Chromosomes in Acute Lymphocytic Leukemia

D.K. Hossfeld

ABSTRACT Results of chromosome analysis in acute lymphocytic leukemia are reviewed. Emphasis is placed on so-called specific translocations and their association with cytology, immunol- ogy, and prognosis. Data presently available suggest that chromosomes in acute lymphocytic leukemia are not only an important, independent prognostic factor, but also contribute to a new understanding of leukemic cell origin and pathway, which may enable us to overcome the limitations of present classification schemes.

INTRODUCTION

The task of reviewing chromosomal findings in acute lymphocytic leukemia (ALL) is not an easy one, not only because a number of comprehensive reviews and re- ports have been published in recent years [1-6], but also due to the fact that many cases have been communicated twice or even more times. Nevertheless, an increas- ing number of specific structural changes plus the realization among clinicians that chromosomes represent an important prognostic factor in ALL justify another re- view.

MODAL CHROMOSOME NUMBER

In Table 1 data collected at the Third International Workshop on Chromosomes in Leukemia [1] and by Secker-Walker [5] are presented. No numerical or structural changes can be detected in 30%-40% of both children and adults with ALL, a figure not very different from that in the prebanding era. Roughly one-third of adult pa- tients have a pseudodiploid chromosome consti tut ion in their leukemic cells; this figure is lower in children. Among children, however, a higher proportion of cases with more than 50 chromosomes can be found. Hypodiploidy continues to be rare in ALL compared with acute myelocytic leukemia (AML), where it occurs in about 20% of the cases. Thus, Sandberg's early statement [7] that a leukemia with more than 50 chromosomes is probably not myeloid and a leukemia with hypodiploidy is unlikely to be lymphatic in nature still holds true.

Though hypodiploidy is unusua l in ALL, extreme chromosome loss with chro- mosome numbers as low as 24 is almost restricted to ALL and the lymphoid type of the blastic phase of chronic myelogenous leukemia (CML) [8]. Such near-haploid ALL, remarkably, have several features in common: Most patients are adults. This corresponds to the observation that the FAB-type is usually L2 with an immuno-

From the Department Oncology and Hematology, Medical University Clinic, Hamburg, Germany.

Address requests for reprints to Dr. D. K. Hossfeld, Department of Oncology and Hematol- ogy, University Clinic, Martinistrasse 52,2000, Hamburg 20-08, West Germany.

Received June 29, 1986; Accepted July 9, 1986.

59

© 1987 Elsevier Science Publishing Co., Inc. Cancer Genet Cytogenet 26:59-64 (1987) 52 Vanderbilt Ave., New York, NY 10017 0165-4608/87/$03.50

60 D.K. Hossfeld

Table 1 Modal chromosome numbers in AL

Children S.-W. Adults S.-W. TIWCL [5] TIWCL [51

Normal 37.6 32.8 30.6 38.3 Pseudodiploid 29.9 22.0 39.3 28.8 Hyperdiploid (47-50) 11.5 12.9 12.7 12.1 Hyperdiploid (>50) 15.9 26.2 9.3 5.2 Hypodiploid 5.1 4.6 8.1 8.2 Number of cases 157 350 173 73

TIWCL. Third International Workshop on Chromosomes in Leukemia.

Data summarized from [1] and [5].

phenotype of C-ALL. The sex chromosomes are almost always kept, which is also true for chromosome pair #21 and, less frequently, for pairs #10, #14, and #18. Misawa et el. [8] pointed out that these are the chromosomes that also contribute to hyperdiploidy, particularly when more than 50 chromosomes are encountered. Structural chromosomal changes are seldom associated with near-haploidy. The prognosis of such patients is poor.

Chromosomes leading to hyperdiploidy--according to the Third Workshop--are mainly #6, #8, #18, and #21. Hypodiploidy is frequently due to loss of #7 and #20. Trisomy 8, as well as monosomy 7, were unexpected findings at the Third Workshop, because both changes had been considered to be typical for myeloid disorders. However, cases with trisomy 8 appear to be overrepresented at the Third Workshop; an analysis of individual reports does not substantiate this finding [2, 3, 5, 6]. It has been said that structural anomalies are uncommon in cases with more than 50 chromosomes per metaphase; this is only relatively so, relative to the num- ber of chromosomes; regarding individual cases, structural changes occur in the great majority [9]. Chromosomes most frequently involved in structural abnormali- ties are #1, #4, #6, #8, #11, #14, and #22. These chromosomes also participate in specific translocations, which will be discussed below.

The presence or absence of normal metaphases in the bone marrow of ALL pa- tients was studied carefully by the Third Workshop [1] because of its prognostic significance in AML. It was found (Table 2) that in chi ldren the proportion of pa- tients with exclusively normal (NN) or some normal (NA) metaphases was higher, and the proportion of patients with exclusively abnormal (AA) metaphases lower than in adults. In children, however, such a differentiation was unrelated to remis- sion rate, remission duration, and survival, whereas, in adults, NN patients had

Table 2 Normal/abnormal metaphases

ALL

Children Adults AML

NN 38.1 30.6 46.5 NA 49.7 43.9 31.4 AA 12.3 25.4 22.3 Number of 157 350 660

cases

Data summarized from [1] and the Fourth Interna- tional Workshop on Chromosomes in Leukemia [201.

Chromosomes in ALL 61

higher remission rates and longer survival times than NA and AA patients. There was no prognostic difference whatsoever between NA and AA patients, in either in children or in adults with ALL. Thus, in ALL the course of the disease is influenced much more by the extent of numerical anomalies and the type of structural chro- mosome anomalies than by the presence or absence of norrhal metaphases.

Karyotypic instability is a phenomenon that occurs in ALL considerably more frequently than previously anticipated. In relapse a great variety of additional or new findings can be demonstrated in 30%-80% of the patients [3, 6, 10, 11]. It is probably an exception that an NN or AA patient retains the original karyotype upon relapse. Usually, karyotypic progression will be observed (i.e., a change from NA to AA or the acquisition of additional numerical or structural anomalies superimposed on the initial karyotype). However, the emergence of new clones, the disappearance of initial clones, and even "normalization" have been documented. Particularly the latter observation, a conversion of an initial AA status to an NN status in relapse, is difficult to understand. And yet it simply means that a leukemic cell may also have a seemingly normal karyotype, that an abnormal karyotype does not necessar- ily provide a growth advantage to the leukemic cells, and that ALL, too, may be a polyclonal disease. The latter notion is corroborated by the fact that two or more clones, some that can be very small and barely detectable, are found in at least 30% of the cases at diagnosis [3, 6, 11].

"SPECIFIC" TRANSLOCATIONS IN ALL

As long as we continue to define ALL morphologically (including cytochemically), the term "specific" is inadequate for the majority of translocations detected so far. The PH chromosome, for instance, obviously is not specific for ALL. The translo- cation t(8;14) is not restricted to L3-ALL, but occurs also in the majority of Burkitt's lymphomas, i.e., small noncleaved non-Hodgkin lymphoma, and in some rare cases of large noncleaved lymphomas, as well as immunoblastic sarcomas [12]. Cells with t(4;l l) may have myeloid or monocytoid features, such as a positive Sudan black stain [13], or Auer rods, or increased serum lysozyme [14]. These observations do not mitigate against the significance of so-called specific translocations in ALL; rather, they uncover the limitations of morphology and cytochemistry. We had to learn that specific translocations are not markers of clinically and morphologically defined diseases but very important markers of leukemic cell origin or pathway. With these reservations in mind, some of these "specific" translocations will be discussed.

The t(9;22)(q34;qll) and Ph, can be observed in about 20% of adult ALL, but only in about 5% of childhood ALL. Accordingly, it is associated with L2 in adults and L1 in children, because L2 is the predominant morphologic type in adults and L1 in children. Immunophenotypical ly the cells carrying the Ph have characteristics of B-cell precursors, i.e., they have no intracytoplasmic immunoglobulin; cALLa, TdT, and HLA-DR are positive. With regard to the karyotype, it is notable that ad- ditional structural and numerical anomalies are seen in about 50% of the cases, the NA status in 75%, and that an i(17q) has not been described yet in Ph-positive ALL [15]. In both children and adults the Ph signals an unfavorable course [1, 4].

The t(8;14)(q24;q32) is not bound to a particular age distribution. The morphol- ogy is invariably L3 and immunophenotyping shows B features, i.e., surface im- munoglobulin can be demonstrated and the cells react strongly with the pre-B markers BA4 and BA1. Variant translocations occur in a frequency comparable to CML (10%); depending on the type of variant translocation either kappa (2;8) or lambda (8;22) light chains are expressed. Translocations involving more than two chromosomes including #8 and #14 have been described [12]. Additional chro-

62 D.K. Hossfeld

mosome anomalies can be found in 60%-75% of the patients; they appear to be more frequent in lymphomas than in ALL. Structural changes are more common than numerica l ones, the former involve mainly chromosome #1, the latter a gain of #7 [12]. Patients with t(8;14) or its variants rarely survive 1 year [1, 9, 12].

Patients with t(4;11) have a b imodal age distr ibution. They are, with very few exceptions, either younger than 18 months or older than 10 years [16]. Both age groups have a very characterist ic cl inical picture, namely a greatly expanded leu- kemic mass with extreme leukocytosis and splenomegaly. Morphology is usual ly L2, sometimes L1; very rarely the cells reveal myelomonocyto id features, as indicated previously. Immnnopheno typ ing disclosed that most of the patients with t(4;11) do not have ALL, but a very undifferent ia ted myelomonocyt ic leukemia [13, 14]. The karyotypic stabil i ty of this subgroup is remarkable; in reviewing the literature, Ko- cova et al. [16] recent ly found that only two of 32 patients showed addi t ional anom- alies at the time of diagnosis. Upon relapse, however, karyotypic progression is common [16, 17]. Survival t imes of more than 20 months are the except ion among patients with this t ranslocat ion [1, 16, 17].

The t(1;19)(q23;p13) is a new finding described at almost the same t ime by Mi- chael et al. [18] and Wil l iams et al. [19]. Too few cases are known so far to make meaningful generalizations. Patient age appears to be variable; morphology in the 12 cases publ i shed was L1 in ten and L2 in two patients. Immunopheno typ ing suggests a pre-B origin of the cells with this translocation; cytoplasmatic immuno-

Figure 1 Hyperdiploid karyotype of a female patient with pre-B ALL characterized by 47,XX,-19, + der(19},t(1;19)(q23;p13), + 21.

l i ! i i t 1 3 4 5

6 7 8 9 10 12

i 11

13 14 15 16 17 18

19 20 21 22

Chromosomes in ALL 63

globulin was weakly posi t ive as was cALLa; six of seven cases tested were HLA-DR positive. Our case revealed to be cALLa but posit ive for BA1 and BA4. Besides the translocation, ten of 13 patients, inc luding our observation (Fig. 1), showed addi- tional, most ly structural, abnormali t ies . According to Michael et al. [18] prognosis appears to be unimpai red .

The t(11;14)(p13;q13) also was publ i shed for the first t ime by Wil l iams et al. [19]. They presented four such cases, and we can contr ibute a fifth. All patients of Wil l iams et al. were children; our pat ient was 23 years old. Morphology was L1 in three and L2 in two cases. Al l patients had a OKT4-, 8-, 10-, and 11-positive phe- notype. One pat ient of Wil l iams et al. exhibi ted a del(6q) in some of the meta- phases. Our patient had a del(1)(p21) in 30% of the spreads in addi t ion to the t(11;14)(Fig. 2). Our patient survived for only a short time. No addi t ional informa- tion is available regarding prognosis.

SUMMARY

Results presented by Secker-Walker [5] and later obtained at the Third International Workshop [1] demonstrate that the knowledge of the chromosome const i tut ion of a pat ient wi th ALL can be a valuable tool in the hands of the physic ian

Figure 2 Pseudodiploid karyotype of a male patient with T-ALL showing a t(11;14) (p13;q13) as the sole anomaly.

1 2 3

i l It 4 5

6 7 8 9 i0 11 12

13 14 15 16

| I i i

19 20 21

17 18

22

6 4 D.K. Hossfeld

car ing for s u c h pa t i en t s . It m a k e s ava i l ab le for h i m p r i m a r i l y a power fu l , i n d e p e n - den t p r o g n o s t i c factor . N e w e r f i nd ings i n d i c a t e t ha t spec i f ic s t r u c t u r a l c h a n g e s wi l l lead to a be t t e r u n d e r s t a n d i n g of the p a t h o p h y s i o l o g y of h e m a t o p o i e s i s , in genera l , a n d in ALL, in pa r t i cu la r .

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