- Email: [email protected]
Elastosis of lung carcinoma
Pathology These measures had little beneficial effect. The median survival time was 3 months. Grossly, all parenchymal masses presented as a cavity with marked central necrosis and left only a peripheral rim of tumor cells. The definite diagnosis depended on more tissue sections and confirmed by immunohistochemical studies. It also reveals significant fewer p53 and c-erbB-2 oncoprotein expressions. This paper describes the distinct clinicopathologic features, which are different from the ordinary NSCLC.
~-2-] Atypical Adenomatous Hyperplasia of the lung: A clinicopathological study of 118 cases containing multiple AAHs R. Nakahara, T. Yokose, K. Nagai, Y. Nishiwaki, A. Ochiai. National Cancer Center Research Institute East, Kashiwa, Chiba, Japan Background: Atypical adenomatous hyperplasia (AAH) of the lung is a putative precursor lesion of adenocarcinoma by a lot of immunohistochemical and genetical studies, though a clinicopathological study using a large number of cases with AAH has not been reported. In recent years, the number of AAH dramatically increased by introduction of helical CT for formal health check in Japan. However, the clinical management of the lung cancer patients with AAH has not been established because there were few clinicopathological studies of patients with AAH lesions. The aim of this study is to clarify the clinicopathological characteristics of lung cancer patients with AAH lesions. Methods: A retrospective study was carried out using consecutive 508 primary lung carcinoma patients who were operated at National Cancer Center Hospital East between January 1995 and July 1998. The number and location of AAH lesions was compared with clinicopathological features as gender, age, smoking history, familial history of malignancy, preceding malignancy, histology of primary carcinoma, and the number and location of primary carcinomas. Results: A total of 311 AAH lesions were found in 118 (23.2%) of 508 cases. Forty-seven (39.8%) out of 118 cases had more than two AAH lesions. AAH lesions were detected in 121 lobes out of 572 lobes examined. AAH lesions were most frequently observed in bilateral upper lobes, but there was no significant difference in AAH distribution among lobes. When the presence of AAH were compared to the histology of cancers, AAH lesions existed most frequently in the cases with adenocarcinoma (P < 0.0001) and were more frequently detected in the cases of multiple primary carcinomas than those of solitary carcinoma (P = 0.0028). Presence of AAH lesions revealed no significant correlation in the following clinicapathological features; gender, age, smoking history, familial history of malignancy and preceding malignancy. Cases with multiple AAH lesions have been proven to possess significantly high frequency of the preceding malignancies including two cases of gastric cancer, three of colorectal cancer, and one of cancer in liver, breast, urinary bladder, thyroid, and head and neck legion, and malignant lymphoma. Conclusions: The present our study highlights the clinicepathological characteristics of AAHs that AAH lesions are significantly associated with both adenocarcinoma and multiple primary carcinoma of the lung. ~-~
Production of malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells
S. Yano1, R.S. Herbst 2, S. Sone1, I.J. Fidler2. 1Third Department of Internal Medicine, Tokushima University, Tokushima, Japan, 2Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA The purpose of this study was to determine the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage human non-small cell lung cancer. Intravenous injection of human PC14 (adenocarcinoma), its highly
217
metastatic variant PC14PE6, or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), resulting in vascular hyperpermeability in the thoracic cavity. Lung lesions produced by H226 cells were confined to the lung parenchyma and did not induce PE. The expression of VEGFNPF mRNA and protein by the cell lines directly correlated with PE formation. Transfection of PC14PE6 cells with antisense-VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation, whereas transfection of H226 cells with either sense-VEGF 165 or sense-VEGF 121 genes did not increase cell invasion into the pleura nor induce formation of PE. However, the injection of the VEGFNPF-transfected H226 cells into the pleural space resulted in induction of vascular hyperpermeability and PE. The production of PE was thus associated with the ability of human lung cancer cells to invade into the pleura, a property associated with expression of high levels of uPA and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGFNPF. Targeting these steps may control malignant PE in lung cancer patients.
[7•
Prognostic significance of proliferation index and expression of p53 in non-small cell lung carcinoma
G. Gonzalez, X. Tarroch, J. Casalots, R Forcada, R. Rami-Porta, M Mateu, A. Salas. Hospital Mutua de Terrassa, Department of Thoracic Surgery, Terrassa; Hospital Mutua de Terrassa, Department of Pathology, Terrassa, Spain
Aims: To determine overexpression of p53 and the proliferation index, by measuring the immunohistochemical expression of Ki-67, in a series of resected non-small cell lung carcinoma and evaluate a possible relationship with the survival rate of patients. Material and Methods: 118 completely resected non-small cell lung carcinoma (66 squamous, 36 adenocarcinoma, 9 large cell carcinoma and 7 others) in 113 males and 5 females (age range 4183), registered in the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCBS). The pathological stage was I in 66 patients, II in 26, III in 22 and IV in 4. All cases were examined for expression of p53 (DO-7) and Ki-67 (MIB1), which were measured as the percentage of stained nuclei. The patients were followed up for 4-74 months (mean 33.7). At the moment, 77 patients are alive and 41 have died. We studied the relationship of survival with the variables: age, sex, histological type, T, N, M, stage, p53 and Ki-67. They were evaluated statistically by using Chi-square test (qualitatives) and Student-t test (quantitatives). A multivariate analysis (Cox proportional hazards model) with a forward stepwise procedure was used to determine the independent effect of each variable on survival. Results: By univariate analysis, survival was related statistically significant only with Stage (p < 0.0001) and N status (p < 0.001). All the other variables, including p53 and Ki-67 values, were not statistically significant. By multivariate analysis the only factor found to be significant, independent predictor of survival, was the N status (p < 0001). This was also true for patients with T1-T2 NO M0 completely resected tumours. Conclusions: In our series, there is not statistically significant relationship between survival and p53 and Ki-67 values. The N status is the only variable independently related with survival.
~-4-~ Elastosis of lung carcinoma M Fukushima, Y. Fukuda 1, K. Koizumi, S. Haraguchi, I. Mikami, H. Kubokura, D. Okada, M Kawamoto 1, N. Yamanaka 1, S. Tanaka. Dept. Surgery (It); I Dept. Pathology, Nippon Medical School, Tokyo, Japan In stroma of lung carcinoma, an increase of elastic fibers which is called elastosis is frequently observed. In this context, we investigated
218
Pathology
the appearance and the grade of elastosis, and the appearance and the distribution of ~-l-Antitrypsin (alAT), the inhibitor of elastase. We investigated lung tissues from operated cases of adenocaminoma (Ad Ca) (n = 106), squamous cell carcinoma (Sq Ca) (n = 60), adenosquamous carcinoma (AS Ca) (n = 7), small cell carcinoma (n = 4), large cell carcinoma (n = 5), carcinosarcoma (n = 1) and atypical carcinoid (n = 1). Elastica Masson Goldner staining for elastic fibers and immunohistochemistry for a 1AT were examined. Electron microscopic observation was performed. Clinicopathological analysis regarding the relationship between elastosis and prognosis was performed in the 52 cases of stage IA and IB adenocarcinoma. Elastosis was detected in Ad Ca (85/106), Sq Ca (11/60), AS Ca (5/7), and not in other types (0/10). The ratio of appearance of elastosis in Ad Ca was higher than Sq Ca (p < 0.0001). Especially in well differentiated Ad Ca, the ratio of appearance of elastosis was higher than moderately differentiated Ad Ca (p = 0.012) and poorly differentiated Ad Ca (p < 0.0001). And elastic fibers were positive for alAT in 86.4% of cases where elastosis was observed. On the other hand, a part of tumor cells stained for alAT unrelatedly to the types of lung carcinoma in all cases except for small cell carcinoma. Clinicopathologically survival curve of adenocarcinomas with elastosis showed significantly better prognosis than of those without elastosis in the cases of stage IA and IB (p = 0.026). It is known that fragments of elastin broken down by elastase promotes to synthesize elastin in culture cells. This suggests that elastase/alAT may participate in the elastosis of Ad Ca in lung and may induce the degradation, the synthesis and the deposition of elastin.
[•
Correlation of metabolic and morphometric tumor response after induction chemotherapy with docetaxellcarboplatin in combination with erythropoietin in stage III NSCLC
F. Griesinger 1, R.P. Baum 2, F. Lahmann 1, C.P. Crime3, H. Schmidberger 1, K. Kienast4, B. Herse4, B. Hemmerlein 1.
1University of G6ttingen, G6ttingen; 2Central Cfinic of Bad Berka, Bad Berka; 3Lung Clinic Lenglern, Bovenden; 4Central Cfinic of Erfurt, Erfurt, Germany Objective: D/C combination chemotherapy has shown high response rates in advanced NSCLC. The aim of this phase II study was to increase tumor oxygenation by administration of Erypo and to correlate morphologic response with metabolic response by FDG-PET carried out before chemotherapy and before surgery. Patients and Methods: 17 patients with stage IliA (4) and stage IIIB (13) were enrolled to receive 4 cycles of D 100 mg/m2 dl and C AUC 7.5 d2 q 3 weeks with Eryp FS 3 x 10.000 IU sc./week and supportive G-CSF. PET was performed before chemotherapy and after 4 cycles prior to surgery. Morphometric response was evaluated according to Junker et al. 1993. Results: 11117 patients are evaluable for response, 8/11 pts had CPJPR, 1 pt SD, 2 pts PD. Metabolic complete response by FDGPET was demonstrated in 4/10 pts, PR in 3 pts, SD in 1, PD in 2 pts. Morphometric response was highly correlated with metabolic response, with all 4 patients in metabolic CR with no vital tumor cells at resection. Conclusion: Docetaxel and carboplatin induction chemotherapy is highly effective for downstaging in NSCLC stage III, response rates with Erypo seem to be at least comparable to the literature. FDGPET may allow non-invasive metabolic response assessment and may respresent a tool to predict pathologic response in stage III NSCLC.
•
Novel histological determinants of outcome in surgically resected non-small cell lung cancer (NSCLC)
M.L. Colosimo, D. Kevat, L. Clarke, E. Duhig, R. Abraham, K. Musgrave, K. Matar, M. Windsor, R. Tam, D. Wyld, K. Horwood, P. Zimmerman, K. Fong. Prince Charles Hospital Chermside,
Brisbane; Prince Charles Hospital, Brisbane, Australia The use of lymphatic invasion (LI), vascular invasion (VI), reactive inflammatory infiltrate (RII) and pleural invasion (PI) to predict outcome following curative surgery for lung cancer is being increasingly recognised. However, most currently reported series involve small patient numbers. We are conducting a large, single institution review of surgical specimens from 1000 consecutive cases of NSCLC resected between 1981 and 1997, for the presence of LI, VI, RII and PI in addition to standard histological features. Chart audits are being performed to confirm clinical stage, performance status and individual outcomes. Preliminary data for 150 cases is available. The median age at diagnosis was 69 (R: 65-80) and there were 105 males and 45 females. Histological subtypes were as follows: squamous cell 39%, adenocarcinoma 36%, large cell 3% and other/mixed 13%. Surgical staging included 64% stage 1, 18% stage 2 and 18% stage 3. Heavy inflammatory infiltrate was evident in 7%, LI present in 23%, Vl in 26% and PI in 19% of cases respectively. With univariate analysis the presence of LI, VI, RII and PI have not predicted for a poorer outcome. We are continuing the pathological review process and correlation of these novel tumour characteristics with traditional prognostic features and outcomes for the entire cohort. Final results incorporating a multivariate regression model will be presented in full.
~-2-] Atypical Adenomatous Hyperplasia of the lung: A clinicopathological study of 118 cases containing multiple AAHs R. Nakahara, T. Yokose, K. Nagai, Y. Nishiwaki, A. Ochiai. National Cancer Center Research Institute East, Kashiwa, Chiba, Japan Background: Atypical adenomatous hyperplasia (AAH) of the lung is a putative precursor lesion of adenocarcinoma by a lot of immunohistochemical and genetical studies, though a clinicopathological study using a large number of cases with AAH has not been reported. In recent years, the number of AAH dramatically increased by introduction of helical CT for formal health check in Japan. However, the clinical management of the lung cancer patients with AAH has not been established because there were few clinicopathological studies of patients with AAH lesions. The aim of this study is to clarify the clinicopathological characteristics of lung cancer patients with AAH lesions. Methods: A retrospective study was carried out using consecutive 508 primary lung carcinoma patients who were operated at National Cancer Center Hospital East between January 1995 and July 1998. The number and location of AAH lesions was compared with clinicopathological features as gender, age, smoking history, familial history of malignancy, preceding malignancy, histology of primary carcinoma, and the number and location of primary carcinomas. Results: A total of 311 AAH lesions were found in 118 (23.2%) of 508 cases. Forty-seven (39.8%) out of 118 cases had more than two AAH lesions. AAH lesions were detected in 121 lobes out of 572 lobes examined. AAH lesions were most frequently observed in bilateral upper lobes, but there was no significant difference in AAH distribution among lobes. When the presence of AAH were compared to the histology of cancers, AAH lesions existed most frequently in the cases with adenocarcinoma (P < 0.0001) and were more frequently detected in the cases of multiple primary carcinomas than those of solitary carcinoma (P = 0.0028). Presence of AAH lesions revealed no significant correlation in the following clinicapathological features; gender, age, smoking history, familial history of malignancy and preceding malignancy. Cases with multiple AAH lesions have been proven to possess significantly high frequency of the preceding malignancies including two cases of gastric cancer, three of colorectal cancer, and one of cancer in liver, breast, urinary bladder, thyroid, and head and neck legion, and malignant lymphoma. Conclusions: The present our study highlights the clinicepathological characteristics of AAHs that AAH lesions are significantly associated with both adenocarcinoma and multiple primary carcinoma of the lung. ~-~
Production of malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by human lung cancer cells
S. Yano1, R.S. Herbst 2, S. Sone1, I.J. Fidler2. 1Third Department of Internal Medicine, Tokushima University, Tokushima, Japan, 2Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA The purpose of this study was to determine the molecular mechanisms that regulate the pathogenesis of malignant pleural effusion (PE) associated with advanced stage human non-small cell lung cancer. Intravenous injection of human PC14 (adenocarcinoma), its highly
217
metastatic variant PC14PE6, or H226 (squamous cell carcinoma) cells into nude mice yielded numerous lung lesions. PC14 and PC14PE6 lung lesions invaded the pleura and produced PE containing a high level of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF), resulting in vascular hyperpermeability in the thoracic cavity. Lung lesions produced by H226 cells were confined to the lung parenchyma and did not induce PE. The expression of VEGFNPF mRNA and protein by the cell lines directly correlated with PE formation. Transfection of PC14PE6 cells with antisense-VEGF165 gene did not inhibit invasion into the pleural space but reduced PE formation, whereas transfection of H226 cells with either sense-VEGF 165 or sense-VEGF 121 genes did not increase cell invasion into the pleura nor induce formation of PE. However, the injection of the VEGFNPF-transfected H226 cells into the pleural space resulted in induction of vascular hyperpermeability and PE. The production of PE was thus associated with the ability of human lung cancer cells to invade into the pleura, a property associated with expression of high levels of uPA and low levels of TIMP-2. Collectively, the data demonstrate that the production of malignant PE requires tumor cells to invade the pleura and express high levels of VEGFNPF. Targeting these steps may control malignant PE in lung cancer patients.
[7•
Prognostic significance of proliferation index and expression of p53 in non-small cell lung carcinoma
G. Gonzalez, X. Tarroch, J. Casalots, R Forcada, R. Rami-Porta, M Mateu, A. Salas. Hospital Mutua de Terrassa, Department of Thoracic Surgery, Terrassa; Hospital Mutua de Terrassa, Department of Pathology, Terrassa, Spain
Aims: To determine overexpression of p53 and the proliferation index, by measuring the immunohistochemical expression of Ki-67, in a series of resected non-small cell lung carcinoma and evaluate a possible relationship with the survival rate of patients. Material and Methods: 118 completely resected non-small cell lung carcinoma (66 squamous, 36 adenocarcinoma, 9 large cell carcinoma and 7 others) in 113 males and 5 females (age range 4183), registered in the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCBS). The pathological stage was I in 66 patients, II in 26, III in 22 and IV in 4. All cases were examined for expression of p53 (DO-7) and Ki-67 (MIB1), which were measured as the percentage of stained nuclei. The patients were followed up for 4-74 months (mean 33.7). At the moment, 77 patients are alive and 41 have died. We studied the relationship of survival with the variables: age, sex, histological type, T, N, M, stage, p53 and Ki-67. They were evaluated statistically by using Chi-square test (qualitatives) and Student-t test (quantitatives). A multivariate analysis (Cox proportional hazards model) with a forward stepwise procedure was used to determine the independent effect of each variable on survival. Results: By univariate analysis, survival was related statistically significant only with Stage (p < 0.0001) and N status (p < 0.001). All the other variables, including p53 and Ki-67 values, were not statistically significant. By multivariate analysis the only factor found to be significant, independent predictor of survival, was the N status (p < 0001). This was also true for patients with T1-T2 NO M0 completely resected tumours. Conclusions: In our series, there is not statistically significant relationship between survival and p53 and Ki-67 values. The N status is the only variable independently related with survival.
~-4-~ Elastosis of lung carcinoma M Fukushima, Y. Fukuda 1, K. Koizumi, S. Haraguchi, I. Mikami, H. Kubokura, D. Okada, M Kawamoto 1, N. Yamanaka 1, S. Tanaka. Dept. Surgery (It); I Dept. Pathology, Nippon Medical School, Tokyo, Japan In stroma of lung carcinoma, an increase of elastic fibers which is called elastosis is frequently observed. In this context, we investigated
218
Pathology
the appearance and the grade of elastosis, and the appearance and the distribution of ~-l-Antitrypsin (alAT), the inhibitor of elastase. We investigated lung tissues from operated cases of adenocaminoma (Ad Ca) (n = 106), squamous cell carcinoma (Sq Ca) (n = 60), adenosquamous carcinoma (AS Ca) (n = 7), small cell carcinoma (n = 4), large cell carcinoma (n = 5), carcinosarcoma (n = 1) and atypical carcinoid (n = 1). Elastica Masson Goldner staining for elastic fibers and immunohistochemistry for a 1AT were examined. Electron microscopic observation was performed. Clinicopathological analysis regarding the relationship between elastosis and prognosis was performed in the 52 cases of stage IA and IB adenocarcinoma. Elastosis was detected in Ad Ca (85/106), Sq Ca (11/60), AS Ca (5/7), and not in other types (0/10). The ratio of appearance of elastosis in Ad Ca was higher than Sq Ca (p < 0.0001). Especially in well differentiated Ad Ca, the ratio of appearance of elastosis was higher than moderately differentiated Ad Ca (p = 0.012) and poorly differentiated Ad Ca (p < 0.0001). And elastic fibers were positive for alAT in 86.4% of cases where elastosis was observed. On the other hand, a part of tumor cells stained for alAT unrelatedly to the types of lung carcinoma in all cases except for small cell carcinoma. Clinicopathologically survival curve of adenocarcinomas with elastosis showed significantly better prognosis than of those without elastosis in the cases of stage IA and IB (p = 0.026). It is known that fragments of elastin broken down by elastase promotes to synthesize elastin in culture cells. This suggests that elastase/alAT may participate in the elastosis of Ad Ca in lung and may induce the degradation, the synthesis and the deposition of elastin.
[•
Correlation of metabolic and morphometric tumor response after induction chemotherapy with docetaxellcarboplatin in combination with erythropoietin in stage III NSCLC
F. Griesinger 1, R.P. Baum 2, F. Lahmann 1, C.P. Crime3, H. Schmidberger 1, K. Kienast4, B. Herse4, B. Hemmerlein 1.
1University of G6ttingen, G6ttingen; 2Central Cfinic of Bad Berka, Bad Berka; 3Lung Clinic Lenglern, Bovenden; 4Central Cfinic of Erfurt, Erfurt, Germany Objective: D/C combination chemotherapy has shown high response rates in advanced NSCLC. The aim of this phase II study was to increase tumor oxygenation by administration of Erypo and to correlate morphologic response with metabolic response by FDG-PET carried out before chemotherapy and before surgery. Patients and Methods: 17 patients with stage IliA (4) and stage IIIB (13) were enrolled to receive 4 cycles of D 100 mg/m2 dl and C AUC 7.5 d2 q 3 weeks with Eryp FS 3 x 10.000 IU sc./week and supportive G-CSF. PET was performed before chemotherapy and after 4 cycles prior to surgery. Morphometric response was evaluated according to Junker et al. 1993. Results: 11117 patients are evaluable for response, 8/11 pts had CPJPR, 1 pt SD, 2 pts PD. Metabolic complete response by FDGPET was demonstrated in 4/10 pts, PR in 3 pts, SD in 1, PD in 2 pts. Morphometric response was highly correlated with metabolic response, with all 4 patients in metabolic CR with no vital tumor cells at resection. Conclusion: Docetaxel and carboplatin induction chemotherapy is highly effective for downstaging in NSCLC stage III, response rates with Erypo seem to be at least comparable to the literature. FDGPET may allow non-invasive metabolic response assessment and may respresent a tool to predict pathologic response in stage III NSCLC.
•
Novel histological determinants of outcome in surgically resected non-small cell lung cancer (NSCLC)
M.L. Colosimo, D. Kevat, L. Clarke, E. Duhig, R. Abraham, K. Musgrave, K. Matar, M. Windsor, R. Tam, D. Wyld, K. Horwood, P. Zimmerman, K. Fong. Prince Charles Hospital Chermside,
Brisbane; Prince Charles Hospital, Brisbane, Australia The use of lymphatic invasion (LI), vascular invasion (VI), reactive inflammatory infiltrate (RII) and pleural invasion (PI) to predict outcome following curative surgery for lung cancer is being increasingly recognised. However, most currently reported series involve small patient numbers. We are conducting a large, single institution review of surgical specimens from 1000 consecutive cases of NSCLC resected between 1981 and 1997, for the presence of LI, VI, RII and PI in addition to standard histological features. Chart audits are being performed to confirm clinical stage, performance status and individual outcomes. Preliminary data for 150 cases is available. The median age at diagnosis was 69 (R: 65-80) and there were 105 males and 45 females. Histological subtypes were as follows: squamous cell 39%, adenocarcinoma 36%, large cell 3% and other/mixed 13%. Surgical staging included 64% stage 1, 18% stage 2 and 18% stage 3. Heavy inflammatory infiltrate was evident in 7%, LI present in 23%, Vl in 26% and PI in 19% of cases respectively. With univariate analysis the presence of LI, VI, RII and PI have not predicted for a poorer outcome. We are continuing the pathological review process and correlation of these novel tumour characteristics with traditional prognostic features and outcomes for the entire cohort. Final results incorporating a multivariate regression model will be presented in full.