170

45

171

PLEOMORPHIC (GIANT AND SPINDLE CELL) CARCINOMA OF LUNG IS GENETICALLY DISTINCT FROM ADENOCARCINOYA. R. Przygodzki, S.D. Finkelstein, N. Fishback, H. Zeren, A. Sakker, P.A. Swalsky, C. Moran, W. Travis, M. Koss. Armed Forces lnstnute of Pathology, Washington, D.C.; Dept. of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Pleomorphic (giant and spindle cell) carcinoma (PC) of lung is a poorly diffemntiated epithelial neoplasm composed of pleomorphic giant and/or spindle tumor cells. Its behavior is, in most instances, aggressive with relatively short survival. The precise histogenetic derivation of this tumor is unclear although an adenocarcinoma component can be seen in approximately 50% of the cases. Treatment for these tumors has no defined regimen. To better define the histogenetic origin of pleomorphic carcinoma and its relationship to adenocarcinoma, we performed comparative DNA oncogene analysis (specific pattern of K-ras-2 and ~53 point mutational change) of archival formalin-fixed, paraffin-embedded tissue specimens using topographic genotyping on a large series of pulmonary pleomotphic carcinomas (n=23) and adenocarcinomas (n=97).

Pulmonary adenocarcinoma was characterized by a notable incidence of first exon K-ras-2 point mutations (46/97, 470/.). Also, these mutations were significantly higher in tumors associated with distant hematogenous metastasis than in localized primry tumors (19/26.66% vs 16E4, 30%). The most frequent K-ras-2 mutation was a codon 12 cystine substitution (22/46, 46%). Pulmonary adenccarcinomas were also frequently ~53 immunoprotein positive with a notable incidence of ~53 point mutations tending to affect exon 6 and more often present in K ras-2 normal tumors. In contrast, PCs manifest a comparatively lower incidence of first exon K-ras-2 point mutations (3/23, 13%). While PCs were frequently ~53 immunoprotein positive, point mutations were rarely found in exon 6. These genotypic diierences support differing profiles of critical growth regulatory gene alterations in the two tumor types. The findings suggest that pleomorphic carcinoma of lung is genetically and therefore biologically distinct from pulmonary adenocarcinoma.

Predicting Progression and Regression of Dysplastic Lesion of the Lung by Quantitative Microscopy. PW Paynd, S. Lam’, J.C. LeRichel, C. MacAulay3, N. Ikedaz, B. Palcic3. 1 .British Columbia Cancer Agency, Vancouver, Canada 2.Dept. of Surgery. Tokyo Medical College Hospital, Tokyo, Japan. 3.British Columbia Cancer Research Centre, Vancouver, Canada

Histopathological evaluation of bronchial biopsies provides valuable information to a clinician for patient management includiig treatment. It is, however, a subjective assessment which has significant interobserver and intraobserver variation, and the significance of grades of dysplasia are debatable. We conducted an experiment to see if recent advances in quantitative microscopy could make predictions as to regression vs. progression of dysplastic lesions. We selected 16 biopsies with a diagnosis of moderate dysplasia which progressed or persisted and 15 cases where the lesion regressed as demonstrated by follow-up bronchoscopy and biopsy of the same site at 3-6 month intervals. We collected about 150 quantitatively stained atypical epithelii cell nuclei plus 50 leukocyte nuclei from the same specimen (control for staining variation) from each biopsy. 60 features of each nuclei were calculated. The features were then tested for their ability to discriminate between lesions which progressed and regressed. We were able to correctly identify the moderate dysplasia specimens which had progressed or persisted according to histology 81.3% of the time. Significant additional information for patient management.could be provided by this method, and could be extended to severe dysplasia and carcinoma in s&d

PRO-GASTRIN-RELEASING PEPTIDE (PRQGRP) AS A SPECIFIC TUMOR MARKER IN PATIENTS WITH SMALL CELL LUNG CARCINOMA (SCLC). Y. Miyakef-2. T. Kodama3, K. Aoyagi4, K. Yamaguchi 1, TGmwth Factor Division, National Cancer Center Research Institute, Tokyo, 2Depatiment of Internal Medicine, School of Medicine, Kitassto University, Kanagawa, aDepartment of Internal Medicine, National Cancer Center Hospital East, Chiba, 4Tonen Co. Ltd., Saii, Japan.

GRP is a specific and an actively-secreted product of SCLC cells and GRP plasma levels are elevated in SCLC patients. In the present study, we developed an enzyme immunoassay, which does not require serum extraction, for an inactive fragment of GRP precursor molecules, PmGRP(31-Q6).

The serum from 1,433 cases, including 829 normal subjects, 124 infectious lung diseases, and lung cancer patients, 129 of whom had SCLC, were analyzed. The ProGRP(31-96) assay required 0.05 ml of unextracted serum per assay, and Serum ProGRP levels could be detected in normal sub@ts; normal upper limit was 47 pg/ml. The results ills shown below. ii is particularly note worthy that the ProGRP levels were elevated specifically in SCLC patients and that the incidence of ProGRP-positive results in SCLC patients with limited disease wb not so much different from that in those with extensive disease. This marker was associate with a sensitivity of 66%. and specifffity of 9896. These results indicate that ProGRP(31-98) is a refii and specific tumor marker for SCLC.

Mean serum

Normal subjects 629 13.0 2 (0.3 Infectious lung diseases 124 14.5 1 ( 0.8) Lung ca.

Adeno 202 16.9 3 ( 1.5) Squamous 122 16.3 2 ( 1.6) Large 27 15.7 1 ( 3.7) Small, limited 56 552.0 33 (56.9) Small, extensive 71 1502.0 52 (73.2)

173

TFIE USE OF HIGH RESOLUTION CYTOMETRY IN PREDICTING BIOLOGICAL BEHAVIOR OF Tl ADENOCARCINOMA OF TBE LUNG N. Ikeda, *C. MacAulay, 9. Lam,**D. Garner, **P. Payne, H. Kate, C. Konaka, *B. Palcic, ***Y. Hayata. Department of Surgery, Tokyo Medical College Hospital, ***Tokyo Medical College Cancer Center, Tokyo, Japan, *Cancer Imaging, Medical Physics Division, British Columbia Cancer Agency, and **Xillix Technologies Corp., Vancouver, British Columbia, Canada

Touch preparations from 61 cases of Tl adenocarcinoma were analyzed by a high resolution automated image cytometer. These cases were divided into two groups. The high risk group consisted of 31 patients who had advanced stage or died of metastatic disease within 36 months after complete surgical resection. The low risk group consisted of 30 patients with Stage I or Stage II disease that were confirmed to be disease-free at least 48 months or more after surgery. In addition to the total DNA content, 56 other nuclear features were analyzed. Using a linear combination of four features: integrated optical density (IOD) and three texture features describing the DNA distribution in the cell nucleus (TARL, ENERGY and FAREAl), aggressive cancer cells belonging to the high risk group could be identitied. When more than 50% of the cancer cells in a sample showed such aggressive characteristics the samples were classified as belonging to the high risk group, while when less than 50% of the cancer cells displayed these characteristics, the samples were classified as belonging to the low risk group. Using this single criterion, sample classification was achieved with an accuracy of 83.6%. These results suggest that high resolution quantitative nuclear morphometry may be of value in predicting the biological behaviour of adenocarcinoma.