Small Pulmonary Adenocarcinoma Research Articles

Novel Imprint Cytological Classification for Small Pulmonary Adenocarcinoma Using Surgical Specimens: Comparison with the 8th Lung Cancer Staging System and Histopathological Classification.

Objectives: Small-size lung lesions suspected of being cancer are now often being identified on computed tomography. Correspondingly, a new lung cancer staging system has been proposed by the International Association for the Study of Lung Cancer (IASLC), in which the T1 factor and adenocarcinoma are re-subclassified. Previously, we proposed an intraoperative cytological diagnosis and its classification of small-size lung adenocarcinoma, which correlated significantly with clinical malignancy, to be used for selecting the surgical strategy. In the current study, the correlation of our intraoperative cytological classification with the new 8th IASLC classification was investigated.Materials and Methods: A total of 139 consecutive small-size lung adenocarcinoma cases were surgically resected from 2000 to 2006 and included in this study. Intraoperative stump imprint cytology using these specimens was performed, and the cases were classified into 5 groups based on our classification. The cytological classification was compared with the IASLC classification and the WHO histopathological grading.Results: According to our classification, 32 patients were in Group I, 38 in Group II, 24 in Group III, 27 in Group IV, and 18 in Group V. Compared with the IASLC classification, most of Group I was pTis or pT1mi, and most of Group II was pT1mi or pT1a (p<0.001). There was also a significant relationship between lymph node metastasis and our cytological classification (p<0.001). The histological patterns according to the WHO classification also had a significant relationship with our classification (p<0.001).Conclusion: Our cytological classification correlated not only with the T classification, but also with the adenocarcinoma subclassification of the 8th IASLC classification.

Intraoperative Diagnosis and Surgical Procedure with Imprint Cytology for Small Pulmonary Adenocarcinoma.

Objectives: For patients with multiple small-sized pulmonary cancers, a lobectomy can disrupt future therapeutic options for other lesions. It was recently reported that limited pulmonary resections were not inferior to lobectomy for the management of selected peripheral small-sized pulmonary adenocarcinomas. Patients with adenocarcinoma in situ or minimally invasive adenocarcinoma, as proposed by the International Association for the Study of Cancer classification, have been reported to have 100% survival after 5 years. However, that classification can be applied postoperatively. Since 2005, we have been intentionally performing limited pulmonary resection procedures for small-sized adenocarcinoma cases based on intraoperative imprint cytological diagnosis and our classification (Nakayama-Higashiyama's classification).Materials and Methods: A total of 120 consecutive cases were included in this study. Lung tumors were removed intraoperatively by wedge resection, and stump smear cytology was performed, from which the cases were classified into 5 groups based on our classification. When the tumor was classified as Group I or II, the operation was finished. When diagnosed as a more advanced classification, a lobectomy and lymph node dissection were additionally performed.Results: The 5-year survival rate for Group I and II was 100%, while those for Group III and IV-V were 95.8% and 94.4%, respectively. The 5-year disease-free survival rates for Group I and Group II were 100% and 97.1%, respectively, and for Group III and IV-V they were 100% and 94.1%, respectively.Conclusion: Use of cytological findings along with Nakayama-Higashiyama's classification for determining operation procedure is effective for treatment of patients with small-sized pulmonary adenocarcinoma.

Abnormality of the hepatocyte growth factor/MET pathway in pulmonary adenocarcinogenesis

Background Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Overexpression of HGF and MET and an increase of the MET gene copy number have recently been found in various cancers that had a poor outcome. Here we investigated the copy number of the MET gene and expression of MET and HGF in small pulmonary adenocarcinomas. Methods Tumor tissues were obtained from 106 pulmonary small adenocarcinomas 2 cm or less in diameter. MET gene copy number, and the expression of MET and HGF, were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry, respectively. Results MET FISH-positive signals were observed in 11 (10.4%) of 106 cases. One case (0.9%) showed gene amplification and 10 (9.4%) exhibited high polysomy. High immunoreactivity for MET and HGF in tumor cells was found in 30 (28.3%) and 19 cases (17.9%), respectively. HGF was also expressed in stromal cells in 32 cases (30.2%). No cases of non-invasive adenocarcinoma (adenocarcinoma in situ, localized bronchioloalveolar carcinoma) showed MET FISH-positive signals or high expression of HGF in the tumor cells. Expression of both MET and stromal HGF was stronger in invasive than in non-invasive adenocarcinoma. MET FISH-positive signals and high immunoreactivity for MET and HGF in tumor cells were associated with factors indicative of poor prognosis such as pleural invasion, vascular invasion, lymphatic permeation, lymph node metastasis, and nuclear grading. Univariate and multivariate analyses that included these factors showed that all statuses except for MET and HGF immunoreactivity were significantly associated with an increased risk of death. However, multivariate analysis revealed no independent factors related to poor prognosis. Conclusion Our results suggest that abnormality of the HGF/MET pathway occurs during the course of progression from non-invasive to invasive pulmonary adenocarcinoma. An increased MET gene copy number is indicative of a poor outcome in patients with small pulmonary adenocarcinomas.

Abstract 352: ERG protein is a marker for vascular tumors and prostatic adenocarcinoma

Abstract ERG belongs to the ETS-family of transcription factors and is expressed in subsets of Ewing sarcomas, myeloid leukemias and prostate carcinomas due to chromosomal translocations. Normal expression of ERG has been detected in vascular endothelial cells. In this study we examined ERG-expression in selected adult and embryonic normal tissues, vascular tumors, and non-vascular tumors as controls. A mouse monoclonal antibody (CPDR ERG-MAb) that specifically recognizes ERG oncoprotein was developed at the Center for Prostate Disease Research. We have utilized CPDR ERG-MAb with a Leica automatic immunostainer in combination with the Leica's avidin-biotin free polymer-based detection system. Diaminobenzidine was used the chromogen. Tissues that demonstrated nuclear ERG-immunoreactivity were scored, and only nuclear immunoreactivity was counted as positive. Approximately 10% of examined tissues lacked any ERG-immunoreactivity suggesting that this epitope may be sensitive to sub-optimal preservation. In normal adult skin, tonsil, thymus, liver, kidney, pancreas and, stomach, and colon nuclear ERG-immunoreactivity was restricted to vascular endothelial cells. In human and mouse embryonic tissues wide-spread immonolocalization of ERG was observed in endothelial cells and restricted expression in precartillage, and hematopoietic tissues. Nuclear ERG-positivity was consistently observed in benign vascular tumors (n = 6, at minimum in each category): capillary and cavernous hemangiomas of different types, papillary endothelial hyperplasia, and lymphangioma. In spindle cell hemangioma, the endothelial component was positive and spindle cells negative. In malignant vascular tumors, majority of spindle cells and endothelial cells in Kaposi sarcomas (n = 11) and tumor cells in epithelioid hemangioendothelioma (n = 11) and angiosarcoma (n = 17), were positive. All non-vascular tumors (minimum 5 cases of each): glomus tumor, epithelioid sarcoma, synovial sarcoma, undifferentiated sarcoma, metastatic malignant melanoma, undifferentiated carcinomas of lung and small intestine, pulmonary adenocarcinomas, and malignant mesotheliomas were negative. Consistent with our previous report, In prostatic adenocarcinomas ERG oncoprotein was present in 45% of the examined cases, with no reactivity in non-neoplastic prostate. ERG oncoprotein is a promising marker for prostatic adenocarcinoma in sepration of it from no-neoplastic prostate and other adenocarcinomas. Our recent study revealed that detecting ERG may also be utilized for the diagnosis of angiosarcoma, epithelioid hemangioendothelioma, and endothelial components of hemangiomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 352. doi:10.1158/1538-7445.AM2011-352

Correlations between thin-section CT findings, histopathological and clinical findings of small pulmonary adenocarcinomas

Study objectives Previously, we reported that small pulmonary adenocarcinomas (tumor diameter 20 mm or less) could be classified according to attenuation on thin-section CT (TS-CT) images as either ‘air-containing type’ or ‘solid-density type’ (Lung Cancer 2002;36:49–57). Air-containing type was defined as having areas where TOM (tumor opacity on mediastinal window images) was half or less than half the size of those noted on lung window images. Solid-density type was defined as having areas where TOM was greater than half the size of those noted on lung window images. Our findings indicated that there was no microscopic evidence of metastasis with air-type nor any relapses nor deaths, after resection. By contrast, patients with solid-density types demonstrated a poor prognosis. At this time, the histopathological characteristics of areas of TOM have not been fully investigated. The purpose of this study is to define the correlations between TOM and histopathological findings of small lung adenocarcinomas. Method We retrospectively reviewed the records and CT scans of 134 patients, who had undergone surgical resection of peripheral adenocarcninomas. All tumor diameters were 20 mm or less in size. All 134 patients had undergone TS-CT prior to surgery. TS-CT Images were acquired by a model X-Vigor/Real or an Aquillion CT scanner (Toshiba Medical Systems). Thin-section images of tumors were obtained at 135 kVp at 250 mAs with 1–2 mm section thicknesses. All images were photographed using mediastinal (level, 40 HU; width, 400 HU) and lung (level, −600 HU; width, 1600 HU) window settings. We researched the histopathological components corresponding to the areas of TOM. Results Areas of TOM demonstrated five possible histopathological findings; (1) collapse (C), (2) collapse with bronchioloalveolarcell carcinoma (CwB), (3) adenocarcinoma cells (Cells), (4) fibroblasts (F), and (5) mucus (M). Areas of TOM in air-containing type adenocarcinomas (52 cases) demonstrated predominantly C and/or CwB (C/CwB type, 44 cases). Areas of TOM in solid-density type adenocarcinomas (82 cases), in comparison, demonstrated predominantly Cells and/or Cells/F (Cell/F type, 67 cases). We noted a statistically significant difference between the histopathological findings of the areas of TOM of air-containing type and solid-density type tumors. The 39 cases of Cell/F type adenocarcinomas revealed microscopic evidence of metastasis (pleural involvement, vascular invasion, lymphatic permeation, or lymphnode metastasis). Whereas, no C/CwB type adenocarcinomas cases revealed any microscopic metastasis. The prognosis of C/CwB type after resection is better than for Cell/F type. Conclusion We found that air-containing type adenocarcinomas demonstrated C/CwB type, and that solid-density type adenocarcinomas demonstrated Cell/F type. The histopathological findings of small pulmonary adenocarcinomas could be classified into three groups: C/CwB type, Cell/F type and M type. The prognosis of C/CwB type is better than for Cell/F type. Our results indicate that there are clear correlations between the areas of TOM and the histopathological components of small pulmonary adenocarcinomas. Therefore TS-CT findings are a useful aid in determining the best surgical methods.

Nicotinic receptor‐associated modulation of stimulatory and inhibitory neurotransmitters in NNK‐induced adenocarcinoma of the lungs and pancreas

Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signalling stimulated by the stress neurotransmitters adrenaline and noradrenaline as an important stimulator of adenocarcinomas, including PAC and PDAC. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent mutagen and the most powerful tobacco carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). Using hamster models of NNK-induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the alpha(7)- and alpha(4)beta(2)nAChRs, causing an increase in stress neurotransmitters and a decrease in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Immunoassays showed a significant increase in serum adrenaline/noradrenaline and increased intracellular cAMP in the cellular fraction of blood of NNK-treated hamsters. Western blots on microdissected control small airway epithelia, alveolar epithelia, pancreatic islet and pancreatic duct epithelia, and from NNK-induced PACs and PDACs showed that the GABA-synthesizing enzyme glutamate decarboxylase 65 (GAD65) and GABA were suppressed in NNK-induced PACs and PDACs. In contrast, protein expression of the alpha(7)nAChR, alpha(4)nAChR as well as p-CREB and p-ERK1/2 were up-regulated. These findings suggest that NNK-induced alterations in regulatory nAChRs may contribute to the development of smoking-associated PAC and PDAC by disturbing the balance between cancer-stimulating and -inhibiting neurotransmitters.

The influence of anthracosis and p16(ink4a) gene abberant methylation to the oncogenesis and progression of small pulmonary adenocarcinoma.

Anthracosis is black dust matter deposition in the pulmonary parenchyma, which can cause bronchial deformity and destruction. Previously reported, anthracosis is closely correlated to the oncogenesis and progression of small pulmonary adenocarcinoma and p16(ink4a) gene aberrant methylation was closely associated with lung carcinogenesis. In this study, we want to characterize the influence of anthracosis and p16(ink4a) gene aberrant methylation on small adenocarcinoma. DNA was bisulfite modified and then Methylation Specific PCR was used to detect p16(ink4a) gene aberrant methylation, and black dust matter was extracted from lung tissues, the absolute absorbance (A) detected by densitometry was defined as anthracotic index (AI). The histopathologic diagnosis was according to Noguchi's classification for small pulmonary adenocarcinoma. For heavy smokers, the mean AI was significantly higher than that of nonsmokers (P =0.005) and the frequency of p16(ink4a) gene aberrant methylation was also significantly higher than that of nonsmokers (P =0.023). The frequency of p16(ink4a) gene aberrant methylation of early stage small adenocarcinoma was lower than that of advanced and poor differentiated small adenocarcinoma, otherwise p16(ink4a) protein expression of early stage small adenocarcinoma was significantly higher than that of poor differentiated small adenocarcinoma (P =0.032). AI and p16(ink4a) gene aberrant methylation detection could be used as a combined potential biomarker of small adenocarcinoma.

D4-01: Correlation between high-resolution CT findings, histopathological and clinical findings of small pulmonary adenocarcinomas

D4-01: Correlation between high-resolution CT findings, histopathological and clinical findings of small pulmonary adenocarcinomas

Small Peripheral Pulmonary Adenocarcinoma

The dichotomous histopathologic separation of lung carcinoma into "small cell" and "nonsmall cell" categories is validated by marked clinical and biologic differences between these groups of tumors. However, nonsmall cell carcinoma represents a heterogenous group of tumors, and the subclassification of nonsmall cell lung carcinoma at the molecular, morphologic, and epidemiologic levels has led to the promise of precise treatment and better prognostication. Histomorphologic aspects of small peripheral adenocarcinomas that represent good prognosis include pure bronchioloalveolar carcinoma, minimal invasion within a mixed invasive and lepidic growth pattern tumor, and minimal scar within a lepidic growth pattern tumor. Activating mutations and increased gene copy number of the epidermal growth factor receptor protein and locus, respectively, have been shown to help predict responsiveness to small molecule receptor tyrosine kinase inhibitors in lung adenocarcinoma. These important concepts of morphology and molecular pathology are reviewed, and recommendations for application of these concepts to the practice of surgical pathology are provided.

Clinicopathologic characteristics of metastatic carcinomas to spleen

To study the clinicopathologic characteristics of metastatic carcinomas to the spleen. Sixteen cases of metastatic carcinoma to the spleen were retrieved from archival clinical, surgical pathology and autopsy records. The demographic data (including sex and age of patients), clinical symptoms, primary sites, tumor histologic types, gross appearance of spleen and growth patterns within the spleen were analyzed. Among the 16 patients studied, 12 were males and 4 were females. The male predilection was obvious. The age ranged from 48 to 90 years, the median age 66.5 years. Major clinical symptoms included discomfort in the left upper quadrant, pain, emaciation and loss of appetite. Splenomegaly was noted in some patients and computerized tomography could show space-occupying lesions in the spleen. In general, lung was the most common primary site for splenic metastasis and accounted for 43.8% of all cases (7/16). In male patients, primary lung tumor was found in 50.0% cases (6/12). On the other hand, primary ovarian tumor was commonly seen in females (2/4). Histologically, undifferentiated carcinoma of lung was frequently encountered (25.0%, 4/16), including 3 cases of small cell undifferentiated carcinoma and 1 case of large cell undifferentiated carcinoma. Other histologic tumor types included bronchioloalveolar carcinoma (2 cases), colonic adenocarcinoma (2 cases), ovarian serous papillary adenocarcinoma (2 cases), and prostatic adenocarcinoma (2 cases). The commonest histologic tumor type found in male patients was pulmonary undifferentiated carcinoma. The growth patterns of metastatic carcinoma in spleen included nodular, diffuse and multinodular. Most cases presented as a single splenic nodule. Sometimes, tumors with high metastatic potential (5/16) showed diffuse and multinodular growth patterns. Examples of these tumors included small cell undifferentiated carcinoma (3 cases), pulmonary adenocarcinoma (1 case) and prostatic adenocarcinoma (1 case). Metastatic carcinoma to the spleen is rare. Understanding of the clinicopathologic characteristics is helpful in guiding clinical management and pathologic diagnosis.

Fluorodeoxyglucose Uptake Correlates with the Growth Pattern of Small Peripheral Pulmonary Adenocarcinoma

Noguchi and colleagues reported that the growth pattern of small-sized adenocarcinoma was related to the vascular involvement and the prognosis of the patient. Noguchi's type A/B tumors had no lymph node metastasis, rare vascular involvement, and an excellent prognosis, which meant that Noguchi's type A/B tumors were preinvasive tumors of the peripheral type. Although Noguchi's classification was usually determined based on resected specimens, it would be useful to make a decision about the therapeutic strategy if the classification could be determined preoperatively based on the fluorodeoxyglucose (FDG) uptake. The FDG uptake in 61 pulmonary adenocarcinomas measuring 3 cm or smaller in diameter was compared with the mediastinal uptake and was classified into five grades. The relationship between the FDG uptake and Noguchi's classification (A to F) was analyzed. The FDG uptake was significantly lower in Noguchi's type A/B tumors than in type C or in type D/E/F. Eleven of 12 tumors (92%) with no increased or a weak FDG uptake were classified as type A/B, whereas 32 of 33 tumors (97%) with a strong or very strong FDG uptake were classified as type C-F. The FDG uptake is helpful for making an accurate diagnosis of Noguchi's classification preoperatively in patients with pulmonary adenocarcinoma.

17 Thin section CT analysis of small pulmonary adenocarcinomas less than 10 mm in diameter correlated with clinical and histopathological characteristics

17 Thin section CT analysis of small pulmonary adenocarcinomas less than 10 mm in diameter correlated with clinical and histopathological characteristics

P-672 Correlation between high-resolution CT findings andhistopathological findings of small pulmonary adenocarcinomas

P-672 Correlation between high-resolution CT findings andhistopathological findings of small pulmonary adenocarcinomas

Prognosis and histologic features of small pulmonary adenocarcinoma based on serum carcinoembryonic antigen level and computed tomographic findings.

In 2001, we proposed the criteria for combined evaluation of the serum carcinoembryonic antigen (CEA) level and the tumor shadow disappearance rate (TDR) to predict pathologic N0 (pN0) disease in pulmonary adenocarcinomas. The objective of the present study was to determine the prognosis and histologic features in small-sized pulmonary adenocarcinomas according to serum CEA level and TDR. We reviewed clinical records of 189 consecutive patients with peripheral pulmonary adenocarcinoma 3.0 cm or smaller who underwent major lung resection and systematic lymph node dissection: 50 patients with TDR 0.8 or more and normal CEA level (group I) and 139 patients with TDR <0.8 and/or elevated CEA level (group II). Among them, we investigated histologic features of 177 adenocarcinomas according to serum CEA level and TDR. The 5-year survival rates were 95% for group I and 75% for group II (P = 0.002) and for pN0 patients, 97% in group I and 87% in group II (P = 0.04). In univariate analyses, TDR, preoperative serum CEA level, and the maximum tumor dimension on computed tomographic (CT) scan were significantly associated with prognosis. Multivariate analysis showed that only preoperative serum CEA level and TDR were significant independent prognostic factors, and the maximum tumor dimension was not significant. Group I patients developed no local recurrence, including lymph node metastases. In 25 group I adenocarcinomas 2.0 cm or smaller, no lymph node involvement, two lymphatic permeation, two vascular invasion, and one pleural involvement tumors were observed. These signs of local invasiveness were less frequent than the remaining adenocarcinomas. CT findings correlated well with histologic findings in small-sized adenocarcinomas. Combined evaluation of preoperative serum CEA level and TDR may enable us to identify minimally invasive adenocarcinomas with good prognosis. Candidates for limited lung resection without systematic lymph node dissection could be selected based on these findings.

Pulmonary adenocarcinoma with massive lymphocyte infiltration: report of three cases

We report on three cases of pulmonary adenocarcinoma with lymphoid stroma. In these cases the lesions were small pulmonary adenocarcinomas, less than 2 cm in diameter, and histologically diagnosed as poorly or moderately differentiated adenocarcinomas. Histologically, the tumors were characterized by a small number of cancer cells and numerous infiltrating lymphoid cells, especially CD8 positive T-cell lymphocytes. No Epstein–Barr virus (EBV) genomes were demonstrated by in situ hybridization in the tumor cells of any of the tumors. Lobectomy and regional lymph node dissection were performed and intrapulmonary and mediastinal lymph node metastases were demonstrated in one of these cases (pT4N0M0, pT1N2M0 and pT1N0M0). Two patients are alive and the other died of pneumonia 26 months after the operation. None of the patients experienced recurrence of carcinoma. This unique type of adenocarcinoma characterized by massive lymphocyte infiltration could be referred to as “pulmonary adenocarcinoma with lymphoid stroma”.

Radiologic–prognostic correlation in patients with small pulmonary adenocarcinomas

We retrospectively studied the correlation between high-resolution computed tomography (HRCT) findings and both pathologic findings and prognosis in 137 patients with small pulmonary adenocarcinomas (tumor diameter 20 mm or less). We then evaluated the usefulness of our classification on HRCT findings for predicting outcome and formulating a therapeutic strategy. Tumors were classified according to attenuation of on HRCT images as the ‘air-containing type’ or the ‘solid-density type’. The air-containing type adenocarcinomas ( n=66) revealed no lymphnode involvement detected surgically or pathologically, and revealed minimal microscopic evidence of metastasis (pleural involvement, vascular invasion, or lymphatic permeation). Furthermore, the relapse-free and overall survival curves of the air-containing types revealed no relapses or deaths. Patients with solid-density type adenocarcinomas ( n=71), on the other hand, demonstrated a poor prognosis. Consequently, it seems likely that air-containing adenocarcinomas 20 mm or less in diameter on HRCT may be treated successfully by limited lung resection.

Immunoreactivity for thyroid transcription factor-1 in stage I non-small cell carcinomas of the lung.

Thyroid transcription factor-1 (TTF-1) is a nuclear protein regulating the transcriptional activity of lung-specific genes in the normal and neoplastic bronchioloalveolar cells. It has been implicated in the normal growth and development of the lung, and the disruption of the TTF-1 locus leads to neonatal death with pulmonary hypoplasia. We evaluated retrospectively the prevalence and clinical significance of TTF-1 immunoreactivity in 222 patients with stage I non-small cell lung carcinoma (NSCLC) with a follow-up time of at least 5 years, and we investigated its relationship with other markers of tumor growth, namely cell proliferation and angiogenesis. TTF-1 immunoreactivity was documented by using the commercially available monoclonal antibody 8G7G3/1 in 72% of 97 adenocarcinomas, 5% of 119 squamous cell carcinomas, and in the glandular component of two adenosquamous carcinomas. Four large cell carcinomas were completely unreactive. In adenocarcinomas, but not squamous cell carcinomas, TTF-1 immunoreactivity correlated significantly with microvessel density (p = 0.04) and inversely with the tumor proliferation fraction assessed by Ki-67 immunostaining (p = 0.03). Also, TTF-1-immunoreactive adenocarcinomas showed a trend for a size less than 3 cm (p = 0.08). TTF-1 expression was not related to specific growth patterns, tumor grade, or tumor cell typing. TTF-1 immunoreactivity did not significantly affect patient survival, although patients with more than 75% immunoreactive neoplastic cells showed a trend for longer overall and disease-free survival. Our findings suggest that TTF-1 could be involved in the development of small pulmonary adenocarcinomas, but it has not prognostic implications in patients with stage I NSCLC.

Thin-section CT findings of the small peripheral pulmonary adenocarcinoma detected by low dose screening CT: CT-pathology correlation based on Noguchi's histological classification

Thin-section CT findings of the small peripheral pulmonary adenocarcinoma detected by low dose screening CT: CT-pathology correlation based on Noguchi's histological classification

Tobacco-Specific Carcinogenic Nitrosamines: Ligands for Nicotinic Acetylcholine Receptors in Human Lung Cancer Cells

Lung cancer demonstrates a strong etiologic association with smoking. Of the two most common histologic lung cancer types, small cell carcinoma (SCLC) is found almost exclusively in smokers, whereas peripheral adenocarcinoma (PAC) also develops in a significant number of nonsmokers. N′-Nitrosonornicotine (NNN) and 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), nicotine-derived nitrosamines, are potent lung carcinogens contained in tobacco products. Because of the structural similarity of NNN and NNK with nicotine, we hypothesized that these carcinogens are ligands for nicotinic acetylcholine receptors (nAChRs). Using cell lines derived from human small cell lung carcinoma and pulmonary adenocarcinoma with the site-selective ligands α-bungarotoxin (α-BTX) and epibatidine (EB) in receptor binding and cell proliferation assays, we found that SCLC expressed neuronal nicotinic receptors with high affinity to α-BTX, whereas PAC cells expressed nicotinic receptors with high affinity to EB. NNK bound with high affinity to α-BTX-sensitive nAChRs in SCLC cells, while NNN bound with high affinity to EB-sensitive nAChRs in PAC cells. The affinity of each nitrosamine to these receptors was several orders of magnitude greater than that of nicotine. NNK stimulated the proliferation of SCLC cells via this mechanism. Our findings suggest that NNK may contribute to the genesis of SCLC in smokers via chronic stimulation of the α-BTX-sensitive nAChR-subtype expressed in these cells. Both nitrosamines may also contribute to a host of nicotine-related diseases that are currently thought to be caused by the chronic interaction of nicotine with nAChRs expressed in a large spectrum of mammalian cells.

Analysis of loss of heterozygosity in small adenocarcinomas of the lung.

Despite the many studies of genetic alterations in advanced lung carcinomas, few reports have analyzed early stage adenocarcinoma of the lung. We focused on small pulmonary adenocarcinomas, classified according to recently proposed histological criteria (Noguchi M., et al. Cancer 1995;75:2844-52) which divided adenocarcinomas 2 cm or less in diameter into two groups; one showing replacing growth of the pulmonary alveolar structure [A, localized bronchioloalveolar carcinoma (LBAC); B, LBAC with alveolar collapse; C, LBAC with active fibroblastic proliferation] and the other showing non-replacing growth (D, poorly differentiated adenocarcinoma). Ninety-four small pulmonary adenocarcinomas, including 40 of type A and B, 30 of type C and 24 of type D, were examined for loss of heterozygosity (LOH) using microsatellite markers. The frequencies of LOH were 19.8% in types A and B, 26.8% in type C and 32.7% in type D tumors. There were no significant differences in the frequency of LOH on chromosomes 2p, 3p, 9p and 17q among tumor types. However, on 17p, the frequency of LOH was significantly lower for types A and B than for type C or D. Three out of six type C tumors which were positive for LOH at several loci showed different LOH patterns in two areas (central and peripheral regions). Allelic losses were detected in very early adenocarcinomas and the frequency of LOHs on chromosome 17p increased during malignant progression of the tumor. Heterogeneous genetic alterations were demonstrated even in small pulmonary adenocarcinomas.