary pulmonary lymphoepithelioma-like carcinoma with positive expression of Epstein-Barr virus and PD-L1: A case report.

INTRODUCTION AND IMPORTANCE: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare type of non-small cell lung cancer (NSCLC) that is classified as a subtype of unclassified carcinoma by the WHO. LELC is usually associated with Epstein-Barr virus (EBV) infection. LELC has often been observed in Southeast Asia; however, it is extremely rare in Japan. CASE PRESENTATION: A 60-year-old Japanese woman presented with an abnormal shadow in the left lung on chest radiography. Chest computed tomography showed a nodule located between the lingular and basal anteromedial segments. A blood test suggested an existing EBV infection, and LELC was suspected preoperatively in the transbronchial lung biopsy. She underwent a lingular and basal bi-segmentectomy. The EBV-encoded small ribonucleic acid in-situ hybridization (EBER-ISH) was positive, and she was diagnosed with LELC. Moreover, programmed death-ligand 1 (PD-L1) expression was moderately positive. No recurrence was observed for 30 months. CLINICAL DISCUSSION: Although LELC has been reported as a low-grade malignancy with a good prognosis, the frequency of PD-L1 expression in LELC seems to be higher than that in other NSCLCs. Moreover, it has been reported that LELC patients with high PD-L1 expression are likely to have early recurrence/metastasis and poor prognosis. CONCLUSION: An investigation of PD-L1 expression for LELC would be useful considering the benefit of PD-1/PD-L1 blockade in patients with pulmonary LELC with high PD-L1 expression. The present case is the first report of LELC with positive expression of EBER-ISH and PD-L1 in Japan.

Metastases in mediastinal and hilar lymph nodes in patients with non-small cell lung cancer: quantitative assessment with diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient.

OBJECTIVE: To evaluate diffusion-weighted magnetic resonance (DW-MR) imaging for detection of metastases in lymph nodes by using quantitative analysis. METHODS: Seventy patients with non-small cell lung cancer were examined with DW and short inversion time inversion recovery (STIR) turbo-spin-echo MR imaging. Apparent diffusion coefficient of each lung cancer and lymph node was calculated from DW-MR images. Difference of the apparent diffusion coefficient in a lung cancer and a lymph node was calculated (D1). From STIR turbo-spin-echo MR images, ratios of signal intensity in a lymph node to that in a 0.9% saline phantom was calculated (lymph node-saline ratio [LSR1]). For quantitative analysis, the threshold value for a positive test was determined on a per node basis and tested for ability to enable a correct diagnosis on a per patient basis. Results of quantitative analyses of DW- and STIR-MR images were compared on a per patient basis with McNemar testing. RESULTS: Mean D1 in the lymph node group with metastases was lower than that in the group without metastases (P < 0.001). When an D1 of 0.24 x 10(-3) mm2/s was used as the positive test threshold, sensitivity, specificity, and accuracy were 69.2%, 100%, and 94.0%, respectively, on a per patient basis. There was no significant difference (P > 0.05) between quantitative analyses of DW-MR images and STIR-MR images. CONCLUSIONS: Quantitative analysis of DW-MR images enables differentiation of lymph nodes with metastasis from those without.

Video-assisted thoracoscopic surgery lowers the incidence of adhesion to the chest wall but not to the mediastinal and interlobar pleurae.

To determine whether video-assisted thoracoscopic surgery (VATS) is associated with a lower incidence of intrathoracic adhesion after pulmonary resection, we assessed the incidence of adhesion for patients who underwent a second pulmonary resection. The site and extent of adhesion were evaluated by reviewing videotapes recorded during surgery. A significantly (P<0.05) lower rate of mediastinal or interlobar adhesion was observed in patients with pneumothorax (10%) in comparison with lobectomy (57%) or partial resection for tumors (63%), although there were no statistically significant differences in adhesion to the chest wall. There were no significant differences between VATS and thoracotomy for mediastinal or interlobar adhesion. However, a significantly (P<0.05) lower rate of adhesion to the chest wall was observed for VATS (54%) in comparison with thoracotomy (100%). Although VATS resulted in less adhesion to the chest wall than thoracotomy, there was no difference in mediastinal or interlobar adhesion.

Brain metastases secondary to tumor emboli from primary lung cancer during lobectomy.

It is assumed that dissemination of tumor cells during pulmonary resection may be followed by metastases. A 70-year-old man with pleomorphic carcinoma of the lung had brain metastases develop secondary to brain infarction caused by tumor emboli during lobectomy. This is a rare case that clearly showed brain metastases as a consequence of tumor emboli during pulmonary resection.

Histopathologic consideration of fiducial gold markers inserted for real-time tumor-tracking radiotherapy against lung cancer.

PURPOSE: Internal fiducial gold markers, safely inserted with bronchoscopy, have been used in real-time tumor-tracking radiotherapy for lung cancer. We investigated the histopathologic findings at several points after the insertion of the gold markers. METHODS AND MATERIALS: Sixteen gold markers were inserted for preoperative marking in 7 patients who subsequently underwent partial resection of tumors by video-assisted thoracoscopic surgery within 7 days. RESULTS: Fibrotic changes and hyperplasia of type 2 pneumocytes around the markers were seen 5 or 7 days after insertion, and fibrin exudation without fibrosis was detected 1 or 2 days after insertion. CONCLUSIONS: Because fibroblastic changes start approximately 5 days after gold marker insertion, real-time tumor-tracking radiotherapy should be started >5 days after gold marker insertion.

HLA class I antigen expression is associated with a favorable prognosis in early stage non-small cell lung cancer.

Human leukocyte antigen (HLA) class I displays a repertoire of endogenously processed peptides to CD8(+) T lymphocytes. The present study assessed correlations between HLA class I expression, clinicopathologic factors, and tumor-infiltrating immune cells in human non-small cell lung cancers (NSCLC). Expression of HLA class I was assessed in 161 resected primary NSCLC by immunohistochemistry using EMR8-5, a novel monoclonal anti-pan HLA class I heavy chain antibody. Expression of HLA class I was classified into three categories: strongly positive, weakly positive, or negative. Tumor-infiltrating CD8(+) lymphocytes and CD56(+) natural killer cells within cancer nests and stroma were also counted. Expression of HLA class I was strongly positive in 50 tumors, weakly positive in 57 tumors, and negative in 54 tumors. Down-regulation of HLA class I was significantly correlated with male sex, history of smoking, non-adenocarcinoma histology, and moderate-/low-grade differentiation. The density of cancer nest-infiltrating CD8(+) cells in HLA class I-negative tumors was significantly decreased compared to that in HLA class I strongly positive tumors (P < 0.01). Kaplan-Meier analysis revealed a significant favorable influence on overall survival for patients displaying tumors with strongly positive expression of HLA class I (P < 0.01). Multivariate analysis revealed down-regulation of HLA class I as an independent factor of poor prognosis in pathological stage I patients, but not in late-stage patients. These results suggest that down-regulation of HLA class I expression in NSCLC is a marker of poor prognosis, and this may play a critical role in immune surveillance of patients with NSCLC.

Subcarinal node is the significant node that affects survival in resected small cell lung cancer.

PURPOSE: Our aim was to clarify the significance of surgery and the prognostic factors in patients with small cell lung cancer (SCLC). METHOD: A retrospective review of 50 patients with limited SCLC who underwent a pulmonary resection and mediastinal nodal dissection during the 10-year period from 1988 to 1997 was undertaken. The TNM classification was applied to all cases of SCLC. RESULTS: A Cox regression multivariate analysis indicated lymph node metastasis (P = 0.0117) and adjuvant therapy (P = 0.0429) to be independent prognostic factors in SCLC patients. Concerning the patients with lymph node metastasis, the prognosis was related only to the involvement of the subcarinal node (station 7). Although no patient with lymph node involvement in station 7 could be a 2-year survivor, in the case of patients with lymph node involvement except in station 7, 47.1% of them were 2-year survivors and 25.1% were 4-year survivors. Among the patients with lymph node metastasis, a univariate analysis indicated the prognosis to be significantly poorer in patients with station 7 involvement than in those without station 7 involvement (P = 0.0224). CONCLUSION: Involvement in the subcarinal node might be a prognostic factor for SCLC.

Deficiency of hMLH1 and hMSH2 expression is a poor prognostic factor in esophageal squamous cell carcinoma.

BACKGROUND: The human Mut-L-Homologon-1 (MLH1) and Mut-S-Homologon-2 (MSH2) are post replication mismatch repair (MMR) genes. METHODS: We examined the correlation of the clinical features of 122 patients with esophageal squamous cell carcinoma (ESCC) with the expression of MLH1 and MSH2 by immunohistochemical analysis. RESULTS: According to our criteria, 34 and 25 cases did not express MLH1 and MSH2, respectively. Expression of both the MLH1 and MSH2 gene products was observed in 73 (59.8%) cases; loss of MLH1 or MSH2 expression was detected in 35(28.7%) cases. Fourteen (11.5%) cases demonstrated loss of both MLH1 and MSH2 expression in ESCC. Loss of MLH1 and/or MSH2 gene expression significantly correlated with increases in malignancy, as evidenced by increases in the existence of metastatic lymph nodes (P = 0.0056), extensive invasion (P = 0.0007), and poor differentiation (P = 0.0992). The MLH1-negative patients had a significantly poorer prognosis than those in the MLH1-positive group (P = 0.0043). Similar results were observed for MSH2 expression (P = 0.0002). Patients both MLH1 and MSH2 negative exhibited the most poor clinical outcome than other patients (P < 0.0001). CONCLUSION: We conclude that MMR protein expression, detected by immunohistochemistry, is a useful marker providing information necessary to decide appropriate therapeutic strategies in patients with ESCC.

Difference of caveolin-1 expression pattern in human lung neoplastic tissue. Atypical adenomatous hyperplasia, adenocarcinoma and squamous cell carcinoma.

Caveolin-1 has been implicated in cellular transformation and tumorigenesis. We assessed lung cancer specimens for caveolin-1 expression immunohistochemistry. A majority of the cell types in the lung and the bronchial epithelium normally exhibited positive staining for caveolin-1. In adenocarcinomas (ADs) of positive staining for caveolin-1, pT1 tumors exhibited significantly higher staining than pT2-pT4 tumors (P=0.0240). In squamous cell carcinomas (SCCs), pT1-pT2 tumors expressed significantly lower expression levels than pT3-pT4 tumors (P=0.0175). In AD, loss of caveolin-1 may be essential for tumor extension and dedifferentiation. In contrast, caveolin-1 overexpression may be correlated with tumor extension in SCC.

CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma.

OBJECTIVE: Recent studies have demonstrated the importance of tumor immunity for a cancer patient's prognosis. In some types of cancer, it has been shown through immunohistochemical analysis that the existence of CD8+ tumor-infiltrating lymphocytes (TILs) is a crucial factor in determining prognosis. In an experimental model, CD4+ lymphocytes together with CD8+ lymphocytes contributed significantly to tumor immunity. METHODS: Specimens were taken from 80 surgically resected pancreatic adenocarcinomas between 1992 and 1999. Immunohistochemical staining of CD4, CD8, and S100 protein was performed, and the levels of these proteins were determined by microscopic analysis. The percentages of patients in the CD4(+) and CD8(+) groups were 59% (47/80) and 25% (16/80), respectively. When separated into 4 groups, CD4/8(+/+), CD4/8(+/-), CD4/8(-/+) and CD4/8(-/-), the overall survival rate was significantly higher in CD4/8(+/+) patients (13 cases) compared with those in all other groups combined (67 cases; P = 0.0098). CD4/8(+/+) status was negatively correlated with tumor depth and TNM stage. Multivariate analyses showed that CD4/8(+/+) status was an independent favorable prognostic factor. The number of tumor-infiltrating S100 protein positive cells was also significantly higher in the CD4/8(+/+) group than in others (P = 0.0084). CONCLUSIONS: In pancreatic adenocarcinoma, the presence of CD4+ TILs together with CD8+ TILs serves as a good indicator of the patient's outcome after surgical treatment.

CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma.

The purpose of this study is to clarify the roles of immune cell types, both individually and synergistically, in esophageal squamous cell carcinoma (ESCC). One hundred and twenty-two patients (105 males and 17 females; mean age, 62.3 years) with primary ESCC underwent surgical tumor resection at the Department of Surgical Oncology, School of Medicine, Hokkaido University and two affiliated hospitals between 1989 and 1999. Immunohistochemical analyses were performed for CD4, CD8, and CD57 (surface markers for natural killer cells). Patient prognosis was found to correlate with the number of CD4(+) and CD8(+) T cells in the stroma and the number of CD8(+) T cells within the cancer cell nest. Furthermore, the number of CD8(+) T cells in the stroma and within the cancer cell nest was found to be correlated [correlation coefficient (r) = 0.790; P < 0.0001). However, no correlation was observed between the number of natural killer cells and patient prognosis. Patients were classified into the following four groups based on CD4(+) and CD8(+) T-cell count: CD4/8(+/+), CD4/8(+/-), CD4/8(-/+), CD4/8(-/-). For the general patient pool, as well as for selected p-stage III and IV cases (n = 48), the survival rate for CD4/8(+/+) patients was significantly higher than that for the other three groups (log-rank test, P = 0.0012 and 0.0088, respectively). Multivariate analysis identified CD4/8(+/+) status, T classification, and N classification as independent prognostic factors. In conclusion, cooperation between CD4(+) and CD8(+) T cells correlates strongly with ESCC patient prognosis.