Abstracts /Lung Cancer 13 (1995) N-104

pS3 and lung cancer - More frequent pS3 overexpression in patients with multiple primary tomoors Rotl T , Poljak M. Staresa 0. Orel J. DebellA A. /nsl~lure ofpalhology. Facult.v ojMedtcme. (inrversi!v hkdrcal Cenfm, Kocvrkovo 2, 61105 L,ubljono. RadIoI Oncol 1994:28-271-5.

The tumor suppressor function ofthe gene ~53 IS abolished with tits mutations. connected also with lifetmte crgarette consumption, leadmg to growth promotmg function of ~53. and cancerogenesis m various organs. Seventeen resected prunary lung cancers and 14 bronchtall fransbronchral biopsy specimens were formalin-fixed and paraffin embedded. Fourteen specimens were from patients with multiple primary tumwrs Sections were incubated with mouse anti-p53 antibodies. bound antrbodres visualized by mcubation with biotinilated rabbit antr-mouse ~mmunoglobolms, followed by streptavidin-alkahne phosphatase Usmg X-phosphate and nitrohlue tetrawhum. posrbve staming IS observed as a dark bluish precipitate. Overexpression ofp.53 was found in 45.2% of all cases. 50% in I4 specimens of pabents with multrple. and in 7 of I7 (41.2%) specimens of patients wtth sohtary ttonottrs. Ten of I6 (62 5%) specimens mth epidennoid carcinoma showed positwe reacbon. 216 adenocarcinomas. l/2 small cell. IA large cell, and none O/2 adenosquamous carcinomas B&tic specimens yielded better results than resected specimens. This difference could be attributed to ioappmpriate fixation Positive reaction for p53 Is more prominent In the basal layers of squarocus m&plastic and dysplastic epithclium. disappearing towards better diUereotiated areas If can be intense in pmrly di5erentiatcd parts of invasive carcinomas. Normal respiratory epithelium did not yield positive reaction. p53 is related to tk degrez of tumor di5eercntiation We have still to elucidate the relatronship between smoking and pS3 expression. and controversial opimons about its ioilwnce on the sunival of the patients. The detectron of p53 m routine bronchialitnnsbroochial biopsis could reveal the patients, es&ally smokers at higher risk for development of solitary or multiple primary malignancies

Genetic evidence for an independent origin of multiple preneoplastic md oeoplastic lung lesions Sazzi G. Miozzo M. Pas¶orino U, Pilotti S. Donghi P. Giarola M et al. Dtvision of Experimenral Oncology A. Isto. Nozionole Studio e Cure Tumori. Eo G. Venezion. 1. ZOIJJMilan. CancaRes 1995;55.135-40

Patients with a primary cancer in the lung or in the upper acrodigestive troti have an increased risk ofdeveloping synchronous or metachronolu second primaty lung tumors. This phenomenon has ken related to the chronic exposure of the bronchial tree to carcinogens through a died ‘fteld caocaimtion’ pmass. This stody was designed to investigate at the somatic level the genetic basis of the field caocwization effect in pabents having multiple simoltaoeous oeoplastic and preneoplastic lesions of the lung. The pattern of specific genetic changes occurring with high frequency and in early stages of long carcinogenesis including p53 mutations, deletions of chromosome 3p, and K-ras mutations, was investigated by immunocytochemical, *genetic. and molectdar approaches in II syochmnoos lesions of five patients with moltlple lung cancers. Dinerent genetic lesions were observed in all ofthe ~IogicaJ specimens analyzed from each patienl. Thepanemoftheoechangeswasdiff~ntbothint~graphicallydislanr or adjacent lesions and in tumors with the same histopathological diagnosis supponing their independent origin. The present data provide further evidence of the clinical relevance of the field caocerization process, and support tk use of genetic markers in the differential dtagnosis of recurrence or roetastasis versus second primaries of the long.

Microsatellite instability sod other molecular abnormalities in non-small cell lung cancer Fong KM, Zimmerman PV, Smith PI. Queensland Cancer Fund Research Unrr, Deportment of Pathologv. Queensland Unrversrly Medrcal School, Hersron, QLD 4006. Cancer Res 1995.55’ 28-30.

Microsatellites are highly polymorphic. short-tandem repeat sequences dispersed throughout the genome. Instability of these repeat sequences ar multiple genetic loct may result from mismatch repair errors and ocar in here&tory nonpolyposis mlorectal carcinoma and certain sporadic caocers In non-small cell lung cancer, we found that micros&.llite instability wasinfrequent. atT&ingonly 7 (6.5%1 of 108 cays D~ilelxinadxrvcdinall histologicalsobtypesandat di5erent tumor s&es, mic.&arellite instability most commonly affected only

one of the six loci tested on five chromosomal arms. In addibon, mrcrosatellite instability was associated with extensive, concurrent molaxlarchanges io&dingK-rasandp53 mutationsaswell arficqoent loss of hetemzygosity at chmmosomal regions 5q. 8p. 9p. Ilp. and l7p.

Co-expression of urokiaase, urokinase receptor and PAL1 is neessmy for optimum invasiveness of coltumi lung cancer cells Liu G, Shuman MA, Cohen RL Genenrech Inc., 460 Porn1 San &uno Boulevonl South San Francrsco. CA 94080. In1 J Cancer 1995;60 501- 6.

We investigated the importance of the umkinase (oPA)-plasmin system in fostering invasionofhuman hmgcancercells through artitictal basement membranea composed of Matrtgel. Eight cell lines (including I small cell and 7 eon-small cell lines) were examined. One cell line did not express any components of the urokinase system. Four cell lines hod substantial levels of endogenow UPA detectable on therr surfaces. Three ofthese cell lines cosxpressed the plasminogen activator inhibrtor PAI-I in addition to UPA. Assays for invasiveness revealed 4 cell lines capable of traversing a Matrigel bamer, including the 3 which co- expressed UPA, PAI-I and oPA receptor. Surprisingly, the cell line expressing only UPA and UPA receptor displayed no invasive capacrty despite levels of secreted UPA more than 20-fold higher than the other cell lines studied. Based on these observations. we hypothesized that both UPA and PA&I might k inqmrtant for invasion by lung tumor oells, at least in vitro. We therefore tested polyclonal antibodies which inhibit oPA and PAI-I activity for their etTects on the highly invasive H292 oell line. After3 days, invasive capacity war inhibited by antibodies to both oPA and PAI-I in a dose-dependent manner. The plasmin inhibitoraprotinin reducedH292 cell invasion by 70%. Taken together our data demonstrate that in cultwed human lung cancer cells the oPA- plasmin system is important in promoting invasion into basement membranes and suggest that a cnticalbalance between UPA and PAI-I isneceswy foroptimal inva.siveoes. Chudataarecoosistentwith results from recent clinical studies showing that PAI-I expression in tumor trssoe is an adverse prognostic feature

Pathology

Alveolar cell hyperplssis in association with adenocarcinoma of lung Rae SK, Fraire AE Depnrrnr~nr o/ Pn~holoyv i’nnvr.~rl~~ o/ Mo.wochu.wrrs, Med,co, Genre,: 5.5 Lole, Ivenue .Vorlh. Ilorce.w,: .\L I 01655. Mod Pathol 1995.8 165-9.

We studred 41 parents, 22 men and I9 women. wth surg,catl> resected adenecarcinoma (AD) ofthe lung. to determine the frcqucncrcs ofassocialed alveolar cell hyperplasia (ACH) and atypical alveolar cell hypaplasia (AACH). and to define the tmmunohwxhcmul protiles (IHP) of the AD, ACH. and AACH The crtterla used to look for ACH included a smgle row of cub&al cells along alveolar falls. cell morphology dlstmct from bronchrolar eplthelium. and the absence of chronic mflammation. AACH was consrdercd whenever nuclear we was double the sue of neighboring ACH andlor m cases wrth marked nuclear irregularity or hyperchromabsm ACH uas rdcnttfied m 24 of the 41 cases of AD AACH was further demonstrated m sf~ of lhc 2-l cases of ACH. Twenty-three oi the 24 cases of ACH were antable for IHP The twnors yielded powwe results m 23123, 22123. 17123. 22123. and IS/23 cases whensminedwith Cam 5 2. AEI/AE3. Lee M-I.CEA. and 872 3. respectively ACH reacted posittvely in 17/23. 17123. 0123. 4/22. and l/23~cases st&d with Cam-5 2. AEi/ AE3, Leo M-l. CEA. and 872.3. respectively. AACH reacted posrtively in 6/6. 6/6,0/6. l/6. and O/6 cases stained with Cam 5 2. AEI/AES. Leu M-l. CEA. and 872 3. respectively. These findmgs suggest that ACH and AACH are common features found m 24 and sw of tk 4 I cases of AD. respectively. The significance of thts linding is not known, but it is possible that ACWAACH may represent precursor changes simtlar to the bronchtal epithelial dysplasia described an squamous cell carcmoma of the lung. Our findings further suggest that AD will almost always be mununoreactwe for at least fourofthe five tested markers. Conversely, a pattern showing positwe~mmooceaamingfor Cam 5.2and AEllAE3, and negative immunostaining for Lcu M-l. CEA. ami 072 3 may be useful in the recognition of ACH and/or AACH. However, these tmmunostains do not appear to be urdul in distinguishing ACH from AACH.