Teruyoshi Ishida

Prognostic value of c-erbB-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma

203 primary human lung tumours, of which 119 were adenocarcinoma and 84 were squamous cell carcinoma, were investigated immunohistochemically for the expression of c-erbB-2 protein. Positive staining was evident in 33 (28%) of adenocarcinomas and 2 (2%) of squamous cell carcinomas. In cases of adenocarcinoma, c-erbB-2 was present in 18% of those with stage I disease. In stage IIIA, stage IIIB and stage IV cases, c-erbB-2 was present in 39%, 50% and 60%, respectively (I vs. IIIA and I vs. IIIB: P less than 0.05, I vs. IV: P less than 0.01). The 5-year survival rates of c-erbB-2 positive patients and those who were negative were 30% and 52%, respectively, with a statistically significant difference (P less than 0.01). These observations suggest that when the expression of c-erbB-2 correlates with invasiveness of the tumour, this correlation may serve as a prognostic indicator, particularly in cases of adenocarcinoma of the lung.

Immunohistochemical evidence of autocrine growth factors in adenocarcinoma of the human lung.

We immunohistochemically examined 131 primary human lung adenocarcinomas for the possible presence of autocrine factors. Transforming growth factor alpha (TGF alpha) and epidermal growth factor (EGF) were considered growth factors with epidermal growth factor receptor (EGFR) as the receptor. Of these tumors, 87 (66%) showed a high expression of TGF alpha, 66 (50%) showed a high expression of EGF, and 55 (42%) were positive for EGFR reactivity. In the EGFR-positive cases, the 5-year survival rates of patients with high TGF alpha and low TGF alpha were 36% and 85%, respectively (P less than 0.05). The 5-year survival rates of patients with high EGF and low EGF were 25% and 77%, respectively (P less than 0.05). In contrast, in the EGFR-negative cases, there was no statistical difference between the 5-year survival rates of patients with either high TGF alpha or EGF and low TGF alpha or EGF. Because autocrine growth mechanisms are present in adenocarcinoma of the human lung, these events may contribute to clarification of tumor development, and perhaps even to a better prognosis.

The usefulness of FDG positron emission tomography for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer : a comparative study with X-ray computed tomography

We evaluated the usefulness of fluorine-18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG PET) in the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer and then compared the findings with the results of X-ray CT by region based on the histological diagnoses. We examined 29 patients with non-small cell lung cancer. One hundred and thirty-two mediastinal lymph nodes were surgically removed and the histological diagnoses were confirmed. FDG PET images, including 146 mediastinal regions, were visually analysed and the mediastinal lymph nodes were scored as positive when the FDG uptake was higher than that in the other mediastinal structures. On the X-ray CT scans, any mediastinal lymph nodes with a diameter of 10 mm or larger were scored as positive. All three examinations were successfully performed on 71 regions. For FDG PET, we found a sensitivity of 76%, a specificity of 98% and an accuracy of 93%. On the other hand, for X-ray CT a sensitivity of 65%, a specificity of 87% and an accuracy of 82% were observed. A significant difference was observed in respect of both specificity and accuracy (P<0.05). Based on the above findings, FDG PET is suggested to be superior to X-ray CT when used for the detection of mediastinal lymph node metastases in patients with non-small cell lung cancer.

K-ras and p53 mutations are an independent unfavourable prognostic indicator in patients with non-small-cell lung cancer.

We examined 159 consecutive cases of non-small-cell lung cancer (NSCLC) for a mutation at codon 12 of the K-ras gene and for a mutation of the p53 gene occurring in exons 5-8. Eleven (6.9%) had mutations of the K-ras (ras+) and 57 (35.8%) had mutations of the p53 (p53+). There were 95 cases (59.7%) with ras- p53-, seven cases (4.4%) with ras+/p53-, 53 cases (33.3%) with ras-/p53+ and four cases (2.5%) with ras+/p53+. The ras+ group had a worse prognosis than the ras group in all cases and in 107 early-stage cases (stage I-II, P<0.05). The p53+ group had a worse prognosis in 107 early-stage cases (P<0.01), but there was no statistically significant difference when 52 advanced-stage cases (stage III-IV) or all patients were considered. Both ras and p53 mutations were unfavourable prognostic factors in 94 cases with adenocarcinoma, but there was no statistical significance in 57 cases with squamous cell carcinoma. According to Coxs model, the pathological stage, ras mutation and p53 mutation were found to be independent prognostic factors. Our results suggest that ras and p53 mutations were independent unfavourable prognostic markers especially in the early stage of NSCLC or in adenocarcinoma.

Relationship between early recurrence and micrometastases in the lymph nodes of patients with stage I non-small-cell lung cancer

OBJECTIVE This retrospective study was designed to detect occult micrometastases in the lymph nodes with the use of monoclonal anti-cytokeratin reagent, which is specific for epithelial cells but not for lymphocytes or plasmacytes, as well as to assess the relationship between the presence of occult micrometastases in the lymph nodes and an early relapse in patients with stage I non-small-cell lung cancer. METHODS The paraffin-embedded sections of 973 regional lymph nodes from 44 patients with stage I non-small-cell lung cancer were studied. We used CAM-5.2 as the primary monoclonal anti-cytokeratin reagent and an indirect staining technique with the streptavidin-biotin-peroxidase complex method. RESULTS We identified cytokeratin-positive cells in 31 (70.5%) of 44 patients and in 91 (9.4%) of the 973 lymph nodes. Of these 31 patients with cytokeratin-positive cells, 19 and 12 were restaged as having N1 and N2 disease, respectively. Thirteen patients had recurrent disease at 17 sites during the follow-up. Two of these recurrences were in the mediastinal nodes and the other 15 occurred at distant organs. Twelve of the 13 patients had micrometastatic disease in the regional lymph nodes. Disease-free survival duration was significantly shorter in the patients with micrometastases in the mediastinal lymph nodes than in patients with node-negative disease (p = 0.004). The independence of this prognostic significance was demonstrated by a multivariate analysis. CONCLUSION These findings indicate that the detection of occult micrometastases in the mediastinal lymph nodes with monoclonal antibodies to cytokeratin can thus be used to predict an early relapse in patients with stage I non-small-cell lung cancer.

LONG-TERM RESULTS OF OPERATION FOR NON-SMALL CELL LUNG CANCER IN THE ELDERLY

We surgically treated 185 patients with non-small cell lung cancer who were 70 years old or older. The operative mortality rate was 3%, and the 5-year survival rate was 48%. The mortality and prognosis were similar to those in younger patients. The number of elderly patients who smoked heavily or who had ventilatory defects was high, but the incidence of pneumonectomy was low. There were no differences based on age in regard to histological type, TNM classification, and curability. Pulmonary complications occurred in 21% of the elderly patients and were correlated with preoperative pulmonary function and smoking habits. When the elderly are to undergo elective pulmonary resection for lung cancer, the preoperative evaluation of pulmonary function should be thorough, and both preoperative and postoperative physical therapy should be given. If postoperative pulmonary function is predicted to be less than 0.8 L/m2 of vital capacity and 0.6 L/m2 of forced expiratory volume in 1 second, a limited resection or nonsurgical therapy should be considered.

Effects of fibrin and fibrinogen-degradation products on the growth of rabbit aortic smooth muscle cells in culture

Fibrin contains a factor which promotes growth of the mesenchymal cells and such may be related tissue repair. Effects of fibrin and fibrinogen degradation products (FDP) on the growth of smooth muscle cells (SMC) of rabbit aortas in culture were investigated, in relation to atherogenesis. Fibrin, free from plasminogen enhanced the proliferation of SMC during the experimental period of 48 h. Fibrin, rich in plasminogen also stimulated the proliferation of SMC within 24 h, but inhibited it after 48 h. FDP (fragments D and E) inhibited the proliferation of SMC. SMC of rabbit aortas demonstrated plasminogen activator activity. Thrombin and urokinase exhibited no promoting effects on the growth of SMC. These results support the hypothesis that the proliferation of SMC is stimulated by fibrin and later inhibited by FDP, as produced by the fibrinolytic activity of SMC. It is proposed that the metabolism of fibrin in the arterial wall may be of importance in the regulation of SMC proliferation and that the coagulation-fibrinolysis system may play a significant role in atherogenesis.

Immunohistochemical Evidence of Urokinase-type Plasminogen Activator in Primary and Metastatic Tumors of Pulmonary Adenocarcinoma

The urokinase-type plasminogen activator (u-PA) was used to study 96 cases of lung adenocarcinoma and 49 cases of lymph node metastatic adenocarcinoma. We made use of the immunohistochemistry of paraffinized samples. u-PA was detected in the cytoplasm of tumor cells, and the number of positive cells was higher in patients with T2 or T3 than in those with T1 disease (P less than 0.01). These u-PA-positive tumor cells were more frequent in patients with N2 than in those with N1 disease (P less than 0.01). Such cells were also detected in patients with N1 rather than N0 disease (P less than 0.01). When we compared the frequency of u-PA-positive tumor cells in metastatic lesions with that in primary ones, the former tended to be higher. On the other hand, the frequency of u-PA-positive cells in primary tumors of patients with a recurrence was higher than in those with no recurrence. Thus, u-PA is an important prognostic indicator associated with tumor growth and lymph node spread. If u-PA is detected in a tumor, a recurrence can be expected.

Prognostic influence of the co-expression of epidermal growth factor receptor and c-erbB-2 protein in human lung adenocarcinoma.

The epidermal growth factor receptor (EGFR) is structurally similar to the c-erbB-2 oncogene protein. One hundred and nineteen specimens of primary human lung adenocarcinoma were investigated immunohistochemically for the expression of EGFR and the c-erbB-2 protein. Positive staining for EGFR was evident in 55 (46%), and c-erbB-2 protein in 33 (28%) cases. Of the 119 cases, the number staining positively for both the EGFR and c-erbB-2 protein totalled 16 (13%). The incidence of both the expression of EGFR and the c-erbB-2 protein was greater in patients with metastasis1 (M1) than in those with M0 (P < 0.01). The 5-year survival rates of patients with EGFR positivity and those with EGFR negativity were 51% and 42% respectively, however, the results did not show statistical significance. On the other hand, the 5-year survival rates of patients with c-erbB-2 positivity and c-erbB-2 negativity were 30% and 52%, respectively, with statistical significance (P < 0.05). Of the cases with EGFR positivity the 5-year survival rates of patients with c-erbB-2 positivity (n = 16) and negativity (n = 39) were 33% and 59%, respectively, with statistical significance (P < 0.05). In contrast, for the EGFR negative cases, the 5-year survival rates of patients who were positive (n = 17) and negative (n = 47) for c-erbB-2 expression were 27% and 46%, respectively, which were not significantly different. Our data thus suggested that erbB oncogenes may play an important role in both the development of cancer and the prognosis of adenocarcinoma of the lung.

Inflammatory pseudotumor of the lung in adults: Radiographic and clinicopathological analysis

Inflammatory pseudotumors of the lung are rare in adults. We treated 7 patients with such tumors and describe the histological evidence, radiographic findings, and surgical treatment. In 5 patients, lung cancer was suspected preoperatively on the basis of the radiographic findings. Intraoperatively, the gross appearance of the pleura resembled lung cancer in 6 patients; the parietal pleura was involved in 3, and pleural indentation was present in the other 3. Two patients underwent partial resection, as the frozen section revealed a benign tumor, and 5 patients underwent lobectomy for what appeared to be lung cancer or a large mass. All of the patients are doing well without other therapy. We believe the lesion should be differentiated from lung cancer at operation by frozen sections, even though this proved pertinent in only 2 of the 7 patients. Limited resection is recommended if the lesion is an inflammatory pseudotumor.