[ RESEARCH 50. 2698-2703. May I. 1990] Chromosome Abnormalities in Malignant in Patients from Kurashiki: Histological and Immunophenotypic Correlations1

Hiroshi Konishi, Masaharu Sakurai,2 Hatsue Nakao, Nobuo Maseki, Yasuhiko Kaneko, Yoshio Yagiri, Kenji Notohara, and Glauco Frizzerà 3 Departments of Internal Medicine ¡H.K., Y, Y.] anil of Laboratory Medicine and Pathology [H. N., K. N.¡,Kurashiki Central Hospital, 1-1-1 M'ma, Kurashiki, Okayama 710, Japan; Clinic [M. S., N. M.J and Department of Laboratory Medicine ¡Y.K.J. Saliamo Cancer Center Hospital, K18 Komuro, Ina, Saitama 362, Japan; ana Department of Laboratory Medicine and Pathology, University of Minnesota Hospital, Minneapolis, Minnesota 55455 [G. F.]

ABSTRACT MATERIALS AND METHODS Clonal chromosomal abnormalities were found in tumor tissue of 43 Patients. Chromosomes were studied in 51 (52.6%) of 97 patients (84%) of 51 patients with non-Hodgkin's lymphoma (B-cell, 32; T-cell, with non-Hodgkin's ML before treatment at the Kurashiki Central 15) from an adult T-cell /I) mphoma-nonendemic area in western Hospital between August 1983 and June 1988. Forty-five patients were mainland Japan. Four tumors were tetraploid, and the other 39 had a studied after February 1985 and constituted a majority (63.4%) of 71 chromosome number in the diploid range. 3, 5, 7, 18, and \. seen in various clinics; many of those who had extranodal diseases and 13, and loss of an X in female and a Y in male were found in were not suspected in advance as having ML were not studied. Six more than three patients each. Structural abnormalities in arms Ip, Iq, patients studied between August 1983 and May 1984 and also included 2q, 3q, 13q, I4q, and 18q were found in eight or more patients each. in this series constituted only a minority (23.1%) of 26 with ML seen Clustering of breaks occurred in 3q25-29 (ten patients, nine of whom during the period. Analyzable data were obtained in all 31 males and with a B-cell tumor), Ilql3 (five patients), dir dup(12)(ql3-15—»q21- 20 females. Their ages ranged from 4 to 90 yr with a median age of 69. 24) (four patients), 14q32 (12 patients), and 18q21 (seven patients). The Most patients were inhabitants of Kurashiki or its vicinity. Kurashiki 14q32 translocations were all associated with B-cell tumors. t(8;14) was is located by the Inland Sea, about 200 km west of Osaka, in the western seen in a small noncleaved cell lymphoma, t(l I;14)(ql3;q32) in one part of the island of Honshu. The area is regarded as nonendemic for follicular and three intermediately differentiated lymphocytic lympho- ATL (10). Anti-HTLV-1 antibodies were tested in 44 patients, and only niiis. and t(14;18)(q32;q2l) in two follicular and one diffuse 4 of them gave positive results. Two of them were immigrants from small cleaved cell tumor. The translocation partner of 14q could not be Kagoshima, an area endemic for ATL in southern Kyushu. All 4 determined in the other four patients, three of whom had patients were diagnosed clinically as ATL. The karyotype and the der(I8)t(18;?Kq21;7). The seven 18q21 abnormalities, including a novel immunophenotype of lymphoma cells of Patient 44 have been reported translocation I(2;18)(pll;q21.3), all occurred in B-cell tumors; even in elsewhere (11). the absence of H14;IS), they were closely associated with lymphomas of Diagnosis and Histological Classification. The tumors were diagnosed follicular center cell origin (six of seven). as non-Hodgkin's ML and classified according to the Working For mulation (12) based on the histological findings of tumor tissues obtained before therapy (Table 1). The tissues had been fixed in 10% buffered formalin and embedded in paraffin. IDLs, a tumor type for INTRODUCTION which there is no specific category in the , were There has been rapid progress in the study of chromosomes considered unclassified (K). in non-Hodgkin's ML4 in recent years. Several specific chro Immunophenotyping. Lymphoma cells in 42 patients were immuno- phenotyped using cell suspensions of tumor tissue. The examination mosomal abnormalities have been associated with histological included E rosette and EAC rosette formation. Surface immunoglobu- type, ¡mmunophenotype, or prognosis of ML (1-8); their roles lins were studied by the direct immunofluorescence method. Surface in lymphomagenesis, via involved , are being inves antigens were studied by the indirect immunofluorescence method using tigated with molecular techniques (9). The distribution of var various monoclonal antibodies, i.e.. OKT1I (CD2). OKT3 (CD3). ious chromosomal abnormalities found in MLs seems to show OKT4 (CD4). OKT8 (CDS) (Ortho Diagnostics), J5 (CD10), B4 some significant geographical or racial variations (6, 8). (CD 19), Bl (CD20), and 12 (HLA-DR) (Coulter). In 45 patients, In addition to MLs in patients from Saitama (6), we have immunohistological studies were performed on tissue sections, using studied the chromosomes of non-Hodgkin's ML in Kurashiki, monoclonal antibodies MB-1 and MT-1 (Bio-Science) and an avidin- biotin-peroxidase complex technique. an area in the western part of Honshu (mainland Japan), and Chromosome Studies. Chromosomes were analyzed on the same have analyzed the association of cytogenetic abnormalities with pretherapy tumor tissue that was used for histological and immunolog- the histological types and immunophenotypes of the lympho ical analysis in all but 2 patients. Peripheral blood was used for one mas. Although the chromosomal patterns in these two ATL- patient (Patient 22) and aspirate for one patient (Patient nonendemic areas in Japan are mostly similar, there seem to 47). be some differences that may require further investigation. Lymph nodes were minced with surgical scissors. Cells were sus pended in RPMI 1640 medium and were processed for chromosome analysis directly or after culture at 37°Cin 5% CO2 in air for 3 to 6 Received 9/25/89; revised 1/11/90. days. Lipopolysaccharide or phytohemagglutinin was added to some The costs of publication of this article were defrayed in part by the payment cultures as a mitogen. Colcemid was added to cell suspension or culture of page charges. This article must therefore be hereby marked advertisement in 0.5 to 2 h before hypotonie treatment with 0.075 M KC1. Cells were accordance with 18 U.S.C. Section 1734 solely to indicate this fact. fixed with a mixture of methanol and acetic acid (3:1) (Carnoy's 1This work was supported in part by a grant-in-aid from the Ministry of Health and Welfare for a Comprehensive 10-Year Strategy for Cancer Control. fixative). Cell suspensions in the fixative were dropped onto a glass Japan, and by granls-in-aid for cancer research from the Ministry of Education. slide and flame dried. Q-. G-, and C-banding methods were used for Science, and Culture of Japan. 2To whom requests for reprints should be addressed. karyotyping. The clonality was defined, and the primary clone was ' On sabbatical leave at the Saitama Cancer Center under the auspices of the selected following the criteria adopted for a previous study (6). Foundation for Promotion of Cancer Research. Japan. Statistical Analyses. Correlations with histological categories and 4The abbreviations used are: ML. malignant lymphoma: ATL, adult T-cell immunophenotypes were sought for chromosome abnormalities found leukemia/lymphoma; HTLV-I. human T-cell leukemia lymphoma virus-I; IDL. in 3 or more patients. Trisomies or (gain or loss of a intermediately differentiated lymphocytic; DM. diffuse mixed; DL, diffuse large cell; IBL. ¡mmunoblastic: SL. small lymphocytic: LBL, lymphoblastic: DSC. whole chromosome without structural abnormalities) were considered diffuse small cleaved cell; FL. follicular. predominantly large cell. to be numerical changes for statistical analyses when the modal chro- 2698 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1990 American Association for Cancer Research. CHROMOSOMES IN LYMPHOMA IN KURASHIKI

mosome number of the lymphoma cells was in the diploid range. Chromosomal Abnormalities. Seven or more cells could be Statistical signficance was tested by the x2 or Fisher's exact test. karyotyped for all the 51 patients studied (Table 2). The tumors of 8 patients showed only normal karyotypes. Three of these RESULTS tumors were B-cell, 3 were T-cell, and 2 had an ambiguous Histológica! Classification. As shown in Tables 1 and 2, the phenotype; the histológica! types varied. Four tumors (3 T-cell most frequent categories were DM (13 patients) and DL lym- and 1 B-cell) were tetraploid, and all the others had near- or phomas (11 patients). Follicular lymphomas were seen in 11 pseudodiploid karyotypes. patients. Of the 4 patients diagnosed as ATL, 3 had DM and Clonal chromosomal abnormalities were detected in 43 pa one had IBL lymphoma. Four patients had IDLs, which are tients. Among numerical abnormalities, trisomies 3, 5, 7, and listed as unclassified (K). 18, monosomy 13, and loss of an X in female and a Y in male Immunophenotype. Immunophenotyping of tumor cells was were found in more than 3 patients each. attempted in all patients, and the immunophenotype was suc Structural abnormalities were found in arms Ip, Iq, 2q, 3q, cessfully determined in 47 tumors: 32 were B-cell and 15 were 13q, 14q, and 18q in 8 or more patients. Clustering of breaks T-cell (see Tables 1 and 2). occurred in 4 or more patients in 3q25-29 (10 patients), 1Iql3 Of the 32 B-cell tumors, 18 exhibited both heavy and (5 patients), dir dup(12)(ql3-15->q21-24) (4 patients), 14q32 chains of surface immunoglobulin; only heavy chain or light (12 patients), and 18q21 (7 patients). Breaks occurred in various chain was demonstrable in 2 and 7 patients, respectively, and positions on Ipand Iq. neither H- nor L-chain was detected in the other 5. Of the 15 Chromosomal Abnormalities versus Immunophenotype and T-cell tumors, 7 were thought to be the helper/inducer type and . 3 was found in 5 B-cell lymphomas; 3 of 2 to be the suppresser/cytotoxic type. them were DL. Trisomy 7 was found in 5 B-cell lymphomas. All the SL, follicular, and IDL lymphomas were B-cell. Also, Loss of a was found in 7 B-cell lymphomas and the majority of the DL lymphomas were B-cell. In contrast, all 1 T-cell lymphoma; 3 of the former had a follicular pattern. the LBL lymphomas were T-cell, and the majority of the DM An abnormality of 3q was found in 10 lymphomas (Tables 2 lymphomas were T-cell. IBL lymphomas were either B-cell or and 3). Seven had translocations, three had deletions, and one T-cell except for one tumor whose phenotype was not inter had a partial duplication. One showed t(2;3)(q21;q27) and pretable. Three other tumors, one each of DSC, DM, and DL another t(3;7)(q27;p 13), but for the other five, the translocation lymphomas, also did not have interpretable immunopheno- partner could not be determined. In all the 10 lymphomas the types. break occurred in bands between q25 and q29. Nine of the 10

Table 1 Immunophenotype ana some chromosomal characteristics by histological group of non-Hodgkin 's lymphoma (12)"Total Histológica!group according to Working Formulation

E5 JK3 no.ImmunophenotvpeB-cellT-cellNot 25 141

1115 4313

interpretableNo.

clones012of abnormal

21Total51321548358abnormal 1F13391382G11911272H6321141I 1 ormoreModal

no.HypodiploidPseudodiploidHyperdiploidPolyploidA222ofchromosome the primary11B2211C2211Dclone111131

11717154 11242211713132

°Malignant lymphoma was diagnosed before therapy for each patient. A. ML. small lymphocytic: B. ML. follicular. predominantly small cleaved cell: C, ML. follicular. mixed, small cleaved and large cell; D, ML. follicular. predominantly large cell: E. ML, diffuse, small cleaved cell: F, ML. diffuse, mixed, small and large cell: G, ML, diffuse, large cell: H. ML. large cell, immunoblastic: I. ML. lymphoblastic: J. ML, small noncleavcd cell: K, unclassified, intermediately differentiated lymphocytic lymphoma.

Table 2 Pretherapy karyotypes of 51 patients with non-Hodgkin's lymphoma from the Kurashiki Central Hospital classified according to the histological types of the Working Formulation (12) No. of cells banded Age Patient (yr) Sex" Immunophenolype Source' Total Normal Abnormal Karyotype of abnormal clone(s)J

lymphocytic)1' Group A (ML, small 702 BH\M ;?).SCA 17,del( 1)(p22P32),i(6p).+der( 17)t( 17:?)(p 11 karvotvpe46,Y,-X,+der(X)t(X;?)(p22;?)+mar= related 69M B^-y«LNLN48504213513749,XY,+Y,+7,- Group B (ML, follicular, predominantly small cleaved cell) 72 M LN 31 27 55.XY,+3,+5.+8,+ IO.+12,-14,1(2:18)(pll:q21.3).+del(X)(q22).dup(l)- (pter-K)32::q42-K)21 ::q32-*qter).+der( 14)t( 14:?)(q32;?), +der( 18)t(2;l 8),+der( 18)t(2; 18),+mar 2 55,XY,+5,+7,+8,+10,+12,-14,t(2; 18),+del(X),del(6)(q 13q 15),+der- (3)t( 1;3)(q 11:p 11),+der( 14)t( 14;?).+der( 18)1(2;18).+der( 18)t(2; 18) 60 LN 21 14 46,XX,dirdup(12)(qI3^q24),t(14;18)(q32.3:q2l.3) 1 SCA = unrelated karyotype Table 2 continues 2699 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1990 American Association for Cancer Research. CHROMOSOMES IN LYMPHOMA IN KURASHIKI

Table 2—Continued No. of cells banded Patient Age (yr) Sex° Immunophenotype* Source' Total Normal Abnormal Karyotype of abnormal clone(s)''

Group C (ML, follicular, mixed, small cleaved and large cell) 5 75 F Bp< Tonsil 50 3 32 53,XX,+X,+ll,+12,+ 13,-14,+ 16,+21,+del(5)(q31q35), +der(14)t(14;?)(q32;?) 15 54,XX,+X,+11,+12,+13,-14,+16,+21 ,+del(5).+del(5), +der(I4)t(14;?) 6 90 M Br LN 16 2 14 46,X,-Y,del(5)(pl3pl5),t(14;18)(q32;q21),+mar

Group D (ML, follicular, predominantly large cell) 7 78 M B,

(p 11;?),+der(8)t(8;?)(p21 ;?).+der(8)t(8;?), +der( 10)t( 10;?)(q26;?),+der( 12)t( 12;?)(p 13:?). +der( 13)t( 13;?)(q22;?),+der(?)t( 11;?)(q 13;?), +r,+3mar with cell to cell variation 11 78 F B-yX LN 50 3 47 46,X,-X,-6,-7,-12,-18,t(2;3)(q21;q27),t(l I;14)(ql3;q32), dir dup( 12)(q 13->q21 ),+der(6)t(6;?)(q 11;?), +der(7)t(7;?)(q21 ;?),+der( 11 )t( 11 ;?)(q25;?).+2mar Group E (ML, diffuse, small cleaved cell) 12 51 F NI Tumor 30 30 0 Normal 13 36 M ByK LN 30 1 29 47,XY,+7.-13,t(14;18)(q32;q21),dir dup(12)(ql5-Ki22), +der(13)t(13;?)(ql2;?) Group F (ML, diffuse, mixed, small and large cell) 14 79 M T(h/i) LN 21 8 12 89.XX,[4n±]-Y,-Y,-6,-14,-15,-16,+22,+der(14)t(6;14)(pl l;pl 1),

1 SCA = related karyotype 15 63 M BUK LN 30 2 12 49,XY,-l,+3.-10,-16.+ 18.del(9)(ql3).+der(10)t(10;l I)(q26;ql4), +der( 16)t( 16;?)(p 13;?).+2mar 14 48.XY,-1 .+3,-10,-16,+18,del(9).+der( 10)t(?; 10)(10:11)(?;p 15q26;q 14), +der(16)t(16;?),+mar 2 49,XY,-l,+3,-10,-16,+ 18,del(9),del(9),+der(10)t(10;l 1), +der(16)t(16;?),+2mar 16 74 M T(h/i) LN 7 5 2 46,Y,-X,-15,+der(15)t(X;15)(ql I;q26),+mar 17 84 F T(s/c) LN 30 30 0 Normal 18 54 M* T(h/i) LN 20 1 19 45,X,-Y,-2,-6,-6,-9,-10.-13,-14,-19,-21,ins(l;?)(q21;?),del(5)- (p 13p15),del(7)(q32),del( 12)(p 11p 13).+der(Y)t(Y;?)(q 12;?), +der(2)t(2;?)(q35?;?),+der(6)t(6;?)(p21 ;?).+der( 13)t( 13;?)- (q34;?),+der(?)t(6;?)(p 12;?),+4mar with cell to cell variation 19 77 F NI LN 28 11 17 46.XX,inv dup(2)(p21^pl3) 20 77 M T Tumor 25 0 25 45.X.-Y 21 66 M T(h/i) Tumor 50 44 5 92.XXYY 1 SCA 22 44 M* T(h/i) PB 70 55 14 46,XY.-14,del(10)(pl l),+der(14)t(14;?)(pl 1;?) 1 SCA = unrelated karyotype 23 64 M B LN 50 3 17 46,XY,-l,-l,-I5,-17,ins(3;?)(p21;?),del(5)(pl5),del(8)(q22q24), +der( 1)t( 1;3)(q42;p 13),+der( 1)t(?; 1)(1;?)(?;p22q42;?), +der( 15)t( 1;15)(q 12;q24),+der( 17)t( 17;?)(pl 1;?) 18 47.XY,-1.-1,-10,-15,-17,ins(3;?),del(5).+del(8),+der( 1)t( 1;3), +der( 1)t(?; 1)(1;?),+der( 10)t(3:10)(p 14;q22),+der( 15)t( 1;15), +der(17)t(17;?) 12 46,X,-Y,-1 ,-4,+5,-9,-10,-17,+der(4)t(4;?)(q25;?),+der( 17)t( 17;?), +der(?)t( 1;?)(q21 ;?).+der(?)t(9;?)(q 11;?),+mar 24 42 F T Tumor 30 30 0 Normal 25 58 M* T(s/e) LN 15 1 13 48,XY,-5,-8,+der(4)t(4;?)(pl l;?),+der(5)t(5;?)(ql 1;?), +der(9)t(8;9)(ql 3;p 12),+mar 1 SCA = related karyotype 26 68 F BX 20 20 0 Normal Group G (ML, diffuse, large cell) 27 44 M T Tumor 100 74 16 46,XY,t(l;2)(pl3;q31) 10 46,XY,-l,-9,-10,-ll,-14,-19,+der(l)t(l;4)(q21;qll),+der(9)t(9;10)- (p 11;q 11 ),+der( 11 )t( 11;?)(p 11;?).+der( 19)t( 19;?)(q 13;?). +der(?)t( 1;?)(q21 ;?),+mar 28 21 M B LN 50 8 29 47,XY,-8,-l l,+ 12.del(2)(ql3q23).dir dup(7)(ql 1-K)22). +der(8)t(8;?)(p 11;?).+der( 11 )t( 11;?)(q23;7) 12 47,XY,-8,-ll,+ 12,-18.del(2),dirdup(7),+der(8)t(8;?),+der(ll)t(ll;?), +der(18)t(18;?)(q21;?) 1 SCA = related karyotype 29 69 M B LN 30 3 22 50,XX,-Y.+3,+5,-8,-12,-17,-2I,-22.del(l)inv(l)(Pter->q21::q42-. q21 ::q44-^qter),del( 11)(p 13).dir dup( 12)(q 13^q24),+der(6)t(6;?)(q23;?), +der(7)t(7;?)(q22;?).+der( 12)t( 12;?)(q21 ?;?M +der(22)t(22;?)(ql3;?),+2mar

Table 2 continues Downloaded from cancerres.aacrjournals.org on October2700 4, 2021. © 1990 American Association for Cancer Research. CHROMOSOMES IN LYMPHOMA IN KURASHIK1

Table 2—Continued No. of cells banded PatientAge (yr) Sex" Immunophenotype* Source' Total Normal Abnormal Karyotype of abnormal clonéis)'

5 SCA = related karyotypes 30 67 F By Tumor 50 0 50 44,X.-X,-2,-7,-7,-9,-l l.-14,-18,-18.-20,-22.del(8)(p21),del(13)- (q21),+der(2)t(2;?)(q37;?),+der(7)t(7;?)(q32;?),+der(7)t(7;?)(p22;?), +der( 14)t(?; 14)(14;?)(?:p 13q32;?).+der( 18)t( 18;?)(q21 ;?), +der(20)t(20:?)(ql3;?).+der(20)t(20;?),+der(22)t(22;?)- (pl l;?).+mar with cell to cell variation 31 72 M NI LN 12 0 12 47.XY.+X 32 54 F BM« LN 20 0 19 52,X,-3,-r?5,-6,+7,+8,-13,-13,-l5,del(X)(q24),del(4)(q33),del<6)- (q 15q21 ),del(22)(q 12),+der( 1)t( 1;?)(p34;?),+der(3)t(3;?)- (q29;?).+der( 12)t(12;?)(q22;?),+der( 13)t( 13;?)(pl 1;?), +der( 13)t( 13;?).+der(21 )t(21 ;?)(q22;?), +der(?)t(6;?)(pl 2;?).+mar 1 SCA = related karyotype 33 92 F B?« LN 30 0 30 47,XX,-l,+3,-6,-7,+9,-13,-17,-19,del(4)(pl2pl5),+der(l)t(l;?)(q21;?)- del( 1)(p 13q22),+der(6)t( 1;6)(q21 ;q21 ),+der( 17)t( 17;?)(p 11;?). +der(19)t(19;?)(ql3;?).+der(?)t(7;?)(?;13)(ql l;?;ql 1) 34 45 M B" LN 20 20 0 Normal 35 72 F B/iX LN 30 0 30 48.XX,+3,+ 18,-19,+der(19)t(19:?)(pl3;?) 36 73 MB LN 30 30 0 Normal 37 77 F BUK LN 33 7 25 55,X,-X,-l,-2,-4,+5,-13,+20,+21,+21.dir dup(l)(q21-Ki25), del( 12)(p 12),+del( 12),+del( 12),i( 13q),+der( 1)t( 1;?)(p36;?), +der(2)t(2;?)(p23;?).+der(3)t(3;?)-(q27;?), +der(3)t(3;?)(pl2;?)del(3)(q27).+der(4)t(4:?)- (q31;?l.+der(8)t(8;?)(qli:?).+2mar 1 SCA = related karyotype

Group H (ML, diffuse, large cell, immunoblastic) 38 58 M* T(h/i) LN 30 3 27 46,XY,t(16;17)(pl 1.2;pl3) 39 72 F B„k LN 32 2 19 46,X.-X.+ 18.inv(l)(pl3q21).del(9)(ql3q22).t(8:22)(q22;ql2.2) 5 46,X,-X,+18,inv (1).t(8;22).del(4)(q31 ) 6 SCA = related karyotypes 40 71 F BuX LN 31 28 2 47,XX.del(l I)(q23).+mar 1 SCA = related karyotype 41 51 M BX LN 30 0 30 46,X.-Y.-2.-14.-18.dir dup (l)(q23-K)42).del(3)(q27q29).+der(2)t(2;?)- (q23;?).+der( 14)t( 14:?)(q32;?).+der( 18)t( 18;?)(q23;?).+mar 42 75 M NI Tumor 20 20 0 Normal 43 85 F T(h/i) LN 50 0 50 45,X,-X,-2.-6,+der(2)t(2;?)(p23;?).+der(6)t(6;?)(p23;?)

Group I (ML, lymphoblaatic) 44 4 M T LN 30 1 29 46,XY.r(21).t(l;14)(p34;ql 1) 45 20 F T LN 30 1 29 87,XXXX,[4n±]-2,-5.-6.-6,-7.-7.-9,-9,-l l.-l 1.-12.-13.-16. -16,-17,-17.-21,-22,-22.del(3)(q21q29),del(3),t(3;4)- (pl3;).t(3;4).+der(7)t(7;?)

with a 3q abnormality showed a B-cell phenotype (not signifi- found in 12 lymphomas, all of B-cell phenotype (P < 0.01). cant), and 4 were FL (P< 0.01). Breaks in 6p21-23 were found t(8;14)(q24;q32) was seen in one patient with small noncleaved in 3 T-cell lymphomas. cell lymphoma. t(l I;14)(ql3;q32) was found in 4 patients. 14q32 translocations, the most frequent abnormality, were Three had an IDL (P < 0.001), and the other one had an FL Downloaded from cancerres.aacrjournals.org on October2701 4, 2021. © 1990 American Association for Cancer Research. CHROMOSOMES IN LYMPHOMA IN KURASHIK1

Table 3 Correlations between and histológica!type in some non-Hodgkin 's lymphomas group"Chromosome No. of patients with each abnormality by histológica!

H(n G K(n abnormality3q25-29 =2)2C(n =2)1D(n =5)4 =2)1F =13) (n =11)6)2 (n = =4)1 3) (n = break 121 2 t(ll;14)(ql3;q32) 1 3Total1047P<0.01 <0.001 18q21 translocations*B(n 1E(n "Classified according to the Working Formulation (12). B, ML, follicular, predominantly small cleaved cell; C, ML, follicular. mixed, small cleaved and large cell; D. ML, follicular, predominantly large cell; E, ML, diffuse, small cleaved cell; F, ML, diffuse, mixed, small and large cell; G. ML, diffuse, large cell; H, ML, large cell, immunoblastic; I, ML, lymphoblastic; K, unclassified, intermediately differentiated lymphocytic lymphoma. 'Three patients (one each in Groups B. C, and E) had a t(14;18)(q32;q21). lymphoma (Table 3). t(14;18)(q32;q21) was found in 2 follicular been found in follicular and diffuse lymphomas, closely asso lymphomas and one diffuse small cleaved cell tumor (Table 3). ciated with t( 14;18) (18, 19). We also presume that, in most of None of the 3 tumors had an extra 18q—chromosome. In the our cases, the 18q21 abnormality may have had on the cell the remaining 4 patients, the translocation partner could not be same biological effect as t(14;18)(q32;q21) (20). The reasons determined. It is to be noted, however, that a break in 18q21 for this presumption are as follows, (a) Three of the 4 patients was found in 2 of 4 such patients. One other patient (Patient also had der(I4)t(14;?)(q32;?); (b) six of the 7 lymphomas with 41) had a der(18)t(18;?)(q23;?), and the possibility could not be 18q21 abnormality were of follicular center origin; and (c) there abandoned that this case also had actually an 18q21 break. are reports of cases with only 14q32 chromosomal transloca All seven 18q21 translocations were found in B-cell lympho tion, in the absence of 18q21 abnormality, in which the be1-1 mas. Three had t(14;18)(q32;q21), as already mentioned. Of gene was translocated to 14q32 (19, 20), and, also, a report of the remaining 4, one had t(2;18)(pl2;q21), and the 3 others a of t(14;18)/der(14)t(14;18),der(18)t(18;?)(q21;?) (5). had an undetermined translocation partner. Of these 4, 2 also In one of our patients, 18q21 was reciprocally translocated with had a 14q32 translocation in the same karyotype (see above). 2pl2, the locus for the IgK chain gene. This abnormality Of the 7 tumors with 18q21 translocations, 4 were follicular, has not been reported previously. Obviously the relation one was DSC, one was DL, and one was IBL. Thus, all but one ship between t(2;18) and t(14;18) parallels that between t(2;8)(pl2;q24) and t(8;14)(q24;q32) in Burkitt's lymphoma were of follicular center cell origin. Most of the recurrent numerical or structural abnormalities (21,22). we found were associated with lymphomas of the B-cell type. Trisomy 3 has been associated with T-cell lymphoma, espe However, since the majority of the lymphomas in this series cially when it occurs as the sole abnormality, and less specifi were B-cell, the correlation of these abnormalities with B-cell cally when it occurs among other abnormalities in the absence phenotype was not significant, except for the 14q32 transloca of T-cell-specific ones such as 14qll abnormalities (8). Inter tion (P < 0.05). On the other hand, no notable clustering of estingly enough, however, all of our 5 patients with trisomy 3 breaks was found for T-cell lymphomas; 14qll-13 transloca showed a B-cell phenotype. All had other abnormalities, and tion was found in one LBL, and 6p21-23 translocation was none had phenotype-specific translocations such as t(14;18) or found in 2 DM lymphomas and one IBL. t(8;14). 3q abnormalities have been amply reported in non-Hodgkin's

DISCUSSION ML. In the series by Kaneko et al. (5) from the United States, most of the lymphomas with 3q+ were DL, and the breakpoints We have reported here the chromosomal findings in 51 ML were between 3q25-29, like in our patients. On the other hand, patients from Kurashiki and its vicinity, an area located in in Japanese patients from Saitama studied by Maseki et al. (6), western Japan and nonendemic for ATL. The majority (32 of a high incidence of 3q abnormalities was also found in DL 47 tested) of the lymphomas were of the B-cell type. lymphoma, but the breakpoint was in 3q21. Our findings differ 14q32 translocations were the most common abnormalities from both these reports in that one third of the 3q abnormalities in this series. Among them, an interesting finding was that 3 of was found in FLs. Of our 10 lymphomas with these abnormal our 4 patients with t( 11;14)(q 13;q32) had IDL (13). A substan ities, 3 had also a 14q32 translocation, and 2 had an 18q21 or tial number of lymphoma cases with this translocation have 23 translocation. Thus, 3q abnormalities in these patients may been reported (1, 2, 5, 7, 14-16), and molecular analysis of the have been secondary changes. 1Iql3 breakpoint has led to the discovery of a putative onco Association of a break in 6p21-23 with T-cell lymphoma was gene, bel-I, on (16). This translocation, how reported by Mecucci et al. (23) and Maseki et al. (6, 24). Since ever, has not been correlated with any specific histological all of our 3 lymphomas with this abnormality were T-cell, the subtype of non-Hodgkin's ML. Small lymphocytic lymphoma/ association now seems definite. chronic lymphocytic leukemia, DSC lymphoma, DL lym We found dup(12)(ql3-15—>q21-24) in 4 lymphomas, all of phoma, and myeloma have all been reported in association with the B-cell type. Partial duplication of 12q (ql2—>q22)was first it, and its incidence in each of these subtypes has not been high. reported in a case of ML by Gahrton et al. (25). They suggested Recently, Weisenburger et al. (17) have found that Ilql3 that this abnormality had the same effect as the trisomy 12 translocations or t(l I;14)(ql3;q32) was frequent in IDL. The often found in chronic lymphocytic leukemia, and that a gene association of 3 of our 4 t(ll;14) cases with an IDL histology (or genes) located in 12q 13-22 might play an essential role in might support the existence of such a correlation; however, it neoplastic transformation. Our findings seem to support the should be noted that the other case was a follicular lymphoma. above hypothesis and indicate the specific involvement of t(14;18)(q32;q21) was found in only 3 patients in this series. 12q 13-15—»21-24in some B-cell lymphomas. It should be Four other patients had 18q21 abnormalities, and only one had noted, however, that, while trisomy 12 in chronic lymphocytic a reciprocal translocation. Most such cases are actually consid leukemia is often found as the sole abnormality, in all our 4 ered to have t(14;18)(q32;q21), and bel-2 rearrangements have cases the 12q abnormality was accompanied by other chromo- 2702 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1990 American Association for Cancer Research. CHROMOSOMES IN LYMPHOMA IN KURASHIKI somal changes; 2 cases had specific t(14;18)(q32;q21) and one 5. Kaneko, Y., Rowley, J. D.. Variakojis, D.. Harén,J.M.. Ueshima, Y., Daly, K..and Kluskens. L. F. Prognostic implications of karyotype and morphology had t(ll;14)(ql3;q32). Neither of our SL lymphomas has tri- in patients with non-Hodgkin's lymphoma. Int. J. Cancer. 32: 683-692. somy 12 or dup(12). 1983. Geographical differences have been shown to exist in the 6. Maseki, N.. Kaneko. Y., Sakurai. M.. Kurihara. M.. Sampi, K.. Shimamuru. K., and Takayama, S. Chromosome abnormalities in malignant lymphoma distribution of various chromosomal abnormalities in non- in patients from Saitama. Cancer Res., 47: 6767-6775, 1987. Hodgkin's MLs. Thus, data from the United States (1-5, 7) 7. Koduru, P. R. K., Filipa. D. A., Richardson, M. E., Jhanwar. S. C., Chaganti, and Japan (6) as well as the data collected for the Fifth Inter S. R., Koziner, B., Clarkson, B. D.. Lieberman. P. H., and Chaganti, R. S. K. Cytogenetic and histologie correlations in malignant lymphoma. Blood. national Workshop on Chromosomes in Leukemia/Lymphoma 69:97-102, 1987. (8), indicated that the incidence of t(14;18)(q32;q21) was much 8. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma. Correlation of chromosome abnormalities with histologie and immunologie higher in the United States than in Japan, while characteristics in non-Hodgkin's lymphoma and adult T-cell Icukemia-lym- t(8;14)(q24;q32) is found in equal frequencies in the two coun phoma. Blood, 70: 1554-1564. 1987. tries. Interestingly, the finding of t(l I;14)(ql3;q32) in as many 9. Croce, C. M. Chromosome translocations and human cancer. Cancer Res., 46:6019-6023, 1986. as 8% of our patients from Kurashiki is also a major difference 10. The T- and B-Cell Malignancy Study Group. Statistical analyses of clinico- with the patients we have studied in Saitama (6), none of whom pathological. virologieal. and epidemiológica! data on lymphoid malignancies showed this abnormality (P = 0.01). There are instead no with special reference to adult T-cell leukemia/lymphoma: a report of the second nationwide study of Japan. Jpn. J. Clin. Oncol.. 15: 517-535, 1985. significant differences in the incidence of t(14;18)(q32;q21) and 11. Kaneko, Y., Frizzerà . G., Shikano. T.. Kobayashi. H., Maseki, N., and t(8;14)(q24;q32) in these 2 areas of Japan. The Fifth Chromo Sakurai, M. Chromosomal and immunophenotypic patterns in T-cell acute lymphoblastic leukemia (T ALL) and lymphoblastie lymphoma (LBL). Leu some Workshop found none with this translocation among the kemia. 3: 886-892, 1989. 260 eligible patients. Since the numbers of our patients and the 12. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkin's lym lymphoma patients studied in Saitama are still relatively small, phomas. Summary and description of a working formation for clinical usage. we do not know whether there are geographical differences in Cancer (Phila.), 49: 2112-2135, 1982. the incidence of this chromosomal abnormality among different 13. Weisenburger, D. D.. Nathwani, B. N.. Diamond. L. W., Winberg, C. D., and Rappaport. H. Malignant lymphoma. intermediate lymphocytic type: a areas within the same country and/or among different coun clinicopathologic study of 42 cases. Cancer (Phila.), 48: 1415-1425, 1981. tries. 14. Fukuhara, S.. Nasu. K.. Kita. K.. Ueshima. Y.. Oguma, S.. Yamabe. H.. Recently, Fukuhara et al. (26) have suggested the frequent Nishigori. M., and L'chino. H. Cytogenetic approaches to the clarification of occurrence of an extra 18q- chromosome which results from a pathogenesis in lymphoid malignancies. Clinicopathologic characterization of 14q+ marker-positive non-T-cell malignancies. Jpn. J. Clin. Oncol., 13: duplication of der(18)t(14;18)(q32;q21) in Japanese t(14;18)- 461-476. 1983. associated lymphomas. None of the 3 lymphomas in the present 15. Van Den Berghe. H.. Vermaelen. K.. Louwagie. A., Criel, A., Mecucci, C., and Vaerman. J. P. High incidence of chromosome abnormalities in IgG3 series and only one of the 3 in a previous series (6) with t( 14;18) myeloma. Cancer Genet. Cytogenet., //: 381-387. 1984. had an extra 18q- chromosome. This frequency of 17% is not 16. Tsujimoto, Y., Jaffe. E.. Cossmann. J., Gorham, J.. Nowell. P. C.. and Croce. significantly different from that (9.5%) reported from the Fifth C. M. Clustering of breakpoints on chromosome 11 in human B-cell neo plasms with the t(l 1;14) chromosome translocations. Nature (Lond.), 315: International Workshop on Chromosomes in Leukemia/Lym 340-343, 1985. phoma. Thus, the association between the extra 18q- chromo 17. Weisenburger, D. D., Sauger. W. G.. Armitage, J. O-, and Purtilo, D. T. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic some and the Japanese t(14;18) lymphoma has not been con findings. Blood. 69: 1617-1621. 1987. firmed. Well-designed, large-scale studies will be necessary to 18. Tsujimoto. Y.. Gorham, J., Cossman. J.. Jaffe. E., and Croce, C. M. The confirm or deny the geographical differences in certain chro t( 14:18) chromosome translocations involved in B-cell neoplasms result from mosomal abnormalities in non-Hodgkin's lymphomas. mistakes in VDJ joining. Science (Wash. DC). 229: 1390-1393, 1985. 19. Lee, M. S., Blick, M. B.. Pathak. S.. Trujillo. J. M.. Buther. J. J.. Katz. R. L., Mclaughlin. P.. Hagcmeister. F. B.. Velasquez. W. S.. Goodacre. A., Cork, A.. Gutterman. J. V.. and Cabarillas. F. The gene located at chromo ACKNOWLEDGMENTS some 18 Band q2l is rearranged in uncultured diffuse lymphomas as well as follicular lymphomas. Blood. 70:90-95. 1987. We thank J. Yamamoto, T. Takahashi, H. Nanba, and S. Kawauehi 20. Lipford. E.. Wright. J. J.. Vrba. V>..Whang-Peng. J.. Kirsch. I. R.. Raffeld. for karyotyping; Y. Hasegawa and H. Katayama for immunofluores- M.. Cossman, J.. Longo, D. L., Bakkshi. A., and Korsmeyer. S. J. 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2703 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1990 American Association for Cancer Research. Chromosome Abnormalities in Malignant Lymphoma in Patients from Kurashiki: Histological and Immunophenotypic Correlation

Hiroshi Konishi, Masaharu Sakurai, Hatsue Nakao, et al.

Cancer Res 1990;50:2698-2703.

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