SHORT COMMUNICATIONS Acute Lymphoblastic Leukemia of Burkitt Type (L3) with a (14;18) and an Atypical (8;22) Translocation S. R. Smith, N. Bown, and J. P. Wallis
ABSTRACT: A 67-year-old man had night sweats, tumor lysis syndrome, and typical histologic and i m m u n o p h e n o t y p i c features of Burkitt-type acute lymphoblastic leukemia (ALL). Cytogenetic analysis showed a previously unreported karyotype, a combination of a (14;18) and an atypical (8;22) translocation.
INTRODUCTION
Burkitt-type acute lymphoma/leukemia (ALL) is a distinct clinicopathologic entity associated with a characteristic histologic appearance [1], a mature B-cell phenotype with expression of surface immunoglobulin (SIg) [2], and an abnormal karyotype [3]. The most frequent karyotypic abnormality noted in approximately 80% of cases of Burkitttype lymphoma/leukemia is t(8;14)(q24;q32); t(2;8)(pll;q24) and t(8;22)(q24;q11) occur less frequently. We describe a patient who had typical histologic and immunophenotypic features of Burkitt-type ALL and a rare karyotypic abnormality, a combination of a 14;18 and an atypical 8;22 translocation. CASE REPORT
A 67-year-old white man had a 3-month history of weight loss (14 kg), weakness, and sweats. No lymphadenopathy or hepatosplenomegaly was detected on physical examination. Initial peripheral blood (PB) count showed hemoglobin level of 105 g/L, a platelet count of 36 x 109/L, and a white blood cell (WBC) count 14.2 × 109/L. The PB smear showed a leukoerythroblastic picture with occasional blast cells. A bone marrow (BM) aspirate and biopsy demonstrated nearly complete replacement of the BM by an infiltrate of large blast cells with intensely basophilic and vacuolated cytoplasm, typical of Burkitt-type ALL [L3, French-American-British (FAB) classification] [1] (Fig. 1). Flow cytometric immunophenotyping (FACscan, Becton Dickinson) of the blast cells showed them to be HLA DR, CD 19, CD 20, and SIg positive; the blasts expressed an IgG k phenotype.
From the Department of Haematology, Freeman Hospital (S. R. S., J. P. W.), and Newcastle University Division of Human Genetics (N. B.), Newcastle upon Tyne, England. Address reprint requests to: Dr. S. R. Smith, Department of Haematology, Freeman Hospital, Freeman Rd., Newcastle upon Tyne, NE7 7DN, England. Received November 13, 1991; accepted January 22, 1992. © 1992 Elsevier Science P u b l i s h i n g Co., Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Metaphase preparations for cytogenetics were obtained by a standard protocol, and slides were G-banded with trypsin and Leishman's stain; 18 cells were studied. Chromosome analysis showed that two of the cells had a normal 46,XY karyotype whereas the other 16 cells had an abnormal karyotype; 47,XY,+ t(8;22)(q24;q1?),12,t(14;18) (q32;q21),+ace. These abnormalities are shown in Figs. 2 and 3. The 8q+ product conformed to the breakpoints of the well-recognized (8;22) translocation, but the 2 2 q - product did not. This chromosome is too large for a simple q l l breakpoint and includes an anomalous prominent dark G-band (clearly evident in Fig. 3, cell iii). A chromatid gap was noted at 22q12 in a single 46,XY cell. The patient was in renal failure on admission, with a serum creatinine of 378/zM (normal range 65-110/zM) and serum urate of 1.8 mM (normal range 0.16-0.43 mM). A chest radiograph and abdominal ultrasound failed to show any lymphadenopathy or hepatosplenomegaly. Serum LDH was 28,700 U/L (normal range 0-430 U/L). Renal function deteriorated rapidly, and the patient had a cardiorespiratory arrest and died before chemotherapy was started. A postmortem examination was not performed.
DISCUSSION
Our patient had the typical morphologic and immunophenotypic features of Burkitt-type ALL and metabolic features of massive tumor lysis. All three karyotypic abnormalities observed in Burkitt lymphoma/leukemia involve reciprocal rearrangements between the c-myc proto-oncogene on chromosome 8(q24) and immunoglobulin gene loci. The c-myc gene is thought to be activated transcriptionally as a consequence of its juxtaposition to an immunoglobulin light or heavy chain gene region [4]. Although in this case the 8q+ translocation product was typical of that reported in Burkitt leukemia/lymphoma, the 2 2 q - product involving the k light chain locus was not. We suspect that the acentric fragment observed in this case is a fragment of 22q and represents a complex variant of the (8;22)(q24;q11) translocation which occurs in Burkitt-type ALL. The obser197 Cancer Genet Cytogenet62:197-199 (1992) 0165-4608/92/$05.00
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S . R . Smith et al.
Figure 1 A May-Grunwald-Giemsa-stained bonemarrow smear (x 100) showing typical Burkitt-type acute lymphoblastic leukemia (L3) blast cells.
vation of a c h r o m a t i d gap at 22q12 lends support to the hypothesis that the origin of the fragment is chromosome 22; 22q12.2 is a c o m m o n a p h i d i c o l i n - i n d u c e d fragile site [5]. Although t(14;18) occurs in a p p r o x i m a t e l y 85% of follicular l y m p h o m a [6], our patient had no history or clinical evidence of a preceding follicular l y m p h o m a . In addition, none of the 18 cells e x a m i n e d s h o w e d either t(14;18) or t(8;22) as the sole karyotypic abnormality, w h i c h may suggest that in our patient these karyotypic abnormalities may have occurred s y n c h r o n o u s l y and not that the t(8;22) arose
Figure 2
by c]onal evolution from a p r i m a r y follicular B-cell lymphoma. Our patient had trisomy 12 as the other karyotypic abnormality, w h i c h frequently occurs as an additional abnormality in follicular l y m p h o m a , w h e n it m a y be associated with a poor prognosis [7]. The cooccurrence of t(8;22) and t(14;18) is rare. Three patients with both t(8;22) and t(14;18) were reported by Thangalevu et el. [8]; none had a history of preceding lowgrade disease and all expressed SIg, but only two had typical L3 morphology. Gluck et al. reported a patient with both translocations but with absent SIg [9], whereas Koduru et al. reported a patient with a large cell i m m u n o b l a s t i c l y m p h o m a with both t(14;18) and t(8;22) [10]. The (8;22) translocation is u s u a l l y associated with )t light chain expression [11, 12], but this case expressed K light chains, as did one of the cases reported by Thangalevu. The combination of translocations d o c u m e n t e d in our patient is unusual, and to our k n o w l e d g e this particular complex variant of the 8;22 translocation with an acentric fragment has not been reported. The reciprocal translocation between 8q24 and c h r o m o s o m e 22 with p r o d u c t i o n of the acentric fragment was associated with the typical morphologic and p h e n o t y p i c features of Burkitt-type (L3) ALL. Our patient had particularly aggressive disease and features of the massive t u m o r lysis syndrome. REFERENCES
1. Bennett J, Catovsky D, Daniel M, Fladrin G, Galton D, Gralnick H, Sultan C (1976): Proposals for the classification of the acute leukaemias. Br J Haematol 33:451-458. 2. Foon K, Todd R (1986): Immunologic classification of leukemia and lymphoma. Blood 68:1-31. 3. BernheiIn A, Berger R, Lenoir G (1981): Cytogenetic studies
Karyotype showing trisomy 12, t(14;18), t(8;22), and acentric fragment.
i| Sq+
Je
Ot
14q+
18q-
22q-
i
ace
Burkitt ALL w i t h t(14;18) and A t y p i c a l t(8;22)
199
(i)
(.)
4¢
(iii) 14q+
18q-
22q-
ace
8q+ Figure 3
4.
5.
6.
7.
8.
Partial karyotypes showing rearranged chromosomes in three other cells.
on African Bnrkitt's lymphoma cell lines: t(2;8) and t(8;22) translocations. Cancer Genet Cytogenet 3:307-312. Klein G (1989): Multiple phenotypic consequences of the Ig/ myc translocation in B cell derived tumours. Genes Chromosomes Cancer 1:3-8. Hecht F, Ramesh KH, Lockwood DH (1990): A guide to fragile sites on human chromosomes. Cancer Genet Cytogenet 44:37-45. Yunis J, Oken M, Kaplan M, Ensrud K, Howe R, Theologides A. (1982): Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphoma. N Engl ] Med 307:1231-1236. Yunis J, Frizzera G, Oken M, McKenna J, Theologides A, Aresen M. (1987): Multiple recurrent genomic defects in follicular lymphoma. N Engl J Med 316:79-84. Thangalevu M, Olopade O, Beckman E, Vardiman J, Larson R, McKeithan T, Le Beau M, Rowley J (1990): Clinical, morphologic, and cytogenetic characteristics of patients with lymphoid malignancies characterized by both t(14;18)
(q32;q21) and t(8;14)(q24:q32) or t(8:22)(q24;q11). Genes Chromosomes Cancer 2:1047-1158. 9. Gluck W, Bigner S, Borowitz M, Brenckman W (1986): Acute lymphoblastic leukaemia of Burkitt's type (L3 ALL) with 8;22 and 14;18 translocations and absent surface immunoglobulins. Am J Clin Pathol 85:636-640. 10. Koduru P, Filippa D, Richardson M, Jhanwar S, Chaganti S, Koziner B, Clarkson B, Leiberman P, Chaganti R (1987): Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97-102. 11. Lenoir G, Preud'homme J, Bernheim A, Berger R (1982): Correlation between immunoglobulin light chain expression and variant translocation in Burkitt's lymphoma. Nature 298:474-476. 12. Magrath I, Erikson J, Whang-Peng J, Sieverts H, Armstrong G, Benjamin D, Triche T, Alabaster O, Croce C (1983): Synthesis of kappa light chains by cell lines containing an 8;22 chromosomal translocation derived from a male homosexual with Burkitt's lymphoma. Science 222:1094-1098.
ABSTRACT: A 67-year-old man had night sweats, tumor lysis syndrome, and typical histologic and i m m u n o p h e n o t y p i c features of Burkitt-type acute lymphoblastic leukemia (ALL). Cytogenetic analysis showed a previously unreported karyotype, a combination of a (14;18) and an atypical (8;22) translocation.
INTRODUCTION
Burkitt-type acute lymphoma/leukemia (ALL) is a distinct clinicopathologic entity associated with a characteristic histologic appearance [1], a mature B-cell phenotype with expression of surface immunoglobulin (SIg) [2], and an abnormal karyotype [3]. The most frequent karyotypic abnormality noted in approximately 80% of cases of Burkitttype lymphoma/leukemia is t(8;14)(q24;q32); t(2;8)(pll;q24) and t(8;22)(q24;q11) occur less frequently. We describe a patient who had typical histologic and immunophenotypic features of Burkitt-type ALL and a rare karyotypic abnormality, a combination of a 14;18 and an atypical 8;22 translocation. CASE REPORT
A 67-year-old white man had a 3-month history of weight loss (14 kg), weakness, and sweats. No lymphadenopathy or hepatosplenomegaly was detected on physical examination. Initial peripheral blood (PB) count showed hemoglobin level of 105 g/L, a platelet count of 36 x 109/L, and a white blood cell (WBC) count 14.2 × 109/L. The PB smear showed a leukoerythroblastic picture with occasional blast cells. A bone marrow (BM) aspirate and biopsy demonstrated nearly complete replacement of the BM by an infiltrate of large blast cells with intensely basophilic and vacuolated cytoplasm, typical of Burkitt-type ALL [L3, French-American-British (FAB) classification] [1] (Fig. 1). Flow cytometric immunophenotyping (FACscan, Becton Dickinson) of the blast cells showed them to be HLA DR, CD 19, CD 20, and SIg positive; the blasts expressed an IgG k phenotype.
From the Department of Haematology, Freeman Hospital (S. R. S., J. P. W.), and Newcastle University Division of Human Genetics (N. B.), Newcastle upon Tyne, England. Address reprint requests to: Dr. S. R. Smith, Department of Haematology, Freeman Hospital, Freeman Rd., Newcastle upon Tyne, NE7 7DN, England. Received November 13, 1991; accepted January 22, 1992. © 1992 Elsevier Science P u b l i s h i n g Co., Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Metaphase preparations for cytogenetics were obtained by a standard protocol, and slides were G-banded with trypsin and Leishman's stain; 18 cells were studied. Chromosome analysis showed that two of the cells had a normal 46,XY karyotype whereas the other 16 cells had an abnormal karyotype; 47,XY,+ t(8;22)(q24;q1?),12,t(14;18) (q32;q21),+ace. These abnormalities are shown in Figs. 2 and 3. The 8q+ product conformed to the breakpoints of the well-recognized (8;22) translocation, but the 2 2 q - product did not. This chromosome is too large for a simple q l l breakpoint and includes an anomalous prominent dark G-band (clearly evident in Fig. 3, cell iii). A chromatid gap was noted at 22q12 in a single 46,XY cell. The patient was in renal failure on admission, with a serum creatinine of 378/zM (normal range 65-110/zM) and serum urate of 1.8 mM (normal range 0.16-0.43 mM). A chest radiograph and abdominal ultrasound failed to show any lymphadenopathy or hepatosplenomegaly. Serum LDH was 28,700 U/L (normal range 0-430 U/L). Renal function deteriorated rapidly, and the patient had a cardiorespiratory arrest and died before chemotherapy was started. A postmortem examination was not performed.
DISCUSSION
Our patient had the typical morphologic and immunophenotypic features of Burkitt-type ALL and metabolic features of massive tumor lysis. All three karyotypic abnormalities observed in Burkitt lymphoma/leukemia involve reciprocal rearrangements between the c-myc proto-oncogene on chromosome 8(q24) and immunoglobulin gene loci. The c-myc gene is thought to be activated transcriptionally as a consequence of its juxtaposition to an immunoglobulin light or heavy chain gene region [4]. Although in this case the 8q+ translocation product was typical of that reported in Burkitt leukemia/lymphoma, the 2 2 q - product involving the k light chain locus was not. We suspect that the acentric fragment observed in this case is a fragment of 22q and represents a complex variant of the (8;22)(q24;q11) translocation which occurs in Burkitt-type ALL. The obser197 Cancer Genet Cytogenet62:197-199 (1992) 0165-4608/92/$05.00
198
S . R . Smith et al.
Figure 1 A May-Grunwald-Giemsa-stained bonemarrow smear (x 100) showing typical Burkitt-type acute lymphoblastic leukemia (L3) blast cells.
vation of a c h r o m a t i d gap at 22q12 lends support to the hypothesis that the origin of the fragment is chromosome 22; 22q12.2 is a c o m m o n a p h i d i c o l i n - i n d u c e d fragile site [5]. Although t(14;18) occurs in a p p r o x i m a t e l y 85% of follicular l y m p h o m a [6], our patient had no history or clinical evidence of a preceding follicular l y m p h o m a . In addition, none of the 18 cells e x a m i n e d s h o w e d either t(14;18) or t(8;22) as the sole karyotypic abnormality, w h i c h may suggest that in our patient these karyotypic abnormalities may have occurred s y n c h r o n o u s l y and not that the t(8;22) arose
Figure 2
by c]onal evolution from a p r i m a r y follicular B-cell lymphoma. Our patient had trisomy 12 as the other karyotypic abnormality, w h i c h frequently occurs as an additional abnormality in follicular l y m p h o m a , w h e n it m a y be associated with a poor prognosis [7]. The cooccurrence of t(8;22) and t(14;18) is rare. Three patients with both t(8;22) and t(14;18) were reported by Thangalevu et el. [8]; none had a history of preceding lowgrade disease and all expressed SIg, but only two had typical L3 morphology. Gluck et al. reported a patient with both translocations but with absent SIg [9], whereas Koduru et al. reported a patient with a large cell i m m u n o b l a s t i c l y m p h o m a with both t(14;18) and t(8;22) [10]. The (8;22) translocation is u s u a l l y associated with )t light chain expression [11, 12], but this case expressed K light chains, as did one of the cases reported by Thangalevu. The combination of translocations d o c u m e n t e d in our patient is unusual, and to our k n o w l e d g e this particular complex variant of the 8;22 translocation with an acentric fragment has not been reported. The reciprocal translocation between 8q24 and c h r o m o s o m e 22 with p r o d u c t i o n of the acentric fragment was associated with the typical morphologic and p h e n o t y p i c features of Burkitt-type (L3) ALL. Our patient had particularly aggressive disease and features of the massive t u m o r lysis syndrome. REFERENCES
1. Bennett J, Catovsky D, Daniel M, Fladrin G, Galton D, Gralnick H, Sultan C (1976): Proposals for the classification of the acute leukaemias. Br J Haematol 33:451-458. 2. Foon K, Todd R (1986): Immunologic classification of leukemia and lymphoma. Blood 68:1-31. 3. BernheiIn A, Berger R, Lenoir G (1981): Cytogenetic studies
Karyotype showing trisomy 12, t(14;18), t(8;22), and acentric fragment.
i| Sq+
Je
Ot
14q+
18q-
22q-
i
ace
Burkitt ALL w i t h t(14;18) and A t y p i c a l t(8;22)
199
(i)
(.)
4¢
(iii) 14q+
18q-
22q-
ace
8q+ Figure 3
4.
5.
6.
7.
8.
Partial karyotypes showing rearranged chromosomes in three other cells.
on African Bnrkitt's lymphoma cell lines: t(2;8) and t(8;22) translocations. Cancer Genet Cytogenet 3:307-312. Klein G (1989): Multiple phenotypic consequences of the Ig/ myc translocation in B cell derived tumours. Genes Chromosomes Cancer 1:3-8. Hecht F, Ramesh KH, Lockwood DH (1990): A guide to fragile sites on human chromosomes. Cancer Genet Cytogenet 44:37-45. Yunis J, Oken M, Kaplan M, Ensrud K, Howe R, Theologides A. (1982): Distinctive chromosomal abnormalities in histologic subtypes of non-Hodgkin's lymphoma. N Engl ] Med 307:1231-1236. Yunis J, Frizzera G, Oken M, McKenna J, Theologides A, Aresen M. (1987): Multiple recurrent genomic defects in follicular lymphoma. N Engl J Med 316:79-84. Thangalevu M, Olopade O, Beckman E, Vardiman J, Larson R, McKeithan T, Le Beau M, Rowley J (1990): Clinical, morphologic, and cytogenetic characteristics of patients with lymphoid malignancies characterized by both t(14;18)
(q32;q21) and t(8;14)(q24:q32) or t(8:22)(q24;q11). Genes Chromosomes Cancer 2:1047-1158. 9. Gluck W, Bigner S, Borowitz M, Brenckman W (1986): Acute lymphoblastic leukaemia of Burkitt's type (L3 ALL) with 8;22 and 14;18 translocations and absent surface immunoglobulins. Am J Clin Pathol 85:636-640. 10. Koduru P, Filippa D, Richardson M, Jhanwar S, Chaganti S, Koziner B, Clarkson B, Leiberman P, Chaganti R (1987): Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97-102. 11. Lenoir G, Preud'homme J, Bernheim A, Berger R (1982): Correlation between immunoglobulin light chain expression and variant translocation in Burkitt's lymphoma. Nature 298:474-476. 12. Magrath I, Erikson J, Whang-Peng J, Sieverts H, Armstrong G, Benjamin D, Triche T, Alabaster O, Croce C (1983): Synthesis of kappa light chains by cell lines containing an 8;22 chromosomal translocation derived from a male homosexual with Burkitt's lymphoma. Science 222:1094-1098.
