chromosome abnormalities in adult t-cell leukemia/lymphoma ... · in order to determine the...

[CANCER RESEARCH 52, 1481-1493, March 15, 1992]

Chromosome Abnormalities in Adult T-Cell Leukemia/Lymphoma:A Karyotype Review Committee Report1

Nanao Ramada, Masaharu Sakurai, Kanji Miyamoto, Isao Sanada, Naoki Sadamori, Shirou Fukuhara, Syuiti Abe,Yukimasa Shiraishi, Tatsuo Abe, Yasuhiko Kaneko, and Masanori Shimoyama2

Department of Hematology, Research Institute for Nuclear Medicine and Biology, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima 734 fN. K.J;Departments of Cancer Chemotherapy [M. Sa.] and Laboratory Medicine [Y. KJ, Saitama Cancer Center Hospital, SIS Komuro, Ina, Saitama 362; ChromosomeResearch Unit, Faculty of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060 fS. A.]; Department of Hygiene, Kyoto Prefectural Universityof Medicine, Kawaramachidori Hirokoji-agaru, Kamikyo-ku, Kyoto, Kyoto 602 [T. A.]; Department of Hematology, Atomic Disease Institute, Nagasaki UniversitySchool of Medicine, 7-1 Sakamoto machi. Nagasaki, Nagasaki 852 [N. S.]; First Division of Internal Medicine, Faculty of Medicine, Kyoto University, S3 Shogoin-Kawaramachi, Sakyo-ku, Kyoto, Kyoto 606 Â¡S.F.J; School of Health Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, Okayama 700 [K. M.J; SecondDepartment of Internal Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto, Kumamoto 860 [I. S.]; Department of Anatomy, Kochi MedicalCollege, Kohasu, Okatoyo-cho, Nangoku, Kochi 781-51 [Y. S.]; and Hematology-Oncology and Medical Oncology Division, National Cancer Center Hospital, 5-1-1Tsukiji, Chuo-ku, Tokyo 104 [M. Sh.J, Japan

ABSTRACTKaryotypes of 107 cases with adult 'I'-cell leukemia/lymphoma (58

male, 49 female; 81 acute or lymphoma type, 26 chronic or smolderingtype) were reviewed by a panel of cytogeneticists and were correlatedwith the subtypes of the disease. Clonal chromosome abnormalities werefound in 103 (96%) cases, of which four had hypotetraploidy. Of 184numerical abnormalities in the remaining 99 cases with near- or pseu-dodiploidy, trisomies for chromosomes 3 (21% of cases), 7 (10%), and21 (9%), mnnosonty for X chromosome (38%) in the female, and loss ofa Y chromosome (17%) in the male were more frequent than expected(/' < 0.01). Of 373 structural abnormalities in all the 103 aneuploid

cases, trenslocations involving 14q32 (28%) or 14qll (14%) and deletionof 6q (23%) were most frequent, followed by deletion of lOp (9%), 3q(8%), Sq, 9q, and 13q (7% each), and Ip and 7p (6% each). The proportionof cases with aneuploid clones (with > or < 46 chromosomes), theaverage numbers per case of both numerical and structural abnormalities,and marker chromosomes were larger in the aggressive acute or lymphoma type than in the nonaggressive chronic or smoldering type (/' <

0.01). The combination of rearrangement in 14q32 and monosomy X(seven cases) or deletion of lOp (six cases), and that of trisomy 3 anddeletion in 6q21 (six cases), occurred only in the acute or lymphoma typeand may be associated with the aggressiveness in adult T-cell leukemia/lymphoma.

INTRODUCTION

ATL3 is a clinical entity defined by specific clinicohematolog-ical features including the association with HTLV-I virus andpleomorphic leukemic "flower cells" with deeply indented or

lobulated nuclei and a T-cell-specific surface marker profile (1-4). The occurrence of ATL shows an uneven geopathologicaldistribution with a much higher incidence in southwesternJapan than in any other part of the world.

Chromosome findings in ATL have been reported from several laboratories in Japan. Although trisomies for chromosomes3 (5, 6) and 7 (6, 7), deletions of the long arm of chromosome6 (5), and structural rearrangements involving band 14qll (8)or 14q32 (5) have been described as major chromosomechanges, no specific abnormalities have been found in ATL (9,

Received 2/21/91; accepted 1/6/92.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1Supported by Grants-in-Aid for Cancer Research (59S-1, 62S-1, and 2S-1)

from the Ministry of Health and Welfare of Japan.2To whom requests for reprints should be addressed.3The abbreviations used are: ATL, adult T-cell leukemia/lymphoma; HTLV-

I, human T-cell leukemia/lymphoma virus type I; IWCL, International Workshopon Chromosomes in Leukemia/Lymphoma; A+L, "acute" and "lymphoma" typesof ATL; C+S, "chronic" and "smoldering" types of ATL; RSCA, related singlecell abnormalities; USCA, unrelated single cell abnormalities; TCRA, T-cellreceptor a chain gene; TCRB, T-cell receptor ÃŸchain gene; TCRD, T-cell receptorti chain gene.

10). Attempts to correlate chromosome abnormalities with theclinical subtypes of the disease (6, 8) have provided only inconclusive results.

In order to determine the incidence of various chromosomeabnormalities seen in Japanese ATL, we established an ad hoccommittee, collected ATL cases from all over Japan, and conducted a joint review of karyotypes. This paper describes theconsensus karyotypes and their correlation to the clinical subtypes in 107 cases with ATL. We were unable to find anyabnormality specific to ATL, but were able to clarify that mostabnormalities, be they numerical or structural, tend to appearmore frequently in the aggressive acute or lymphoma type thanin the nonaggressive chronic or smoldering type.

MATERIALS AND METHODS

The Committee. The "ATL Karyotype Review Committee 1985(ATLKRC85)" (M. Shimoyama, chairperson) was organized ad hoc in

1985 to review both clinical and cytogenetic data.on then publishedand unpublished cases with ATL in Japan. The committee consisted ofthe 11 authors of this paper and was sponsored by the study group,"Multidisciplinary Treatment of Solid Cancer," which was being sup

ported by grants from the Ministry of Health and Welfare of Japan.Queries. Clinical data including WBC and the percentage of abnor

mal lymphocytes in the peripheral blood, positivity for anti-HTLV-Iantibody, the patient's survival time, and the subtype diagnosis of ATL,

i.e. acute type (1), lymphoma type (4, 11), chronic type (11), or smoldering type (4, 11), or pre-ATL (12), were submitted for each casebefore the joint review in 1985. The method of tumor cell culture wasalso ascertained. Additional clinical and laboratory data were collectedfor most (105 of 107) cases in 1989 to confirm the originally diagnosedsubtype of ATL. The survival data were updated simultaneously.

The Patients. A total of 139 cases with ATL were submitted from 16institutions. Twelve cases were submitted with karyotypes prepared bycommercial laboratories. For all the other cases, chromosomes wereanalyzed in either the current authors' laboratories or other hospitals

under the supervision of the authors.The clinical diagnoses given by original hospitals were reviewed

centrally by members of the committee on the basis of the submittedclinical data. Pathology slides of lymph nodes from 31 cases werereviewed by members of the Lymphoma Pathology Panel of Japan, andtheir consensus diagnoses helped in the classification of some borderlinecases.

Review of Karyotypes. Twelve cytogeneticists (including all the authors except for M. Shimoyama, who served as a moderator, and twoothers) reviewed the karyotypes. The committee met 7 times at theNational Cancer Center in Tokyo, Japan, during 1985 and 1986 andspent 13 full days for reviewing. At least 3 karyotypes from each clonewere reviewed by 5 to 10 (most often 7) cytogeneticists. The International System for Human Cytogenetic Nomenclature (ISCN) (13) wasused for description of karyotypes. An abnormal clone was defined as2 or more cells with the same structural rearrangement or extra chro-

1481

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CHROMOSOMES IN ADULT T-CELL LEUKEMIA/LYMPHOMA

mosome, or 3 or more cells with the same missing chromosome. Onesingle normal metaphase was considered as sufficient evidence of anormal clone. Debatable karyotypes were finalized at plenary meetings.

Methods Used in Chromosome Studies for the Accepted Cases. Chromosome analyses had been performed on peripheral blood in 81, lymphnode in 18, bone marrow in 6, and pleural effusion or ascites in 2 cases.The samples were cultured for varying lengths of time (within 6 h in18, 24 h in 51, 48 h in 6, 72 h in 18, and 120 h or over in 14 cases).Either phytohemagglutinin, T-cell growth factor, or recombinant inter-leukin 2 was used for culture in 13 cases. Chromosomes were analyzedby G- and/or Q-banding.

Data Analysis. All collected data were analyzed by ACOS System750, using a previously reported program for karyotype (14), and acommercially available BMDP program for clinical data. Significancefor the difference was evaluated by the t test between the averagenumbers, by the x2 or Fisher's exact test between the proportions, and

by the generalized Wilcoxon and Mantel-Cox tests between the survival

RESULTS

Clinical Findings. Of the 139 cases submitted, 32 were rejected because of central diagnosis of a disease other than ATL,previous therapy, inadequate karyotypes, or other reasons. Ofthe 107 cases accepted as adequately studied, 31 were fromOkayama, 17 were from Kumamoto, 13 were from Nagasaki,10 were from Kyoto (Kyoto University), 9 were from Sapporo,and 8 were from Kochi; the remaining 19 were from variousother centers (Table 1). Thirty-one of the 107 cases had beenaccepted for the Fifth IWCL (34) (Table 1). Individual kary-otypic data were not published as part of the workshop report.

Central review of the original clinical diagnoses indicateddifficulty in the differentiation between the acute and lymphomatypes or between the chronic and smoldering types for somecases. Accordingly, the acute type and the lymphoma type, andthe chronic type and the smoldering type (or pre-ATL), werecombined, respectively, and 81 were classified as having theA+L type, and 26 were classified as having the C+S type (Tables1 and 2). Survival times are not different between the acute andlymphoma or between the chronic and smoldering type ofpatients (35).

There was a slight male predominance in the accepted cases(not significant). Thirteen cases were under 40 yr of age, 17cases were in the 40s, 30 cases were in the 50s, 30 cases werein the 60s, and 17 cases were 70 yr or over; the ages rangedfrom 24 to 77 yr with a median of 58 yr. There was no significantdifference in the age distribution between the A+L and C+Sgroups (Table 2).

Immunologie-ai studies were performed for 90 cases. In allthese cases, the tumor cells formed E-rosettes or reacted withone or more monoclonal antibodies against T-cell-associatedantigens. The anti-HTLV-I antibody was tested in 93 patients;it was positive in 91, with titers ranging from 1:20 to 1:1280,and negative in 2. The 2 HTLV-I-negative cases were out of 3cases submitted from an institution located in an ATL-nonen-demic area where HTLV-I-negative ATL was being extensivelystudied. They were examined for proviral DNA of HTLV-I andexhibited no signs of viral integration (28); these patients had49% and 96% of "flower cells" typical of ATL in the peripheral

blood, respectively.Abnormal clinical and laboratory findings, except for the

bone marrow involvement and skin lesions, were significantlymore frequent in the A+L type than in the C+S type of patients(Table 2). Hypercalcemia, hyperbilirubinemia, and hepatosple-nomegaly were never or only occasionally seen in the C+S type

of patients, but were frequent in the A+L type of patients. TheC+S type of patients survived longer than did the A+L type ofpatients (P< 0.01).

Karyotypes. The karyotypes of the 107 accepted cases aregiven in Table 1. Of these, 34 cases have been reported withthe revised karyotypes after the joint review (8, 15, 16, 18, 24,27, 28, 30, 31, 33); 28 cases were only reported before it withthe original karyotypes (5, 6, 17, 19, 20-23, 25, 26, 29, 32),and 45 cases have never been reported.

Four cases (Patients 9, 73, 81, and 103) had no clonalabnormalities. A total of 103 cases (96%) had clonal chromosome abnormalities; 89 cases had only one abnormal clone, and14 had 2 or more abnormal clones, 4 (Patients 5, 83, 106, and107) of which had clones unrelated to each other (Table 3).USCA were seen in 17 patients. Sixty-one patients (59%), i.e.,41 (52.5%) in the A+L group and 20 (80%) in the C+S group,had cells with a normal karyotype besides those with an abnormal one. Four (Patients 59, 64, 80, and 87) had complexhypotetraploid karyotypes, and numerical changes were notdescribed for these karyotypes since the precise number of lostor gained chromosomes was not always determinable. Of theremaining 99 cases with near- or pseudodiploidy, 3 had onlynumerical abnormalities, 9 had only structural abnormalities,and 87 had both types of abnormalities.

Modal Chromosome Numbers. Modal chromosome numbersby clinical subtype are shown in Table 3. Aneuploidy (hypo- orhyperdiploidy or hypotetraploidy) was more frequent in theA+L type than in the C+S type (P < 0.01).

Numerical Chromosome Abnormalities. There were 184 ofgain or loss of whole chromosomes in 90 of the 99 near- orpseudodiploid cases (Table 4). Numerical abnormalities, preponderantly loss of chromosomes, occurred more frequently inthe A+L type than in the C+S type (P < 0.01).

Trisomy for chromosome 3 (21 cases, 21%), 7 (10 cases,10%), or 21 (9 cases, 9%) and monosomy for X chromosomein the female (17 cases, 38%) or loss of a Y chromosome in themale (9 cases, 17%) occurred more frequently than expected (P< 0.01) (Fig. 1; Table 5). All these abnormalities, except trisomy21, occurred more frequently in the A+L type than in the C+Stype, but only with borderline significance (0.05 < P < 0.1)(Table 5). There was no age dependency in the incidence of Xchromosome loss occurring in lymphoma cells in the ages over40; loss of an X chromosome was seen in 4 of 7, 3 of 9, 8 of19, and 2 of 7 females in the 40s, 50s, 60s, and 70s, respectively.Only 3 female patients were under 40 yr and did not show lossof an X chromosome.

Marker chromosomes also occurred more frequently in theA+L type than in the C+S type (P < 0.01) (Table 4).

Structural Chromosome Abnormalities. A total of 373 structural chromosome abnormalities were observed in 100 of the103 cases with abnormal karyotypes, including the 4 hypotetraploid cases (Table 4). Translocations (derivative chromosomes)with an unidentified chromosome segment were most frequent,followed by partial deletions, balanced (reciprocal) translocations, and unbalanced translocations (derivative chromosomeswith an identified chromosome segment).

Breaks relating to rearrangements (including translocations,inversions, etc.) occurred most frequently in band 14q32 (31breaks in 29 cases), followed by band 14qll (14 cases) (Fig. 2;Tables 5 and 6). The only recurrent rearrangement was inversion of 14q, which involved both 14ql 1 and 14q32 and occurredin 6 cases. The most common abnormality involving band14q32 was translocation of an unknown chromosome segment

1482




Table 1 Consensus karyotypes of 107 patients with ATL attained by the ATLKRC8S

Patient Center0Age,sex Source

No. ofcells

analyzed Karyotype Ref.*

3'

4

820

860

870

940

58F

49M

BM'

PB

41M PB

51M PB

10

14

18

15

Acute (A) and lymphoma (L) types46, XX (60%)/47, X, -X, -4, -7, -12, -16, +20, inv

dup (1) (q21 -Â»q32), del (2) (q33), inv (9) (p24q22),del ( 13) (q 12q3 1), t (3; 14) (q 12; q32), -t-der (4) t (4; ?)(pli; ?), +der (7) t (7; 12) (q32; ql3), +3mar (40%)

47, XY, -1, -3, -5, +7, -10, -14, del (10) (pl2), +der(1) t (1; ?) (q42; ?), +der (3) t (3; ?) (ql2; ?), +der (5) t(5; ?) (q35; ?), +der (10) t (10; ?) (q24; ?), +der (14) t

9

10

11

12

13

14

800

870

830

810

810

820

820

820

820

820

61M LN

63F PB

83M PB

22

17

51M

59M

73F

68M

54F

24M

44F

LN

PB

BM

PB

PB

PB

PB

52

30

12

12

20

12

46, XY (6%)/47, XY, -2, +8, t (6; 17) (q21; pl3), -l-der(2) t (2; 3) (q37; pi 1) (77%)/RSCA (1 1%)/USCA (6%)

50, X, -Y, -13, -15, -17, -20, +21, inv (I)(pl3q23),+i ( 1) (qter -Â»q23::p 13 -Â»cen -Â»p 13::q23 -Â»qter),+der ( 1q3p), +der ( 15) t (7; 15) (q2 1; q24), +der ( 17) t(Y; 17) (ql 1; pl2), +der (20) t (20; ?) (pl3; ?), +3mar(67%)/50, X, -Y, -15, -17, -20, +21, inv (1), +i (1),+der (1q3p), +der ( 15), +der ( 17), +der (20), +2mar(33%)

46, XY (5%)/48, XY, -1, +der (1) t (I; ?) (pll; ?), +der(4) t (4; ?) (q27; ?), +mar (50%)/92, XXYY, 2p-,llp+, 12q+(45%)

46, XX (6%)/47, XX, +3, -16, -21, dup (1) (q21 -Â»q32), t (6; 13) (p23; ql4), +der (16) t (16; ?) (pl3; ?),+der (21) t (21; ?) (pll; ?) (88%)/RSCA (6%)

46, XY (57%)/53, X, +X, -Y, - 1, -6, +7, +8, - 17,-19, del (1) (q25), +del (3) (ql2), +dup (3) (p23p25),+der (1) t (1; ?) (q23; ?), +der (6) t (6; ?) (q21; ?), +der(19) t (19; ?) (p 13; ?), +der (?) t (1; ?) (q25; ?), +der(?), +der (?), +mar (43%)

46, XY (31%)/47, XY, +3, -17, del (1) (p36), del (6)(q21), +der (17) t (17; ?) (pl3; ?) (54%)/RSCA (15%)

46, XY (97%)/USCA (3%)

46, XX (8%)/48, XX, +7, -8, -8, -10, +12, -19, -21,del (3) (q21q25), del (6) (ql5q21), +del (6), del (9)(p22), +der (8) t (8; ?) (q?; ?), +der ( 19) t (19; ?) (q 13;?), +2mar (92%)

49, XY, +3, -6, -17, -18, -18, +der (6) t (6; ?) (ql5;?), +der (18) t (18; ?) (pi 1; ?), +der (18) t (18; ?) (q23;?), +3mar (100%)

46, XX (70%)/47, XX, -4, -5, +7, -8, -11, -17, -18,t (7; 11) (q22; p 15), +der (8) t (8; ?) (q?; ?), +der ( 17) t(17; ?) (p?; ?), +der (18) t (18; ?) (pll; ?), +3mar(30%)

48, XY, -2, +3, -9, del (6) (q21q25), dup (7) (qll -.q22), +der (7q9p), +der (2) t (2; ?) (q3?; ?), +mar(100%)

47, XX, -3, +7, -14, -14, del (9) (:pl2-. q32:), t (7;12) (ql 1; pl3), +der (3) t (3; ?) (ql3; ?), +der (14) t(14; ?) (pi 1; ?), +der (14) t (14; ?) (q32; ?) (100%)

75(10), 16 (7)

17(3)

5(9)

/Â«(N55)

5(10)

75(1), 16 (\)

15(1), 16(6)

15(3), 16 (\0)

15 (8), 76(12)

1582016

82017

83065F46M33FPBPBPB1012447,

XX, -1, +3, del (6) (q21q25), del (10) (p 13),+der46,

XY (33%)/47, XY, +3, -14, t (5; 7; 6) (qlS; q22;q21), +der (14) t (14; ?) (q24; ?)(67%)47,

XX, -16, t (10; 14) (pll; qll), +der (16) t (16; ?)(q23;?), +mar(100%)15(4),

16(\\)15(6),

16 (\3)

" 800, Saitama Cancer Center (Saitama); 810, Hokkaido University (Sapporo); 820, Kyoto University (Kyoto); 830, Kyoto Prefectural University of Medicine

(Kyoto); 840, Hiroshima University (Hiroshima); 850, Nagasaki University (Nagasaki); 860, Kochi Medical College (Nangoku, Kochi); 870, Okayama Blood Center(Okayama); 880, Kumamoto University (Kumamoto); 890, National Cancer Center (Tokyo); 900, Ryukyu University (Okinawa); 910, Fukuoka University (Fukuoka);920, Aichi Cancer Center (Nagoya); 940, Jikei University Aoto Hospital (Tokyo); 970, Kokura Memorial Hospital (Kitakyushu, Fukuoka).

* The italicized references were published after the joint review by ATLKRC85. The numbers or letters in parentheses refer to cases in each reference. Twenty-

eight cases were reported only before the review, 20 were reported only after the review, and 14 were reported both before and after the review; 45 cases have beenreported neither before nor after the review.

' BM, bone marrow; PB, peripheral blood; LN, lymph node; PE, pleural effusion; AS, ascites.â€¢¿�*Case accepted for the Fifth IWCL.' der (14) t (14; ?) (q32; ?) and one of the markers may possibly be products of t (14; 14) (qll; q32).^Anti-HTLV-I antibody-negative cases. No proviral DNA of HTLV-I was detected in either of these cases. The antibody was not tested for Cases 5, 21, 28, 29,

30, 31, 32, 34, 59, 66, 70, 85, and 86. All the other cases were anti-HTLV-I antibody positive.

1483




Table 1 Continued

Patient Center0Age,sex Source

No. ofcells


18

19

20"

21'

22'

23'

24'

25'

26'

27'

28

29

30

31'

32'

33"

34'

35'

36"

37'

840

840

850

850

850

850

850

850

850

850

860

860

860

870

870

870

870

870

870

870

49M

39M

48F

55M

56M

57F

68F

62F

52M

68M

47F

62F

40F

36M

29M

45M

58F

44M

72F

54M

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

PB

31

18

15

25

27

21

24

21

20

20

15

16

16

10

10

11

10

11

10

13

47, XY, -l, -4, -12, +18, del (7) (p 14), del (13) (q32),+der (4) t (4; 12) (q31; ql3), +der (1) t (1; ?) (q42; ?),+mar (100%)

48, X, -Y, -3, -3, -9, - 12, - 13, - 14, del (9) (q 13q22),+der (1) t (?; 1) (1; ?) (?; pllq42; ?), +der (3) t (3; ?)(pl3; ?), +der (9) t (3; 9) (pl3; pl3), +der (12) t (12; ?)(q24; ?), +der (13) t (13; ?) (ql4; ?), +der (14) t (14; ?)(q32; ?), +3mar (83%)/USCA (17%)

47, X, -X, +3, -4, +15, inv (14) (qllq32), +der (4) t (4;?) (q35; ?) (93%)/RSCA (7%)

45, X, -Y, -2, -3, -3, -5, -8, -9, -11, -15, -16, -17,del ( l ) (q42), +del (6) (q2 1), inv (14) (q 11q32), +der (2)t (2; ?) (p25; ?), +der (3) t (3; ?) (p21; ?), +der (11) t(11; ?) (q25; ?), +der (15) t (15; ?) (pli; ?), +5mar(100%)

48, XY, +15, -22, +del (14) (qllq32), t (14; 14) (qll;q32), +mar(100%)

46, X, -X, -10, -12, -14, -17, +der (14) t (14; ?) (q32;?), +4mar (62%)'/RSCA (38%)

44, X, -X, -1, -3, -5, -10, -12, -13, -14, -17, -17,-18, del (14) (qllql3), +der (1) t (1; ?) (p36; ?), +der(3) t (3; ?) (q29; ?), +der (14) t (14; ?) (q32; ?), +der(17) t (17; ?) (q25; ?), +5mar (100%)'

48, X, -X, +2, -4, - 14, del (5) (q 13), del (14) (q 11q 13),+der (4) t (4; ?) (pl6; ?), +der (14) t (14; ?) (q32; ?),+2mar (52%)'/RSCA (48%)

46, XY (5%)/47, XY, -2, +3, -6, +7, -14, -15, +der(1 1) t (1 1; 14) (pl3; ql3), +der (2) t (2; ?) (q37; ?), +der(6) t (6; ?) (p25; ?) (95%)

46, XY, -4, -9, -10, -12, del (1) (p32), +der (4) t (4; ?)(pl6; ?), +3mar (95%)/RSCA (5%)

46, XX (7%)/46, X, -X, +3, -13, -14, -14, -17, -18,-19, del (2) (pl5p22), del (6) (q21), del (6) (ql3q25),del (18) (pi 1), +der (13) t (13; ?) (q34; ?), +der (14) t(14; ?) (q24; ?), +der (14) t (14; ?) (q32; ?), +der (17) t

3;?), +2mar (93%)

46, XX (13%)/47, XX, -2, +3, -5, -13, -14, del (10)(p 12), del (10), +der (2) t (2; ?) (q37; ?), +der (5) t (5;?) (q31; ?), +der (13) t (13; ?) (q34; ?), +der (14) t (14;?) (q32; ?) (81%)/RSCA (6%)

46, XX (13%)/48, X, -X, -3, -4, -7, +11, -14, -21,+der (3) t (3; ?) (q25; ?), +der (7) t (4; 7) (ql2; q36),+der (21) t (21; ?) (q22; ?), + 4mar (87%)

46, XY (10%)/46, XY, del (9) (ql2q32), inv (14) (ql Iq32),t (1; 7) (p36; q21), t (12; 15) (ql3; q26) (90%)

46, XY (10%)/48, Y, -X, +3, +del (1) (pi2), t (5; 14)(q22; q32), +mar (60%)/RSCA (30%)

46, XY (55%)/47, XY, +3, del (8) (pl2), t (1; 22) (q23;pl3), t (5; 19) (ql3; pl3), t (6; 17) (p21; q23) (45%)

45, XX, -3, -10, -13, -17, -19, -20, inv (2) (p23q33),del (15) (q23), i (18q), +der (20) t (17; 20) (ql 1; pl3),+der (3) t (?; 3) (3; ?) (?; p25q21; ?), +der (10) t (10; ?)(pli; ?), +der (13) t (13; ?) (ql4; ?), +der (19) t (19; ?)(pl3; ?) (50%)/RSCA (50%)

46, XY (27%)/46, XY, -7, -9, -19, del (3) (q27), i (14q),+der (9) t (9; 19) (pi 1; pi 1), +der (7) t (7; ?) (q36; ?),+der (19) t (?; 9) (9; 19) (?::9p24 -Â»9pll::19pll -Â»19qter) (37%)/45, X, -Y, -7, -9, -19, del (3), i (14q),+der (9), +der (7), +der (19) (27%)/RSCA (9%)

46, XX (10%)/46, X, -X, +4, del (5) (ql3q22), t (6; 7)(ql5; q32), t (8; 10) (q24; q22) (70%)/RSCA (20%)

46, XY (15%)/46, X, -Y, +3, -4, -9, -19, del (1) (p34),del (10) (pi2), del (13) (ql3), del (14) (q21), +der (4) t(4; ?) (q34; ?), +der (9) t (9; ?) (p22; ?), +der (19) (pi3;?) (46%)/46, X, -Y, +3, -4, -7, -9, -19, del (1), del(10), del (14), del (15) (q21), +der (4), +der (7) t (7; ?)(q22; ?), +der (9), +der (19) (39%)

1484

Â«(6),19(21), 20(6)

Â«(8),19 (24), 20 (9), 21

Â«(3),19 (11), 20 (3)

Â«(7),19(23), 20(10)

Â«(5),19 (13), 20 (11)

Â«(2),19(10), 20(2)

Â«(1),19(9), 20(5)

Â«(4),19 (12), 20 (7)

17(2)

17(8)

5 (21), 22 (1), 23 (2),24(2)

S (17), 23 (1), 25 (2)

5(25)

5 (22), 23 (7)

24(1)

5 (11), 24 (2)

5 (24), 23 (12), 26(1)




Table 1 Continued

Patient Center"Age,sex Source

No. ofcells


38

39'

40'

870

870

870

4 1' 870

42' 870

43

45

46

47

48

49

50

51

52

53

54

55

870

870

870

870

870

880

880

880

880

880

880

880

880

890

60F

78F

51M

77M

46M

58M

72F

76F

64M

56M

58F

70M

74M

71F

62F

29M

45F

59M

71M

PE

PB

PB

PB

PB

PB

PB

PB

PB

PB

LN

PB

PB

PB

PB

PB

PB

PB

PB

10

20

24

10

13

12

4

10

15

10

25

11

39

5

10

10

134

Si' 890

58 890

59 900

43F

34M

61M

PB

PB

PB

10

12

18

46, XX (10%)/47, X, -X, +3, del (6) (ql5q21), del (13)), +mar (60%)/RSCA (30%)

46, XX (5%)/47, XX, + 3 (95%)

46, XY (4%)/48, XY, -1, -14, +21, del (6) (ql5), +der(1) t (1; ?) (p36; ?), +der (3) t (3; ?) (p21; ?), +der (?) t(14; ?) (ql 1; ?) (80%)/RSCA (8%)/USCA (8%)

47, XY, -6, -9, - 18, del (9) (q22), +der (6) t (6; ?) (q 15;?), +der (9) t (9; ?) (p22; ?), -t-der (18) t (18; ?) (q21; ?),+der(I8)(100%)

46, XY (10%)/47, XY, -15, +21, dup (2) (q21 -Â»q31),del (5) (qllql3), del (6) (ql5q21), del (7) (pl5), del (9)(ql2q22), t (10; 14) (q21; q32), +der (15) t (15; ?) (q26;?) (90%)

52, X, -Y, +5, +7, +1 1, -14, -16, +21, del (3) (q27),+del (3) (q21q25), +del (3) (q21q25), del (6) (ql5q21),+del (9) (q22), del (13) (ql4q32), +der (16) t (7; 16)(qll; q24), +der (14) t (14; ?) (p 12; ?) (46%)/RSCA(54%)

46, XY (8%)/47, XX, t (4; 9) (pl2; p22), +mar (92%)

47, X, -X, +3, -6, -6, +der (X) t (X; ?) (qll; ?), +der(6) t (6; ?) (ql2; ?), +der (6) t (6; ?) (ql4; ?) (100%)

46, XY (50%)/47, XY, -1, +7, dup (1) (q21 -Â»q42), del(9) (ql2q22), t (10; 20) (pi 1; pi 1), +der (1) t (1; ?) (p35;?) (50%)

47, XY, -13, -18, +21, del (5) (ql3ql5), t (3; 14) (p25;ql 1), +der (13) t (3; 13) (pl3; pi 1), +der (18) t (18; ?)(q23; ?) (53%)/46, XY, t (3; 14) (47%)

47, XX, -10, +del (3) (ql2q27), del (6) (ql3q23), t (3; 7)(ql3; q32), +der (10) t (10; ?) (q26; ?) (70%)/RSCA(30%)

46, XY (28%)/47, XY, -10, -14, +18, +der(10) t (1; 10)(qll; pl3), +der (14) t (14; ?) (q32; ?) (72%)

48, XY, -2, -6, -7, -20, +21, +dup(3)(pter-Â»p21::p25-> p21::p25 -> qter), +der (2) t (2; ?) (q31; ?), +3mar(73%)/RSCA (27%)

46, XX (64%)/45, X, -X (13%)/USCA (23%)

47, XX, +3, -10, -14, +der(10) t (10; ?)(q26; ?) del (10)(pi 1), +der (14) t (14; ?) (q32; ?) (80%)/RSCA (20%)

48, XY, -2, +5, -13, -14, +der (1) t (1; ?) (pl3; ?), +der(2) t (2; ?) (q33; ?), +der (13) t (13; ?) (q22; ?), +mar(90%)/RSCA(10%)

46, XX (20%)/47, XX, -2, -3, +7, -9, -14, del (2)(q33q37), del (15) (q24), t (4; 12) (pl6; qll), +der (3) t(3; ?) (pi 3; ?), +der (9) t (9; ?) (q34; ?), +2mar (80%)

47, XY, -1, +3, -4, -13, -15, -18, -22, +del (X) (q24),del (6)(p21), +der(15)t (1; 15)(pll; pll), +der (1) t(1; ?) (pi 1; ?), +der (18) t (18; ?) (pi 1; ?), +der (22) t(22; ?) (ql 1; ?), +mar (60%)/RSCA (40%)

46, XY (49%)/43, X, -1, -2, -4, -6, -8, -9, -9, -10,-13, -14, -15, -16, -18, -20, +21, -22, del (6) (p21),t (Y; 4) (qll; q31), +der (1) t (1; 14) (pl3; qll), +der(2) t (?; 2) (2; ?) (?; pl6q31; ?), +der (9) t (9; ?) (p22; ?),+der(13)t (13; ?) (pll; ?), +der (14) t (14; ?)(pll;?),+der (15) t (15; ?) (pi 1; ?), +der (18) t (18; ?) (pi 1; ?),+4mar (34%)/4n, same abnormalities (17%)

48, X, -X, -5, -12, +der (5) t (5; 12) (q22; ql3), +der(3) t (3; ?) (ql2; ?), +3mar (100%)

45, XY, -7, - 13, - 16, - 17, del (4) (p 14), t (9; 20) (p 13;pll), +der(16)t(13; 16) (qll; qll), +der (17) t (7; 17)(q22; P13), +der (7) t (7; ?) (q22; ?) (92%)/RSCA (8%)

46, XY (83%)/83, XX, -Y, -Y, del (1) (p34), del (6)(ql3q21), inv (14) (ql Iq32), del (16) (ql3), der (1) t (1;?) (p36; ?), der (5) t (5; ?) (pl3; ?), der (5) t (5: ?) (q33:?), der (6) t (6; ?) (ql3; ?), etc. (17%)

5(6), 23(11)

5 (26), 26 (4)

5 (14), 24 (3), 26 (6)

5 (3), 23 (5)

24(5), 27

6(5)

6(7)

6(9)

2Â«(1)

28 (2)

1485



Table 1 Continued

Patient Center"Age,sex Source

No. ofcells


60

61

62

63

64

65

66

900

910

810

810

810

810

820

60M BM

66F

57M

37M

53F

65F

52M

PB

BM

LN

LN

LN

AS

20

15

30

32

23

26

15

67

68'

69'

70'

71

72

73

74

75

76

77

78

79

820

850

850

850

880

880

880

880

880

880

910

920

970

66F LN

49F LN

74M

35M

28F

53M

53M

62F

51M

59F

62F

LN

LN

PB

PB

LN

LN

LN

LN

LN

66M PB

67M LN

21

27

22

20

11

11

12

10

11

13

49

12

27

80

81

970

860

46F LN

42F BM

10

20

46, XY (15%)/46, X, -Y, -14, -15, del (5) (q31), del (7)(pl3), +der (14) t (14; ?) (q32; ?), +der (15) t (15; ?)(pli; ?), +mar (80%)/USCA (5%)

46, XX (60%)/48, XX, -7, -17, -18, -19, +der(7) t (7;?) (q32; ?), +der (11) t (11; ?) (pli; ?), +der (19) t (19;

), +3mar(40%)

46, XY (43%)/45, XY, +2, -4, -4, -7, -14, -19, -21,+ 4mar (20%)/RSCA (7%)/USCA (30%)

46, XY (6%)/50, XY, +7, -14, +del (6) (ql3q25), +der(14) t (14; ?) (q32; ?), +2mar (56%)/51, XY, +7, +12,-14, +del (6), +der (14), +2mar (16%)/RSCA (22%)

90, XXXX, der(l) t (1; ?)(pll; ?),der(l), der(l), 16mar,etc. (26%)/RSCA (74%)

49, XX, +4, +8, +18, t (2; 3) (q35; p23) (69%)/RSCA(31%)

44, -X, die (Y) (ql2), -2, -3, -4, -8, -10, +13, -14,-16, -17, -19, -19, del (5) (q31q33), i (7q), del (8)(p21), t (14; 18) (qll; pll), +psudic (4) t (4; 8) (pl6;p21), +der (X) t (X; ?) (p22; ?), +der (2) t (2; ?) (p23;?), +der (3) t (3; ?) (pl3; ?), +der Qg) t (10; ?) (pl5; ?)del (10) (q24), +der (14) t (14; ?) (pl2; ?), +der (16) t

46, XX (10%)/46, X, -X, -4, -11, -13, -14, -14, -16,del (7) (p 15), i (18q), +der (4) t (4; ?) (q3 1; ?), +der (11)t (1 1; ?) (q23; ?), +der (14) t (14; ?) (pl2; ?), +der (?) t(14; ?) (qll; ?), +3mar (90%)

47, XX, -2, -5, -6, +11, -12, -14, -16, -18, del (5)(ql 1), del (6) (qlS), del (10) (q24), +der (2) t (2; ?) (p25;?), +der (5) t (5; ?) (q31; ?), +der (6) t (6; ?) (p23; ?),+4mar (96%)/RSCA (4%)

46, XY (5%)/47, XY, +3 (90%)/RSCA (5%)

45, X, -Y (80%)/RSCA (20%)

46, XX (18%)/46, XX, -14, +der (14) t (14; ?) (q32; ?)(46%)/47, XX, -14, +del (1) (p 13), +der (14) (18%)/RSCA(18%)

45, X, -Y, -1, -6, -10, -13, -14, -17, -22, inv (14)(qllq32), +der (1) t (1; ?) (q32; ?), +der (14) t (14; ?)(q32; ?), +der (22) t (22; ?) (ql3; ?), +4mar (73%)/RSCA (18%)/USCA (9%)

46, XY (42%)/USCA (58%)

46, X, -X, -13, -14, del (6) (q21q23), +3mar (90%)/RSCA (10%)

46, XY (18%)/46, XY, t (2; 2) (p25; q21) (82%)

46, X, -X, -9, -14, +der (9) t (9; ?) (ql3; ?), +der (14) t(14; ?) (pi 1; ?), +mar (62%)/47, X, -X, -8, -9, -14,+21, +der (9), +der (14), +2mar (31%)/RSCA (7%)

46, XX (14%)/47, X, -X, -1, -3, -11, -14, -15, -16,-18, -22, +der (1 1) t (1; 11) (pl2; ql4), +der (15) t (1;15) (q21; pll), +der (1) t (1; ?) (pl2; ?), +der (3) t (3;?) (q21; ?), +der (3) t (3; ?) (P25; ?), +der (14) t (14; ?)(pll; ?), +der (16) t (1 1; 16) (ql4; ql3), +3mar (78%)/USCA (8%)

46, XY, -9, -14, -16, -18, del (6) (q22), del (7) (pll),del (10) (pi 3), +der (9) t (9; ?) (q34; ?), +der (14) t (14;?) (q32; ?), +der (16) t (16; ?) (ql3; ?), +der (18) t (18;?) (pll;?) (100%)

46,XY(19%)/45, Y,-X,-1, -3, -5, -9, -10, -15, -16,- 17, - 18, -20, del (3) (q 12q2 1), del (6) (q 15), +del (13)(q32), inv (14) (ql Iq32), +der (X) t (X; ?) (q26; ?), +der(3) t (3; ?) (pl3; ?), +der (5) t (5; ?) (pl3; ?), +der (9) t(9; ?) (pl3; ?), +der (10) t (1; ?; 10) (Ipter -Â»Ipl3::?::10pll -Â»lOqter), +der (?) t (1; ?) (q23; ?),+3mar(81%)

46, XX (20%)/89, XXX, -X, del (7) (pi 3), del (10) (pll),der (14) t (7; 14) (pi 3; pl3), der (2) t (2; ?) (p23; ?), der(8) t (8; ?) (p23; ?), mar etc. (

46, XX (100%)

29(3)

29(7)

19(1), 30 (B)

19(2)

31(2)

31 (S)

31(3)

31(6)

il (10)

31(9)

15(14), 16 (9), 29 (U)

15(15), 16(5), 29(6)

1486



CHROMOSOMES IN ADULT T-CELL LEUKEMIA/LYMPHOMATable 1 Continued

PatientCenter"Age, sexSourceNo.

ofcells

analyzedKaryotypeRÃ©f.'Chronic

(C) and smoldering (S)types828384'8586"878889"90"91"9293"94"9596979899100101102103104"10510610781083085085086086086087087087081087087087087087088088090097087081087087088087070M37M61F64F74M36M51F76M53M69F28MSOM54F72F60M62M64FSOM64M71M69F42F50F35F62F60FPBPBLNPBPBPBPBPBPBPBBMPBPBPBPBPBPBPBPBPBPBPBPBPBPBPB22527202217251010261713162081019472014231313102361846,XY, -19, +mar (64%)/RCA(36%)48,

Y, -X, +5, -7, -14, -14, +del (6) (ql4q21),+der(14)t (1; 14) (pi 1; q21), +der (3) t (3; ?) (q21; ?),+der(7)

t (7; ?) (pi 1; ?), +der (14) t (14; ?) (pi 1; ?)(60%)/46,Y, -X, -6, +der (3) t (3: ?) (ql2; ?), +der (6) t(6;48,

XX, +X, +4, -10, -12, -14, +18, -19, -21, del(3)(q2l),del (11) (q23), del (17) (q23), +der (10) t (10;?)(q22;

?), +der (12) t (12; ?) (q24; ?), +der (14) t (14;?)(q32;?), +der (21) t (21; ?) (pi 1; ?) (96%)/RSCA(4%)47,

XX, +3 (80%)/RSCA(20%)46,

XY (27%)/46, XY, del (8) (q24), t (9; 21) (p22; ql1)(73%)46,

XY (12%)/89, XXYY, del (6) (q21), der (6) t (6;?)(p23;?), der (13) t (13; ?) (pl3; ?), der (?) t (1; ?)(pli;?)

etc. (82%)/RSCA(6%)46,

XX (28%)/46, XX, inv (15) (pl3q22)(60%)/RSCA(12%)46,

XY (10%)/46, XY, inv ins (6) (p23q21ql3)(90%)46,

XY (10%)/47, XY, -7, del (1) (q32), del (6)(ql5q21).t(4; 5) (q33; ql3), +der (7) t (7; ?) (q22; ?), +der (18)t(18;

?) (q21; ?) (40%)/47, X, -7, inv dup (Y) (pter-Â»ql2::ql2-> ql 1:), del (1), del (6), del (13) (q22q32),t(4;

5), +der (7), +der (18) (30%)/RSCA(20%)46,

XX (92%)/46, XX, -10, del (6) (q21), +der (10) t(10;46,

XY (53%)/49, XY, -6, del (3) (ql3), +del (3),+3mar(12%)/USCA(35%)46,

XY (8%)/50, XY, +3, +6, +2mar(92%)46,

XX (44%)/47, XX, +X, -10, del (6) (ql5q21),+der(10)t (10; ?) (q26; ?) (25%)/46, XX, -10, del (6),+der(10)(I9%)/RSCA (6%)/USCA(6%)46,

XX (5%)/48, XX, -3, +22, del (10) (pl4), +der (3)t(3;?) (ql2; ?), +mar (90%)/USCA(5%)46,

XY (13%)/46, XY, -12, -13, +der (12) t (12; ?)(q22;?)

del (12) (pl2), +der (13) t (13; ?) (q34; ?)(87%)46,

XY (10%)/46, XY, -7, -14, del (6) (ql5q25),+der(7)t (7; ?) (q35; ?), +der (14) t (14; ?) (q32; ?)(90%)46,

XX (42%)/46, X, del (X) (q26) (16%)/USCA(42%)46,

XY (81%)/47, XY, +mar (6%)/RSCA(2%)/USCA(11%)46,

XY (45%)/47, XY, -4, -9, -9, -19, -21, -22,del(10)(p 13), +der (3) t (3; ?) (q29; ?), +der (4) t (4;?)(q21;

?), +der (19) t (19; ?) (pl3; ?), +4mar(45%)/USCA(10%)46,

XY (7%)/47, XY, +21, del (6) (ql5q21)(93%)46.

XX (13%)/46, XX, -7, -14, +20, -22, +der (7) t(7;14)(pi 1; ql 1), +der (14) t (14; ?) (q32; ?)(87%)46,

XX(100%)46,

XX (8%)/46, XX, dup (7) (q22 -Â»q32)(92%)46,

XX (10%)/46, XX, -10, t (3; 14) (q21; q32),+der(10)t(10;?)(q24;?)(90%)46,

XX (82%)/45, X, -X, (3%)/47, XX, +X(2%)/47,XX,+mar (1%)/USCA(12%)46,

XX, -19, t (1; 14) (p36; q32), +mar (55%)/45, X,-X(17%)/46,XX, -2, -14, del (10) (q22q24), +der (2)t(2;

?) (q37; ?), +der (14) t (14; ?) (q32; ?)(17%)/RSCA(11%)19(14)17(5)5

(7), 23 (14), 32(6)5

(4), 23 (6), 32(4)5(15)5

(17), 23 (13), 32(5)5(13)6(10)ÃŽ5(16),

/6(15)24(4)5(19)33

1487




Table 2 Clinical and laboratory findings in 107 patientswith ATL by clinical subtype

Table 4 Frequencies of numerical and structural chromosome abnormalities inpatients with ATL by clinical subtype

Subtype ofATLMale/femaleAge

(yr)MedianRangeWBC(xlOVliter)MedianRange%

of leukemic cells in peripheralbloodMedianRangeBone

marrowinvolvementLymphadenopathy

(%)Hepatomegaly(%)Splenomegaly(%)Skin

lesions(%)Highserum lÃ¡clatedehy-drogenase

(%)Hypercalcemia(%)Hyperbilirubinemia(%)Survival

(days)1*MedianRangeA+L45/3657(81)'24-8320.1

(81)3.1-287.041

(72)0-9680'

(69)85

(74)60(72)36(72)42(71)87

(70)45

(69)33(54)160

(75)5-2,748+C+S(n

=26)13/1360.5

(26)28-7612.4(26)4.6-130.020

(23)1-9081C(21)55

(22)14(21)10(21)23

(22)38(21)0(21)0(12)366

(25)4-4,426PNSÂ°NS<0.01<0.05NS<0.01<0.01<0.05NS<0.01<0.01<0.05<0.01

" NS, not significant.*Numbers in parentheses, number of cases for which relevant information was

available.' Percentage of cases with a positive finding.* From the day of the chromosome test. + after the number of days indicates

that the patient with the longest survival is still living.

Subtype ofATLNumerical

abnormalities'Gainofchromosomes'Lossofchromosomes'Total

of gains andlossesMarkerchromosomes'Structural

abnormalities'Translocations''*Translocations

withanunidentifiedsegment'Partial

deletionsOtherabnormalities'TotalA+Ln

=7559(0.79)f103

(1.37)162(2.16)98(1.31)n

=7861(0.78)158*(2.03)86(1.10)15320(4.10)C+Sn

=2411(0.46)1

1(0.46)22(0.92)14(0.58)n

=258(0.32)26(1.04)19

(0.76)053(2.12)Totaln

=9970114184112n=

10369184*IOSIS373PNS*<0.01<0.01<0.01<0.05<0.01NSNS<0.01

" Four cases with hypotetraploid karyotypes (3 in A+L and 1 in C+S) were

not included.* Each type of abnormality was counted only once when there were 2 or more

of the same abnormality.' Numbers in parentheses, average number per case.d NS, not significant.'Apparently identical marker chromosomes in a karyotype were counted

repeatedly, since whether or not they were truly identical was often unknown.f Different abnormalities on a chromosome were counted separately.'Includes 31 balanced and 24 unbalanced translocations, 10 inversions, one

pseudodicentric, one dicentric, one insertion, and one isochromosome whichapparently occurred in a chromosome with an inversion.

* Also includes 4 translocations in Cases 10, 12 (2 translocations), and 13, for

which the breakpoint was not exactly determinable.' Includes 4 isochromosomes, 2 derivative chromosomes each consisting of 2

whole arms from different chromosomes, and 9 chromosomes with a partialduplication.

Table 3 Number of abnormal clones and modal chromosome number of theprimary clone Â¡npatients with A TL by clinical subtype

Subtype ofATLNo.

of abnormalclones012

ormoreModal

chromosome no. oftheprimaryclone*<444546

(abnormal)4748-5383-90

(hypotetraploid)A+Ln

=813699(1)"n

=783814(17.9)'31193C+Sn

=261205(3)"n

=250112(48.0)'651Totaln=

10748914

(4)Â°n=

103392637244

* Numbers in parentheses, cases with unrelated clones (Cases 5, 83, 106, and

107).* Cases with 46 chromosomes (pseudodiploidy) were less frequent, and cases

with other numbers of chromosomes (aneuploidy) were more frequent (P< 0.01)in the A+L group than in the C+S group.

' Numbers in parentheses, percentage.

to this band, and it was seen in 19 cases. Other recurrentlyaffected bands included Ipil (7 cases), 3pl3, 7q22 and 18pll(6 cases each), Ipl3, Ip36, Iq23, 3ql2, 9p22, and 14pll (5cases each), and 2q37, 4pl6, 6p23, 6q21, 7q32, lOpl 1, 12ql3,and 17pl3 (4 cases each).

Deletion occurred most frequently on 6q (24 cases, 23%),followed by 10p (9 cases, 9%), 3q (8 cases, 8%), 5q, 9q, 13q,Ip, and 7p (Fig. 3; Table 5). The deleted segment on 6q involvedall or a part of 6q21 in 23 of 24 cases. Other overlapping deletedsegments included Ip36â€”Â»Ipter(6 cases), 7pl5â€”>7pter(6cases), and 10pl4â€”Â»lOpter(9 cases) (Fig. 3).

Structural abnormalities as a whole, preponderantly derivative chromosomes with an unknown segment (P < 0.01), andbalanced and unbalanced translocations (P < 0.05) occurredmore frequently in the A+L type than in the C+S type (Table

25-

20

15

ID

Chromosome 1234567"LOT.8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y

$ 10

Io'S

15-

20

Fig. 1. Distribution of 70 gains and 114 losses of whole chromosomes in 99cases of ATL with abnormal karyotypes. Four hypotetraploid cases were notincluded. Trisomies 3, 7, and 21 were more frequently observed than expected (/'< 0.01). Monosomy X in the female and loss of a Y in the male were also seenin increased frequencies (P< 0.01, respectively). Monosomy X in the female, lossof a Y in the male, and trisomy of 3 or 7 were more frequent in the A+L typethan in the C+S type, but with only borderline significance (0.05 < P < 0.10).

1488



CHROMOSOMES IN ADULT T-CELL LEUKEM1A/LYMPHOMA

Table 5 Major numerical and structural chromosome abnormalities in patientswith A TL by clinical subtype

Subtype ofATLNumerical

abnormalities+3+7+21-XFemaleMale-Y,

maleStructural

abnormalitiest(14qll)t(14q32)del(lp)del(3q)del(5q)del(6q)del(7p)del(9q)del(lOp)del(13q)A+Ln

=751910815/331/429/42n

=781325*667176776C+Sn

=242012/121/120/12n

=2514*02070021Totaln

=992110917/452/549/54n=

10314296g7246797PÂ°0.0620.0530.0760.0840.0950.094

"Obtained by Fisher's exact test. Values greater than 0.100 are not given.

Trisomy 3, trisomy 7, loss of an X in the female, loss of a Y in the male,translocation with a break in 14qll, and translocation with a break in 14q32occurred more frequently in the A+S type than in the C+S type, but only withborderline significance (0.05 < P < 0.10).

* One each in both groups had two 14q32 translocations (cf. Table 6).

4). Individually, however, translocations with a break in band14qll or band 14q32 were the only structural abnormalitiesthat occurred more frequently in the former than in the latter,although the incidences differed only with borderline significance (Table 5).

More than one of the aforementioned structural and numerical abnormalities occurred together in many cases. Besides thecases with inv(14q), 4 had rearrangements in both 14qll and14q32. Rearrangement in 14q32 was associated with mono-

somy X in 7 cases. Trisomy 3 and deletion in 6q21, andrearrangement in 14q32 and deletion in 10p, occurred togetherin 6 cases each. All these combinations occurred only in theA+L type.

Translocations and Inversions Possibly Involving the TCR orIGH Genes. Fourteen cases (14%) had translocations involvingband 14qll containing TCRA and TCRD gene loci (Fig. 2;Table 6). In addition, the 14ql 1 break occurred in 3 deletions(Fig. 3). Three cases may possibly have had a break in band7q35 where the TCRB gene has been assigned (Table 6).

Band 14q32 (sites of the IGH gene, AKT1, and a putativeprotooncogene TCL1) was involved in translocation (or inversion) with a known chromosome band in 12 cases and with anunknown chromosome segment in 19 (Table 6). A 14q32 breakalso occurred in an interstitial deletion (Fig. 3).

There were 39 balanced translocations, including 4 inversions, or unbalanced translocations, not listed in Table 6. Noneof these abnormalities was the same, although there were bandsin which breaks occurred in association with more than oneabnormality, as can be seen in Fig. 2.

Cases with a Single Chromosome Abnormality. Fourteen ATLcases had only a single abnormality. Three cases (Patients 39,69, and 85) had a single trisomy 3, which was the only singleabnormality that was seen in more than one patient. One caseeach had loss of an X (Patient 51) or a Y (Patient 70) chromosome as a single abnormality.

inv(15)(pl3q22) (Patient 88), inv ins(6)(p23q21ql3) (Patient89), dup(7)(q22-Â»q32) (Patient 104), del(X)(q26) (Patient 98),and t(2;2)(p25;q21) (Patient 75) were seen as a single structuralabnormality in one patient each. Two other cases (Patients 47

and 71) had a clone with a single structural abnormality[t(3;14)(p25;ql 1) and -14, +der(14)t(14;?)(q32;?), respectively]

and another clone with abnormalities additional to the primarychange. One patient (Patient 99) had an unknown markerchromosome as a single abnormality. One case (Patient 106)had 3 clones with different single abnormalities, i.e., one withloss of an X, one with additional X, and the other with a markerchromosome.

Additional Abnormalities. Two or more related clones weredetected in 10 patients (Patients 4, 35, 37, 47, 56, 63, 71, 76,90, and 94). Six trisomies, 6 monosomies, 7 deletions, 10derivative chromosomes, one reciprocal translocation, one inversion duplication, and 4 markers were seen as additionalabnormalities. No particular autosomes or chromosome bandswere specifically involved in additional abnormalities, eithernumerically or structurally. There was an excess of the involvement of sex chromosomes (2 monosomies X, 2 trisomies X,one missing Y, and an inversion duplication of a Y) as expected.

DISCUSSION

We reported here the clinical and cytogenetic findings obtained from 107 adequately studied ATL patients. These casesincluded almost all cases of ATL whose chromosomes had beenstudied by 1985 in Japan. The karyotypes and the clinicaldiagnoses were reviewed by a committee formed by the currentauthors. Ninety-eight % of the patients tested for anti-HTLV-I antibody showed a positive result. The clinical features of theHTLV-I-negative cases were the same as those of the antibody-positive patients (28, 36, 37).

Four cases showed only cells with a normal karyotype.Whether these were ATL cells or nonmalignant cells is uncertain. The fact that 3 cases had chromosomally unrelated clonesmay indicate that ATL could arise with a normal karyotype,and that chromosome abnormalities could appear later. Detec-

Table 6 Inversions and translocations possibly involving T-cell receptor orimmunoglobulin genes in 103 patients with ATL

AbnormalityNo. ofcases

Abnormalities probably affecting TCRA or TCRDgenes in Band 14qll

inv(14)(qllq32)der(l)t(l;14)(pl3;qll)t(3;14)(p25;qll)der(7)t(7;14)(pll;qll)

t(14;14)(qll;q32)

Abnormalities possibly affecting TCRB genes inBand 7q35

der(7)t(4;7)(qI2;q36)der(7)t(7;?)(q35;?)der(7)t(7;?)(q36;?)

Abnormalities possibly affecting IGH genes or aputative oncogene in Band 14q32

inv(14)(qllq32)t(l;14)(p36;q32)t(3;14)(ql2;q32)t(3;14)(q21;q32)t(5;14)(q22;q32)t(10;14)(q21;q32)t(14;14)(qll;q32)der(14)t(14;?)(q32;?)

6*Â»\'

a

19"

" Counted also for 14ql 1 abnormalities.*One case (Patient 72) also had der(14)t(14;?)(q32;?).' This case (Patient 107) also had der(14)t(I4;?)(q32;?).'One case (Patient 72) also had inv(14)(ql Iq32), and one other case (Patient

107) also had I(l;14)(p36;q32).

1489




IS 18

D

Q

3

17 18 18

Fig. 2. Distribution of chromosome breaks in 103 cases of ATL with abnormal karyotypes. The breaks in 4 hypotetraploid cases were also counted. A total of 139breaks due to 31 balanced and 24 unbalanced translocations, 10 inversions, and 4 other abnormalities (a pseudodicentric, a dicentric, an insertion, and a complexisochromosome) are depicted on the left, and 180 breaks due to translocations with unknown chromosome segments are depicted on the right of each chromosome.The exact breakpoints for derivative chromosomes of this type were not determinable (Table 4, Footnote h) and hence are not depicted here. Breaks occurred mostfrequently in band 14q32 (29 cases), followed by band 14ql 1(14 cases). Other recurrently affected bands included lpt1 (1 times); 3pl3, 3ql2, 7q22, and 18pl 1 (6times); Ipl3, Ip36, Iq23, 3ql2, 9p22, and 14pl 1 (5 times each); 2q37, 4pl6,6p23, 6q21, 7q32, lOpl 1, 12ql3, and 17pl3 (4 times each), etc. There were no recurrenttranslocations or inversions except for inv(14)(ql Iq32), which was observed in 6 cases.

tion of only normal or simple abnormal karyotypes at diagnosisand later appearances of complex karyotypes at relapse havebeen described in serially studied ATL patients (6, 28, 38). Thehigher incidence of aneuploidy in the aggressive A+L patientsthan in the nonaggressive C+S patients is a reflection of thedifference in the complexity of karyotypes between these 2groups. Previous studies on T-cell lymphomas or chronic T-cell leukemias have reported lower incidences of aneuploidclones than the present study (18, 39-42).

The present study demonstrated high frequencies of recurrentnumerical chromosome changes such as trisomies for chromosomes 3, 7, and 21 and monosomy for X in the female or lossof a Y in the male (Table 5; Fig. 1). Previous observations haveonly emphasized trisomy 3 (5, 6, 43) or 7 (6, 7, 43) as a majornumerical change in ATL. We do not really know whether ornot the loss of an X chromosome occurred depending on age;only 3 patients were less than 40 yr of age, and the incidenceof the loss in younger patients was not known. Although theincidence of numerical abnormalities as a whole, especially thatof chromosome loss, was significantly higher in the A+L typethan in the C+S type, no individual chromosomes were provento be involved more frequently in one group than in the otherwith any meaningful significance.

Recurrent chromosomal breaks in T-cell neoplasia includingATL have been reported to occur in bands 6ql5-q21 (5-8, 44-48), 14qll (5, 8, 45, 46, 49, 50), and 14q32 (5-8, 17, 45, 46).Also in this study structural abnormalities involving these bandswere most frequently observed (Figs. 2 and 3). inv(14)(ql Iq32)was the only recurrent rearrangement in the present series ofATL cases.

Partial deletions of chromosomes were most frequent in 6q,where all or a part of band 6q21 was commonly (in 23 of 24)deleted (Fig. 3). Deletion of 6q has been reported in lymphoidmalignancies including acute lymphoblastic leukemia and non-Hodgkin's lymphoma (18, 34, 39, 51). Particularly, it has been

found in a large proportion of Japanese cases of ATL (5, 34)or American cases of HTLV-I-positive leukemia-lymphoma(47), all or a part of band 6q21 being deleted in almost all thecases that had a 6q deletion. Since in no cases were consecutivechromosome studies done, we were not able to confirm theprevious findings that 6q abnormalities were associated withthe aggressive course, short survival and clinical parametersindicating these features, and also occurred in later stages (47,52). No difference existed in the incidence of 6q abnormalitiesbetween the A+L type and the C+S type in the present series.A gene (or genes) suppressing lymphomagenesis of ATL may

1490




5 6

i 817 IB 19 M 21 K X Y

Fig. 3. Distribution of 180 partial chromosomal deletions in 103 ATL patients with abnormal karyotypes. Deletion occurred most frequently on 6q, almost always(in 23 of 24) involving all or a part of 6q21. Overlapping deletion was also seen in segments Ip36â€”Â»Ipter(6 cases), 7pl5â€”>7pter(6 cases), 10pl4-Â»10pter (9 cases),

reside in 6q21. Protooncogene MYB is located in 6q22-23 (51).Band 6q22 was deleted in 18 of the 24 cases in our study, whichcontrasted to an observation (48) that this band was consistentlybordered by the chromosomal breakpoints, and that MYB sequences, which the investigators located precisely in 6q22, wereunaffected. Other recurrently deleted regions, such as Ip36-pter, 7pl5-pter, or 10pl4-pter, may also contain genes withsimilar tumor-suppressing effects. All or a part of 13ql4, theband in which the tumor suppresser gene RB (retinoblastoma)resides, was deleted in 4 of our cases.

Deletion or rearrangement of 7q has been reported in T-cellleukemias including ATL (7, 45). In this series no deletion of7q was observed (Fig. 3), although translocation and duplicationof 7q were seen in 11 and 2 patients, respectively.

Deletion 5q has been said to be rather common in lymphoiddisorders (53). The deletions were interstitial in 4 and terminalin 3 cases in our series, and they were not distinguishable fromthose found in myeloid disorders (53).

As in the case of numerical abnormalities, structural abnormalities occurred more frequently in the A+L than in the C+Stype as a whole; however, none of the translocations or deletionswas more frequently seen in the former than in the latter withacceptable significance. Marker chromosomes also occurredmore frequently in the former.

More than one of the numerical and structural abnormalitiesoften occurred in the same case in combination. Most frequentcombinations included rearrangement in band 14q32 and mon-osomy X or deletion lOp, and trisomy 3 and deletion in band

6q21. All these combinations occurred in cases in the A+Lgroup and may have been associated with the aggressiveness ofthe disease.

Some of the bands in which breaks recurrently occurredcontain loci for known or putative protooncogenes; MYB,MET, and AKT1 and TCL1 genes have been located to 6q22-q23, 7q31-q32, and 14q32, respectively (48, 51, 54, 55). Also,TCR genes have been shown to be rearranged with known orputative protooncogenes or unidentified genes in T-cell malignancy-associated chromosome translocations involving 14qll(TCRA and TCRD) and 7q35 (TCRB) (51, 54, 55). Theinv(14)(qllq32) and other 14q32 translocations have breakpoints in either the Kill locus or a region proximal to it, and,if the break occurred in the latter, may involve a T-cell-relatedprotooncogene (54, 55).

Trisomy 3 was the only single abnormality that appeared inmore than one patient. This trisomy was observed as a singleabnormality in 2 cases of T-cell diffuse mixed lymphoma besides an ATL patient at the fifth IWCL (34) and may meritconsideration as a primary change in T-cell malignancies.

In conclusion, the present study on a large number of ATLcases, whose karyotypes were reviewed by a panel of cytogene-ticists, provided evidence that the complexity of chromosomeabnormalities is associated with the clinical subtype of ATL,although none of the abnormalities found was proven to bespecificto ATL. The increase in the complexity of chromosomeabnormalities in the advanced, aggressive type of ATL suggeststhat many of the abnormalities seen in such a condition may

1491




have appeared with the evolution of the disease. Lack of recurrent single abnormalities (except for trisomy 3), apparentlyrandom occurrences of additional abnormalities, and ratherfrequent occurrences of chromosomally unrelated clones orsingle cell abnormalities may also indicate that the variouschromosome abnormalities observed, together with invisiblechanges, may constitute steps in the genesis and the progressionof ATL. These hypotheses should be ascertained by furthermolecular-cytogenetic analysis of ATL cells.

ACKNOWLEDGMENTS

We thank Dr. K. Araki, Ryukyu University, Dr. K. Fujita, KokuraMemorial Hospital, Dr. N. Tomono, Osaka Red Cross Hospital, Dr.T. Suchi, Aichi Cancer Center, Dr. M. Kikuchi, Fukuoka University,Dr. I. Miyoshi, Kochi Medical College, and Dr. H. Nagoshi, JikeiMedical College, for providing samples for chromosome study; members (Dr. S. Watanabe, Dr. M. Kikuchi, Dr. K. Nanba, Dr. T. Suchi,and Dr. A. Mikata) of the Lymphoma Pathology Panel of Japan forreviewing the pathology slides; and Dr. H. V'uniamolo for computer

analysis. We also thank Dr. N. Ochi-Takeuchi and Dr. K. Nishida fortheir cooperation in the karyotype review, Dr. N. Maseki for helpfuladvice, and N. Kobayashi for clerical assistance.

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1992;52:1481-1493. Cancer Res Nanao Kamada, Masaharu Sakurai, Kanji Miyamoto, et al. Leukemia/Lymphoma: A Karyotype Review Committee ReportChromosome Abnormalities in Adult T-Cell

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