A polymorphism in the 5'-flanking region of the CYP2E1 gene and elevated lung adenocarcinoma risk in a Japanese population.

Cytochrome P450 2E1 (CYP2E1) catalyzes the metabolic activation of the procarcinogen, N-nitrosodimethylamine, and cytotoxic carbon tetrachloride compounds. A tandem repeat polymorphism in the 5'-flanking region of the CYP2E1 gene was investigated in non-small cell lung carcinoma (NSCLC) patients to clarify the relationship between CYP2E1 gene polymorphism and lung cancer susceptibility. Blood samples were taken from 236 healthy control subjects (192 males and 44 females) and 111 patients (78 males and 33 females) who underwent surgery for NSCLC in Japan. DNA was isolated from these samples and the 5'-flanking region of the CYP2E1 gene was amplified by polymerase chain reaction and examined for tandem repeat polymorphisms using DNA fragment analysis. Sequence analysis confirmed the presence of three alleles, A2, A3, and A4 (361, 367, and 457 bp, respectively), with four genotypes observed in the lung cancer group and five genotypes in the control group. There was a statistically significant difference in genotype distribution between the lung adenocarcinoma and control group (P=0.0088, A4/A4 vs. non-A4/A4). In the lung adenocarcinoma group, the univariate risk estimates for the A4/A4 subgroup compared to the most common subgroup (A2/A2) was 4.300 (95% confidence interval = 1.358-13.618, P=0.0131). We conclude that the A4/A4 genotype of the 5'-flanking region of CYP2E1 was significantly more frequent in lung adenocarcinoma cases than in healthy controls and, therefore, may be involved in the development of lung adenocarcinoma.

Endobronchial neurogenic tumors treated by transbronchial electrical snaring and Nd-YAG laser abrasion: report of three cases.

Neurogenic benign tumors arising from the trachea and bronchus are relatively rare. We experienced three cases of neurofibroma of the bronchus which were successfully treated by transbronchial electrical snaring and Nd-YAG laser abrasion. The first was a 67-year-old man with right lung cancer, who was pointed out to have a neurofibroma in the left main bronchus. The second was a 34-year-old man with an obstruction in the right main bronchus due to neurofibroma. The third was a 66-year-old woman with a complete obstruction in the left main bronchus due to schwannoma. All patients were successfully treated to remove the tumors and obtain a patency of the bronchus by transbronchial electrical snaring and Nd-YAG laser abrasion. We also review 23 reported cases of endobronchial neurogenic tumors and discuss the efficacy of endoscopic treatments for endobronchial neurogenic tumors.

Clinicopathological analysis of pulmonary sclerosing hemangioma.

BACKGROUND: Sclerosing hemangiomas of the lung are uncommon tumors and are thought to be benign. However, the histogenesis and clinicopathological features of these tumors have not been elucidated. METHODS: We analyzed the clinicopathological features of 26 sclerosing hemangiomas. The immunoreactivity for Ki-67 and p53 of sclerosing hemangiomas was determined and compared with that of pathological stage 1 pulmonary papillary adenocarcinomas. RESULTS: The patients of sclerosing hemangioma were predominantly female. Eighteen patients were detected as a result of routine medical examinations and 15 were nonsmokers. Seven patients underwent tumor enucleation, 10 underwent a wedge resection, and 9 underwent a lobectomy. The mean tumor size was 2.2 cm (range 1 to 5 cm). Pathological findings demonstrated a papillary pattern in 23 cases, sclerotic pattern in 26 cases, hemorrhagic pattern in 22 cases and a solid pattern in 25 cases. Twenty-five cases had an excellent prognosis with no evidence of recurrence following surgery. However, 1 patient who had undergone a wedge resection developed a local recurrence and required an additional wedge resection. The Ki-67 labeling index of sclerosing hemangiomas was significantly lower than that of adenocarcinomas, whereas the Ki-67 labeling index of the recurrent case was 0.4%. No significant immunohistochemical staining for p53 was observed in sclerosing hemangioma cases. CONCLUSIONS: Sclerosing hemangioma exhibits various histologic findings. Although we experienced one case with a recurrent tumor, sclerosing hemangiomas did not exhibit malignant behavior.

Genetic alterations in early-stage pulmonary large cell neuroendocrine carcinoma.

BACKGROUND: Small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC) are high-grade malignant neuroendocrine tumors. Histologic differentiation between SCLC and LCNEC is difficult in some cases and to the authors' knowledge, genetic alterations associated with LCNEC have not been identified. Therefore, the authors studied genetic alterations found in LCNEC and compared them with those of SCLC and classic large cell carcinoma (CLCC). METHODS: Twenty-two patients with UICC TNM Stage I LCNEC, 12 patients with Stage I CLCC, and 11 patients with SCLC with limited disease were studied. All tumors were resected completely. Loss of heterozygosity (LOH) of the tumor cells was detected using fluorescent primers. Methylation status of the p16 gene and expression of the p53 protein, retinoblastoma protein, and p16 protein were evaluated immunohistochemically. RESULTS: LOH at TP53 and 13q14 was observed in most patients. The prevalence of LOH at D3S1295, D3S1234, and D5S407 was significantly higher in patients with LCNEC and SCLC than in patients with CLCC. The prevalence of LOH at D5S422 was higher in patients with CLCC and in patients with SCLC than in patients with LCNEC. Expression of the p16 protein was observed more frequently in SCLC than in CLCC or LCNEC. Hypermethylation of the p16 gene was observed more frequently in LCNEC than in SCLC. Patients with allelic losses at D3S1234 and D10S1686 had poorer prognoses compared with patients without allelic losses at these sites. CONCLUSIONS: Genetic alterations of LCNEC were akin to those of SCLC. However, allelic losses at 5q and abnormalities in the p16 gene may differentiate LCNEC from SCLC.

Fatal infectious mononucleosis with evidence suggestive of the development of B cell lymphoma.

A 4-year-old girl presented to a local hospital in August 1999 with fever and cervical lymphadenopathy. A diagnosis of Epstein-Barr virus (EBV) infection was made and the patient was treated with corticosteroids. One month later she developed dyspnea secondary to tonsilar swelling, and underwent tonsillectomy and adenoidectomy. Her dyspnea increased, however, and by mid September she required mechanical ventilation. Six weeks later, she was transferred to Chiba Children's Hospital (Chiba, Japan). Despite vigorous treatment, she died within four weeks of admission. At autopsy, microscopic examination revealed numerous histiocytes with frequent hemophagocytosis in her lungs, liver, spleen, thymus, and lymph nodes. The tentative diagnosis was EBV-associated hemophagocytic syndrome (EBVAHS). A proliferation of atypical lymphocytes was observed in the lymph nodes, the majority of which stained positive with CD79a antibody. A whitish nodule, 8 mm in diameter, was noted in her right ovary. It consisted of a proliferation of pleomorphic lymphoid cells expressing CD79a antigen. In situ hybridization detected EBV RNA within CD79a antigen-positive cells in the lungs, spleen, thymus, bone marrow, lymph nodes, and the right ovary. Polymerase chain reaction analysis of DNA from the ovarian nodule demonstrated a monoclonal rearrangement of the immunoglobulin heavy chain gene indicating that it consisted of a clone of B lymphocytes. We suggest that EBVAHS develops into polyclonal and monoclonal lymphoproliferative disorder in a short period, and that EBVAHS is a preneoplastic condition that may result in B cell lymphoma.

Ki-67 expression and prognosis for smokers with resected stage I non-small cell lung cancer.

BACKGROUND: The cigarette smoking status of patients before surgery is an important prognostic factor in evaluation of stage I non-small cell lung cancer, and the proliferative activity of lung tumors is also related to the patient's prognosis. This study evaluates relationships between various clinicopathologic factors, including tumor proliferative activity and smoking status, and the patient's prognosis in stage I non-small cell lung cancer. METHODS: One hundred eighty-seven stage I adenocarcinoma and squamous cell carcinoma cases were evaluated. The patients underwent complete resection between 1988 and 1993 at Chiba University Hospital. Expression levels of Ki-67 nuclear antigen, p53 protein, and retinoblastoma protein were determined immunohistochemically, and postoperative survival rates for patients in the categories of clinicopathologic factors were estimated. RESULTS: The mean Ki-67 labeling index (LI) for all cases was 19.3%. Labeling index values were significantly higher in squamous cell carcinoma than in adenocarcinoma (p < 0.0001). Postoperative survival of adenocarcinoma patients was significantly related to the LI values and to the patient's smoking status (p = 0.0164 and 0.0268, respectively). The LI values were also related to smoking status and the extent of histologic differentiation (p = 0.0112 and p < 0.0001, respectively). For non-smoking adenocarcinoma patients, higher LI values were associated with abnormalities in p53 expression (p = 0.0048). Retinoblastoma protein abnormalities were not related to LI values. CONCLUSIONS: In smokers with stage I pulmonary adenocarcinoma, tumor proliferative activity and smoking status before surgery were important prognostic determinants. The LI values were related to several clinicopathologic factors.

Systemic arterial supply to the left basal segment without the pulmonary artery: four consecutive cases.

Systemic arterial supply from the descending thoracic aorta to the basal segment of the left lower lobe without a pulmonary artery supply is a rare congenital anomaly within the spectrum of pulmonary sequestration cases. We encountered four consecutive cases, which were treated successfully by three basalectomies and one lower lobectomy to preserve lung function.

Pulmonary large cell carcinoma with rhabdoid phenotype.

A 70-year-old woman presented with a coin lesion in her left lung. The tumor was well circumscribed and had a large area of central necrosis with a thin rim of viable tumor cells. It showed a solid growth pattern of polygonal cells with eosinophilic intracytoplasmic inclusion bodies. Immunohistochemically, the tumor cells were positive for vimentin, neural cell adhesion molecule, neuron-specific enolase, and vascular endothelial growth factor. Electron microscopy revealed intracytoplasmic inclusion bodies consisting of whorled intermediate filaments. Based on histological and immunohistochemical findings, the patient was diagnosed as having pulmonary large cell carcinoma with rhabdoid phenotype (LCCRP). The patient was in stage IA, and the histological findings may be the prototype of pure LCCRP. The tumor recurred after 6 years, and the second tumor had more apparent intracytoplasmic inclusion bodies. It is worthwhile detecting and recognizing the significance of these intracytoplasmic inclusions because of the poor prognosis of this tumor.

Proliferative activity and apoptosis in thymic epithelial neoplasms.

The classification of thymic epithelial tumors is controversial because prediction of the biological behavior of these tumors from their morphologic appearance is difficult. The aim of this study was to evaluate the proliferative activity and rate of apoptosis of thymic epithelial tumors classified according to World Health Organization histological classification. We also attempted to determine the importance of a number of proapoptotic factors in these processes. We investigated 46 surgically resected thymic epithelial tumors (8 Type A, 8 Type AB, 7 Type B1, 7 Type B2, 6 Type B3, and 10 Type C). Immunohistochemical staining was performed to determine the tumor expression of p53 protein, Bax, Bcl-2, and survivin. In addition, the Ki-67 labeling index (LI) and apoptotic index (AI) of these tumors were evaluated. Type C thymoma had a higher LI (16.55 +/- 12.12%) than did the other histological subtypes. Stage IV thymoma (12.36 +/- 9.99%) had a higher LI than did Stage I tumor. The AI was significantly elevated in Type B1 thymoma (1.47 +/- 0.55%). Overexpression of p53 protein was observed in Type B3 and C thymomas. p53 protein-positive tumors had a higher LI than did p53 protein-negative tumors (P <.0001). Bcl-2 expression was observed in Type A, AB, and C thymomas. Bcl-2-positive thymoma had a lower AI than did Bcl-2-negative thymoma (P =.0157). These results suggest that overexpression of p53 protein is associated with a higher tumor proliferative activity and that Bcl-2 acts as an inhibitor of apoptosis in thymoma. Bcl-2 and p53 protein expression may be useful markers in differentiating thymoma subtypes.

Evidence of neoangiogenesis and an increase in the number of proliferating cells within the bronchial epithelium of smokers.

BACKGROUND: Normal bronchial epithelium gradually acquires cellular and genetic changes that result in the formation of invasive tumors. The objective of this study was to evaluate the degree of proliferative change and the amount of neovascularization in both normal and preneoplastic lesions in smokers who were at high risk for developing lung carcinoma. METHODS: The authors studied bronchial biopsy specimens from 7 nonsmokers and 52 smokers. Immunohistochemical staining of the specimens with antibodies for the presence of p53 protein, Ki-67 and CD34 antigens, and vascular endothelial growth factor was performed. The proliferation index (PI) was assessed by immunohistochemical staining for Ki-67 antigen. RESULTS: Overexpression of p53 protein was observed frequently in regions of squamous dysplasia and in squamous cell carcinoma tissue. The PI of normal epithelium from smokers was increased compared with nonsmokers, and the difference was statistically significant (P < 0.05). The microvessel count (MC) in normal mucosa obtained from smokers was higher compared with the MC in normal mucosa obtained from nonsmokers (P < 0.05). A significant difference in MC also was observed between regions of squamous metaplasia or dysplasia with projections of capillary loops into the bronchial mucosa and similar lesions without capillary loops (P < 0.005); however, there was no difference in either the PI or the incidence of p53 overexpression between these groups. CONCLUSIONS: These results show that smoking appears to induce both a proliferative response and neovascularization in bronchial mucosa. The projection of capillary loops into the bronchial mucosa also may be a result of neovascularization occurring within the lamina propria of the bronchial wall.

Preoperative cytodiagnosis of very small-sized peripheral-type primary lung cancer.

To demonstrate the importance of preoperative diagnosis of pulmonary cancers presenting as peripheral small-sized solitary shadows we evaluated the results of morphologic definitive diagnosis together with various clinical factors in 91 tumors with less than 15-mm diameter resected surgically between 1983 and 1999. Histologically, these tumors consisted of 73 adenocarcinomas, nine squamous cell carcinomas, and nine other types. Regarding the pathologic stage, 57 tumors were classified in stage IA, three in IB, six in IIA, seven in IIIA, 14 in IIIB, and four in IV. Comparing various biopsy techniques, the sensitivity of preoperative cytodiagnosis was 43.7% for transbronchial brushing (n = 48), 52.9% for transbronchial forceps biopsy-stamp cytology (n = 51), 66.6% for transbronchial fine needle aspiration (n = 78), and 85.0% for percutaneous fine needle aspiration (n = 20). The overall sensitivity of preoperative cytodiagnosis was 79.0% for transbronchial biopsy (n = 81), and 87.3% for transbronchial and percutaneous biopsy (n = 87). Of 73 clinical N0 cases in which lobectomy was performed, 10 cases (13.6%) were diagnosed as between pathological degrees N1, N2 and N3. However, lung cancer cases with less than 10-mm diameter did not have lymph node metastasis. Our study of histologic differentiation showed that all cases of well-differentiated adenocarcinomas (n = 20) were pathological degree N0. The overall sensitivity of preoperative diagnosis increased to 89.1% in cases (n = 74) of tumors with 11-15-mm diameter. The sensitivity of cytodiagnosis for peripheral small-sized primary lung cancers is high, and we can estimate histological differentiation based on the cytological findings. Therefore, cytodiagnosis is an effective and indispensable diagnostic method for determination of the optimal treatment approach, including approaches such as intentionally limited resection.

Prognostic significance of neuroendocrine differentiation in adenocarcinoma of the lung.

BACKGROUND: The relative incidence of adenocarcinoma of the lung is increasing and some patients with lung carcinoma, detected at an early stage, still develop recurrent disease despite complete resection of the tumor. Recently, neuroendocrine differentiation in large cell carcinoma of the lung has been reported to be of prognostic significance. Therefore, we have evaluated the prognostic significance of neuroendocrine differentiation in adenocarcinoma of the lung. METHODS: A total of 90 resected specimens of adenocarcinoma of the lung measuring 3 cm or less (T1 N0 M0 or T2 N0 M0) were reviewed histologically and immunohistochemical staining was performed to determine the degree of neuroendocrine differentiation. RESULTS: Seven adenocarcinomas exhibited neuroendocrine differentiation in 10% or more of tumor cells. The disease-free survival rate for these patients was significantly lower than that of patients with tumors exhibiting neuroendocrine differentiation in less than 10% of tumor cells or with absent neuroendocrine differentiation (p < 0.0005). Other conventional pathologic factors such as vascular invasion (p < 0.0005), lymphatic invasion (p < 0.05), and pleural involvement (p < 0.05) were also of prognostic significance. In multivariate analysis, the presence of 10% or more neuroendocrine marker-positive tumor cells, vascular invasion, and lymphatic invasion were found to be significantly adverse prognostic factors (p = 0.0162, p = 0.0111, and p = 0.0173, respectively). CONCLUSIONS: Neuroendocrine differentiation of tumor cells is a prognostic factor in lung adenocarcinoma. It is suggested that the identification of neuroendocrine differentiation as well as vascular invasion by tumor in small peripheral adenocarcinoma of the lung may predict the prognosis of these patients.

Alpha-fetoprotein-producing lung carcinoma: report of three cases.

Three cases of alpha-fetoprotein (AFP)-producing lung carcinoma were studied histologically and immunohistochemically. Samples were obtained from two men and one woman who ranged in age from 64 to 71 years. Serum AFP levels for the three samples were 9826, 74.4 and 24.3 ng/mL. One case was classified as stage IIIA and two as stage IIIB. Two cases were diagnosed as large cell neuroendocrine carcinoma, and AFP expression was detected immunohistochemically. One of these samples showed differentiation to a hepatoid carcinoma, while the other was combined with a squamous cell carcinoma. The remaining case was a squamous cell carcinoma, and AFP was detected in only some of the tumor cells. All patients died within 2 years. The Ki-67 labeling indices of the AFP-producing pulmonary carcinomas (30.2 +/- 4.6%) were significantly higher than those of AFP-negative pulmonary carcinomas (P < 0.05). The high proliferative activity, advanced stage at presentation, vascular endothelial growth factor expression and vascular invasion observed in these tumors may explain the poor prognosis of AFP-producing lung carcinomas.