Biomedical subjects

Kanji Nagai

Publications and source records attributed to Kanji Nagai.

At least 37 records · Page 2Linked to original sources

PubMed2005

Cytologic factors associated with prognosis in patients with peripheral adenocarcinoma of the lung measuring 3 cm or less in greatest dimension.

BACKGROUND: Recently, peripheral lung adenocarcinomas (PLA) measuring < or = 3 cm in greatest dimension often have been diagnosed using diagnostic radiology. The objective of the current study was to determine which cytologic factors are associated with a favorable outcome and an unfavorable outcome in patients with PLA. METHODS: Imprint smears from 134 patients with PLA were examined. Sixteen cytologic factors, including necrosis, cellular distribution, overlapping of cell clusters, cluster aggregation, cluster size, cluster thickness, nuclear irregularity, nuclear size, variation in nuclear size, multinucleated cells, intranuclear inclusions, type of intranuclear inclusions, appearance of nucleoli, eosinophilic nucleoli, multinucleoli, and mitosis, were evaluated using univariate and multivariate analyses. A counting method was used to determine the prognosis for individual patients. RESULTS: In the univariate analysis, a cluster size that measured > or = 831 microm in short dimension (P = 0.0011), moderate or severe nuclear irregularity (P = 0.0030), > or = 5 multinucleated cells per 100 tumor cells (P = 0.0047), moderate or severe variation in nuclear size (P = 0.0061), medium or large nuclear size (P = 0.0169), and > or = 1 mitotic cell per 100 tumor cells (P = 0.0412) were associated significantly with a poor outcome. In the multivariate analysis, cluster size in short dimension (P = 0.0018), multinucleated cells (P = 0.0066), and nuclear irregularity (P = 0.0310) were found to be independent prognostic factors. CONCLUSIONS: The combination of cytologic features using intraoperative imprint smears, namely, cluster sizes < or = 830 microm in short dimension, < or = 4 multinucleated cells per 100 tumor cells, and mild nuclear irregularity, may provide favorable predictive information in patients with PLA.

Adenocarcinoma↗

PubMed2005

Histopathologic prognostic factors in resected colorectal lung metastases.

BACKGROUND: Pulmonary metastasectomy is a standard method of treatment for selective pulmonary metastases of colorectal cancer. However, the pathologic factors of metastatic lesions that affect survival and tumor recurrence after pulmonary resection are less well defined. The pathologic findings of colorectal pulmonary metastases have not been correlated with clinical outcome. The study was conducted to clarify the characteristics and identify the prognostic factors of the pulmonary metastases of colorectal cancer. METHODS: Between July 1992 and November 2002, 89 patients underwent the complete resection of pulmonary metastases of primary colorectal carcinoma, and we pathologically reviewed the surgical specimens of 136 metastatic lesions from these patients. RESULTS: There were no perioperative deaths. The overall 5-year survival rate was 61.4%. No clinical factors were associated with the outcome. The univariate analysis of pathologic factors revealed aerogenous spread with floating cancer cell clusters (ASFC) (p = 0.004), vascular invasion (p = 0.002), lymphatic invasion (p = 0.032), and pleural invasion (p = 0.037) to be prognostic factors. The multivariate analysis showed vascular invasion (p = 0.02) and ASFC (p = 0.02) to be independent prognostic factors. The 5-year survival rate of patients whose lesions were positive for both ASFC and vascular invasion was 24.7% and much poorer than in the patients with ASFC without vascular invasion (78.6%), vascular invasion but without ASFC (80.2%), and patients negative for both (93.3%) (p = 0.0002). CONCLUSIONS: The morphologic features of ASFC and vascular invasion at metastatic sites are prognostic factors for colorectal cancer patients who have undergone pulmonary metastasectomy.

Adenocarcinoma↗

PubMed2005

Predictive factors for local recurrence of resected colorectal lung metastases.

BACKGROUND: Wedge resection or segmentectomy are the preferred treatments for pulmonary metastasis from colorectal cancer. However, local recurrence at the surgical margin is a problem with limited resections. This study attempted to identify predictive factors associated with local recurrences at the surgical margin after resection of pulmonary metastases. METHODS: A total of 96 lesions in 61 patients who had undergone a pulmonary wedge resection or segmentectomy for the treatment of pulmonary metastasis from colorectal cancer were investigated. Various clinical and pathologic factors were reviewed, and the risk of a local recurrence at the surgical margin was investigated. RESULTS: After pulmonary resection, 34 of the 61 patients (56%) experienced recurrences in their lungs. Local recurrences at the surgical margin were found in 17 patients (28%), even though 15 of these 17 cases had been histologically confirmed as completely resected cases. No clinical factors associated with local recurrence at the surgical margin were identified. Pathologically, lesions exhibiting 10 or more aerogenous spreads with floating cancer cell clusters around the main tumor (p = 0.02) and a malignant positive surgical margin (p = 0.04) had a significantly higher risk of local recurrence. CONCLUSIONS: The present study indicated that local recurrence may occur even in cases with a pathologically negative surgical margin. In cases with pulmonary metastases from colorectal cancer, lesions with 10 or more aerogenous spreads with floating cancer cell clusters around the main lesion and a malignant positive surgical margin in the resected specimens have a significantly higher risk of local recurrence at the surgical margin than those without.

Adult↗

PubMed2005

Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience.

OBJECTIVE: This study was undertaken to determine the recurrence rate after limited resection of small lung carcinoma and to evaluate intraoperative frozen-section examination accuracy for Noguchi classification. METHODS: Enrollment requirements were as follows: pulmonary nodule 2 cm or smaller, diagnosed or suspected clinical T1 N0 M0 carcinoma in the lung periphery, and ground-glass opacity findings and lack of evident pleural indentations or vascular convergence on high-resolution computed tomographic scan. A wedge or segmental resection specimen, removed with custom stapler cartridges, was immediately reinflated and examined by frozen-section with hematoxylin-eosin and Victoria blue-van Gieson stains. If the tumor was confirmed as Noguchi type A or B with resection margins greater than 1 cm, the patient was closed and followed up on an outpatient basis. End points were 5-year disease-free survival and intraoperative classification accuracy. RESULTS: From August 1998 through October 2002, a total of 50 patients were enrolled (20 men and 30 women, ages 30-77 years). Tumor sizes ranged from 2 to 21 mm (11 mm average). There were 2 Noguchi type A tumors, 23 Noguchi type B tumors, 15 Noguchi type C tumors, 5 atypical adenomatous hyperplasias, 4 fibroses, and 1 granuloma. Frozen-section accuracy was approximately 98% (39/40). One intraoperative type B diagnosis was revised to type C after postoperative pathologic study. No morbidity, mortality, or recurrence has been seen with a median follow-up of 50 months. CONCLUSION: Noguchi type A and B tumors may well be in situ carcinomas, and frozen-section examination was highly accurate. Neither local recurrence nor distant metastases have been found to date. Limited resection initial results appear promising.

Adult↗

PubMed2005

Visceral pleural invasion is an invasive and aggressive indicator of non-small cell lung cancer.

OBJECTIVE: Although visceral pleural invasion by non-small cell lung cancer is considered a poor-prognostic factor, further information is lacking, especially in relation to other clinicopathologic prognostic factors. We assessed the relationship between visceral pleural invasion and other clinicopathologic characteristics and evaluated its significance as a prognostic factor. METHODS: We reviewed 1074 patients with surgically resected T1/2 non-small cell lung cancer for their clinicopathologic characteristics and prognoses. The patients were divided into 2 groups according to visceral pleural invasion status (visceral pleural invasion group and non-visceral pleural invasion group). Both groups were compared with regard to age, sex, histology, tumor size, tumor differentiation, lymph node involvement, lymphatic invasion, vascular invasion, scar grade, nuclear atypia, mitotic index, serum carcinoembryonic antigen level, and survival. Univariate and multivariate analyses were conducted. RESULTS: Visceral pleural invasion was identified in 288 (26.8%) of the resected specimens. Survival was 76.0% at 5 years and 53.2% at 10 years in the non-visceral pleural invasion group and was 49.8% at 5 years and 37.0% at 10 years in the visceral pleural invasion group. The difference between groups was highly significant ( P < .0001). Visceral pleural invasion was also significantly associated with a higher frequency of lymph node involvement. However, regardless of N status (N0 or N1/2), there was a significant difference in survival when the visceral pleura was invaded. Visceral pleural invasion was observed significantly more frequently in tumors with factors indicative of tumor aggressiveness/invasiveness: moderate/poor differentiation, lymphatic invasion, vascular invasion, high scar grade, high nuclear atypia grade, high mitotic index, and high serum carcinoembryonic antigen level. By multivariate analysis, visceral pleural invasion proved to be a significant independent predictor of poor prognosis in non-small-cell lung cancer patients with or without lymph node involvement. CONCLUSIONS: Visceral pleural invasion is a significant poor-prognostic factor, regardless of N status. Our analyses indicated that visceral pleural invasion is an independent indicator of non-small cell lung cancer invasiveness and aggressiveness.

Aged↗

PubMed2005

Pitfalls in lymph node staging with positron emission tomography in non-small cell lung cancer patients.

BACKGROUND: The evidence of clinical value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in lymph node (LN) staging in non-small cell lung cancer (NSCLC) has been shown in numerous papers. However, few studies have assessed its limitations. The aim of the present study is to clarify clinico-pathologic factors responsible for false PET results. METHODS: From July 2000 through December 2001, 71 NSCLC patients underwent both FDG PET and surgical intervention at the National Cancer Center Hospital East, Chiba. Clinical records, computed tomographic (CT) scan findings, PET findings, and histologic findings were retrospectively reviewed. RESULTS: Sensitivity, specificity, accuracy in nodal staging for CT were 29, 83, and 65% and for PET were 39, 79, and 66%, respectively. There were 10 (14%) false-positive PET scans and 14 (20%) false-negative PET scans. The causative factors for false-positive PET scan were: (1) inflammatory conditions in seven patients; (2) PET mis-localization of an interlobar LN as a mediastinal LN in one patient; (3) inability to distinguish the endobronchial polypoid growth of a primary tumor from a lobar LN in one patient; (4) unknown in one patient. All false-positive LNs due to inflammatory conditions showed reactive lymphoid hyperplasia histologically. The causative factors for false-negative PET scan were: (1) limitation of spatial resolution of the PET scanner in 12 patients (maximum tumor focus dimensions in false-negative LNs ranging from 1 to 7.5 mm, with an average of 3.4 mm); (2) PET mis-localization of a mediastinal LN as a hilar LN in one patient; (3) weak FDG uptake by microscopic tumor foci due to necrosis with massive bleeding in a metastatic LN in one patient. CONCLUSIONS: Inflammatory conditions were most responsible for false-positive PET scans, and spatial resolution limitation of FDG PET was the causative factor of false-negative PET scans. Recognizing these factors in advance would be clinically helpful in accurate nodal staging with FDG PET.

Adult↗

PubMed2005

Expression and localization of mRNAs for matrix metalloproteinases and their inhibitors in mixed bronchioloalveolar carcinomas with invasive components.

Matrix metalloproteinases (MMPs) are believed to play an essential role in cancer invasion, although detailed differences between noninvasive and invasive lung carcinomas are still unclear. To elucidate the expression and activity patterns of MMPs in noninvasive and invasive carcinoma of the lung, we performed in situ hybridization and real-time reverse transcription-polymerase chain reaction to detect messenger RNAs (mRNAs) of MMPs and their tissue inhibitors (TIMPs). The basement membrane was evaluated by immunohistochemistry for type IV collagen. Gelatinase activity was examined by zymography and in situ zymography. A total of 14 surgically resected primary pulmonary adenocarcinomas were used for this study. All the tumors were adenocarcinoma mixed bronchioloalveolar carcinomas according to the 1999 WHO classification. MMP and TIMP2 mRNAs were detected by in situ hybridization in all samples, in both noninvasive and invasive carcinoma components. Signals for MMP mRNAs were significantly higher in both noninvasive and invasive carcinomas than in tumor-free lung tissue. However, the differences were small between noninvasive and invasive carcinomas, not only in the amount of mRNA but also in the activity of the MMPs. In most carcinomas, stromal fibroblast-type cells tended to express levels of MMP and TIMP2 mRNAs that were higher than or at least similar to those expressed in epithelial cells. Our data on mixed adenocarcinoma suggest that noninvasive carcinoma areas already express a molecular mechanism involving MMPs similar to that expressed by invasive carcinoma areas. Stromal fibroblast-type cells seem to be the most important source of MMPs, from the earliest event of tumor invasion by pulmonary adenocarcinomas.

Adenocarcinoma, Bronchiolo-Alveolar↗

PubMed2005

Twenty-four-hour urinary cortisol levels before complete resection of non-small cell lung cancer and survival.

Cortisol has been speculated to play a role in survival from cancer. The objective of this study was to investigate the association between 24-h urinary cortisol levels and survival from non-small cell lung cancer. From June 1996 to April 1999, a total of 226 patients with resectable non-small cell lung cancer were enrolled. Urine samples were collected over a 24-h period before the curative resections. A total of 14 650 person-months (median = 71 months, range = 1-97 months) were accrued. Over the follow-up period, 56 deaths from all causes were identified through January 2004. Cox proportional hazards regression analyses were used to estimate the relative risk (RR) of death from all causes according to three categories of 24-h urinary cortisol levels. Multivariable RRs of death from all causes for individuals in the highest and intermediate categories, compared with the lowest category, were 1.09 (95% confidence interval = 0.54-2.21) and 1.17 (0.55-2.46), respectively (p for trend = 0.17). The present data do not support the hypothesis that 24-h urinary cortisol levels are associated with survival from non-small cell lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Multiple sclerosing hemangiomas with a 10-year history.

We report a case of multiple sclerosing hemangiomas arising in a 38-year-old woman. Computed tomography (CT) scans of the chest showed multiple small nodules in all lobes of the right lung. The nodule sizes ranged from a few millimeters to the largest of 3.1 cm, which was located in the right middle lobe. She underwent right middle lobectomy to confirm the histological diagnosis. The resected specimen revealed multiple sclerosing hemangiomas. We followed this patient by annual chest CT scans for 10 years and demonstrated that all residual nodules remained unchanged. This is the first report of stable multiple pulmonary sclerosing hemangiomas observed for such a long period.

Adult↗

PubMed2005

Gefitinib in the adjuvant setting: safety results from a phase III study in patients with completely resected non-small cell lung cancer.

Standard therapy for stage I-IIIA non-small cell lung cancer (NSCLC) is surgery, although adjuvant therapies are required to prevent disease recurrence and improve patient survival. This is the first study that planned to administer adjuvant gefitinib (Iressa) 250 mg/day or placebo to randomized patients with completely resected NSCLC (stage IB-IIIA) 4-6 weeks following surgery, for 2 years, until recurrence/withdrawal. However, recruitment was stopped after the randomization of 38 patients, because interstitial lung disease (ILD)-type events were being increasingly reported in Japan in the advanced disease setting. Finally, the trial was halted. Safety data for 38 recruited patients (18 gefitinib and 20 placebo) showed no unexpected adverse drug reactions (ADRs), with the most common being grade 1/2 gastrointestinal and skin disorders in 12 and 16 patients receiving gefitinib and in five and six patients receiving placebo, respectively. Grade 3/4 ADRs occurred in four patients receiving gefitinib and one patient receiving placebo. ILD-type events were reported in one patient receiving gefitinib (concomitantly with other ILD-inducing drugs) who died and two patients receiving placebo. Eight patients receiving gefitinib withdrew due to ADRs compared with three patients receiving placebo. Adverse events associated with surgical complications were reported for six patients receiving gefitinib and four patients receiving placebo. In the adjuvant setting there were no unexpected adverse events observed. Gefitinib had no impact on surgery-related complications when given within 4-6 weeks post-operatively.

Aged↗

PubMed2005

Primary lung adenocarcinoma with massive lymphocyte infiltration.

We report 6 cases of adenocarcinoma with massive lymphocyte infiltration. This adenocarcinoma is found in 0.7% of surgically resected primary lung adenocarcinomas. The tumor was located in the peripheral portion in all cases. Lymph node metastasis was detected in 4 cases. The mean follow-up period was 49.8 months; all patients were alive without recurrence despite advanced pathologic stage. Histologically, the tumors revealed an acinar and glandular structure, and the cancer epithelium was destroyed by infiltrating lymphocytes. The lung parenchyma was destroyed by the severe inflammatory cell infiltration without dense fibrosis. Immunohistochemical staining revealed that most infiltrating lymphocytes were positive for CD3 or CD20. None of the tumors were positive for latent membrane protein-1, bcl-2, or Epstein-Barr virus-encoded small RNA-1. This type of adenocarcinoma occurs in old age, and good outcome and distinctive histologic features were observed. We refer to it as primary lung adenocarcinoma with massive lymphocyte infiltration.

Adenocarcinoma↗

PubMed2004

Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung.

PURPOSE: Gefitinib (IRESSA; AstraZeneca, Osaka, Japan) shows excellent antitumor activity against advanced non-small-cell lung cancer, especially for the treatment of adenocarcinoma. However, the predictive factors for the response to gefitinib are still controversial. The aim of this study was to identify the clinicopathological and immunohistochemical features that are favorable to the use of gefitinib in adenocarcinoma patients. EXPERIMENTAL DESIGN: Between June 2002 and October 2003, 36 adenocarcinoma patients who experienced a relapse after surgical resection were treated with gefitinib at our hospital. The histologic patterns of the tumors were divided into four distinctive subtypes according to the revised World Health Organization histologic classification, and the dominant histologic subtype for the maximum cut surface of each resected specimen was documented. Association between the response to gefitinib and the clinicopathological features or immunohistochemical expression of epidermal growth factor receptor (EGFR), phosphorylated EGFR, or c-erbB-2 were then investigated. RESULTS: A significant association between the response to gefitinib and dominant papillary subtype findings was observed (P = 0.0021); the survival time of papillary subtype patients was also significantly prolonged compared with that of non-papillary subtype patients (P = 0.03). No other clinicopathological features or the expression of EGFR, phosphorylated EGFR, or c-erbB-2 were associated with the response to gefitinib. CONCLUSIONS: The results of the present study indicate that dominant papillary subtype findings of lung adenocarcinomas can be an important predictor of the response to gefitinib. Thus, this type of adenocarcinoma might be susceptible to postoperative adjuvant treatment with gefitinib.

Adenocarcinoma↗

PubMed2004

Growth inhibition of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice by a ligand-specific antibody to human insulin-like growth factors.

Advanced prostate cancer frequently involves the bone that has the largest content of insulin-like growth factors (IGFs). However, the role of bone-derived IGFs in bone metastasis of prostate cancer has not been studied extensively because of the lack of a reliable animal model. Therefore, we investigated whether a novel antibody directed against human IGF-I and IGF-II (KM1468) could inhibit the development of new bone tumors and the progression of established bone tumors in nonobese diabetic/severe combined immunodeficient mice implanted with human adult bone. We first confirmed that KM1468 bound specifically to human IGF-I, human IGF-II, and mouse IGF-II but not to insulin. It also blocked autophosphorylation of the type I IGF receptor induced by the binding of IGFs in human-type I IGF receptor-overexpressing BALB/c 3T3 cells, and it inhibited the IGF-stimulated growth of MDA PCa 2b cells in vitro. Then mice were injected intraperitoneally with KM1468 once weekly for 4 weeks either immediately or 4 weeks after inoculation of MDA PCa 2b cells. KM1468 markedly and dose-dependently suppressed the development of new bone tumors and the progression of established tumor foci, as determined by histomorphometry, and it also decreased serum prostate-specific antigen levels, compared with the control. This is the first report of an IGF ligand-specific inhibitory antibody that suppresses the growth of human prostate cancer cells in human adult bone. These results indicate that the IGF signaling axis is a potential target for prevention and treatment of bone metastases arising from prostate cancer.

Animals↗

PubMed2004

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Adenocarcinoma↗

PubMed2004

Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment.

OBJECTIVE: The definition of visceral pleural invasion in lung cancer TNM classification of the International Union Against Cancer lacks detail. The purpose of this study was to evaluate the significance of the extent of pleural involvement as a prognostic factor and to propose a refined TNM classification on the basis of visceral pleural invasion. METHODS: We reviewed 1653 consecutive patients with T1, T2, and T3 surgically resected non-small cell lung cancer for their clinicopathologic characteristics and prognoses. Visceral pleural invasion was classified by using the Japan Lung Cancer Society criteria: p0, tumor with no pleural involvement beyond its elastic layer; p1, tumor extension beyond the elastic layer but no exposure on the pleural surface; and p2, tumor exposure on the pleural surface. RESULTS: The 5-year survivals for patients with p1 or p2 tumors of 3 cm or less were identical and significantly worse than those for patients with p0 tumors of the same size. Patients with p1 or p2 tumors of greater than 3 cm and patients with T3 cancers had essentially identical survivals. CONCLUSIONS: Visceral pleural invasion should be defined as tumor extension beyond the elastic layer of the visceral pleura, regardless of its exposure on the pleural surface. A tumor of 3 cm or less with visceral pleural invasion should remain classified as a T2 tumor, as presently occurs in the International Union Against Cancer staging system, and tumors of greater than 3 cm with visceral pleural invasion should be upgraded to T3 status in the International Union Against Cancer TNM classification.

Adult↗

PubMed2004

A randomized trial comparing adjuvant chemotherapy versus surgery alone for completely resected pN2 non-small cell lung cancer (JCOG9304).

The purpose of this study was to evaluate the efficacy of adjuvant chemotherapy with three courses of cisplatin and vindesine, in comparison to observation only, for N2 non-small cell lung cancer that had been completely resected. Patients with pathologically demonstrated mediastinal lymph node metastasis (N2), who had undergone complete resection, were randomized to observation or adjuvant chemotherapy (cisplatin 80 mg/m2 on day 1; vindesine 3 mg/m2 on days 1 and 8: x3 courses). Cycles started within 6 weeks after complete resection and were repeated every 4 weeks. This trial was terminated before accumulation of the planned numbers for registration because of a slow accrual rate. A total of 119 patients were randomized (59 patients in the adjuvant arm and 60 with surgery alone). The median survival was 36 months for both groups. Postoperative cisplatin with vindesine chemotherapy was not shown to be efficacious in cases of completely resected N2 non-small cell lung cancer in this setting of timing, dose and agents studied.

Adult↗

PubMed2004

Molecular analysis of the TSC1 gene in adenocarcinoma of the lung.

We previously reported that loss of heterozygosity (LOH) in tuberous sclerosis 1 (TSC1)-gene-associated region on chromosome 9q34, was frequently observed in adenocarcinoma (AC) of the lung and its putative precursor lesion, atypical adenomatous hyperplasia (AAH). Some novel tumor suppressor gene for AC of the lung may be present in this region, and the TSC1 gene located on chromosome 9q34 is one candidate. The aim of this study was to determine whether the TSC1 gene itself acts as a tumor suppressor gene in the pathogenesis of AC of the lung. DNA extracted from frozen tumor tissue was used to screen 47 ACs of the lung for the presence of mutations in 21 coding exons of the TSC1 gene. When using these bulk tissue specimens, three different types of mutations were detected in five ACs. These positive samples were then submitted to laser capture microdissection to selectively collect tumor cells, DNA extraction and finally analysis of LOH and mutations of the TSC1 gene. Mutations were detected in three ACs, and LOH was detected in another AC. No mutations or LOH was detected in the other AC. Loss of heterozygosity and mutations were not detected simultaneously in the same tumor. We concluded that the TSC1 gene itself does not act as a tumor suppressor gene in the pathogenesis of AC of the lung in accordance with classical Knudsen's two-hit hypothesis. However, the frequent LOH in AC and AAH shown in our previous studies indicate the following possibility in the etiology of AC of the lung: the presence of a novel tumor suppressor gene close to the TSC1 gene, aberrant promoter methylation, or haploid insufficiency of the TSC1 gene.

Adenocarcinoma↗

PubMed2004

Topographical distribution of allelic loss in individual lung adenocarcinomas with lymph node metastases.

Adenocarcinomas of the lung are characterized by morphological heterogeneity, and since carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, the morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors. Therefore, to elucidate whether, and which, genetic alterations accumulated in relation to morphological cancer progression, we examined 56 microdissected sites for topographical distribution of loss of heterozygosity (LOH) in 12 adenocarcinomas of the lung with bronchioloalveolar (BA) and invasive components in their primary tumors and metastases to lymph nodes. The morphological changes from noninvasive BA lesions to invasive and metastatic components were characterized by a significant rise in the prevalence of allelic losses (P<0.05). Individually, eight cases (67%) showed accumulation of genetic alterations from BA lesions to metastases. LOHs in multiple foci in one case were compared to determine whether they were shared at all tumor sites as an early event or localized in metastases as an additional event. LOHs at 5q and 17p may be crucial steps in the early phase of development to metastasis, while 18q loss may be an additional step. These findings suggested that the cancer cells in some pulmonary adenocarcinomas evolved from the BA lesions to the invasive and metastatic lesions.

Adenocarcinoma↗