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Complex karyotype including 14q+ marker in a case of Waldenström's macroglobulinemia
Complex Karyotype Including 14q + Marker in a Case of Waldenstr6m's Macroglobulinemia Juan Cruz Cigudosa, Maria Jos Calasanz, Carmen P rez, Jos Rifbn, Braulia Cuesta, and Arturo Gullon
ABSTRACT: We describe a case of WaldenstrSm's macroglobulinemia with a complex karyotype includ•ng a 14q + marker. Secondary changes affected chromosomes 2, 4, 6, 7, 8, and 17. The cytogenetic significance ef the changes and their prognostic value, as compared with these described in previous reperts, are discussed.
INTRODUCTION Waldenstr6m's macroglobulinemia (WM) is a proliferative disorder of lymphoid elements that have both surface and cytoplasmic IgM and also secrete substantial amounts of IgM. Other features of the disease are diffuse bone marrow (BM) infiltration by lymphoplasmatic cells, anemia, hepatosplenomegaly, and a hyperviscosity syndrome [1]. During the prebanding era, a large marker chromosome, similar in size to a group A chromosome, was detected in about 70% of reported patients with WM [2]. Since then, a few cytogenetic descriptions with banding techniques in WM have been reported [1, 3, 4]. After identification of the large marker chromosome as a deleted chromosome 3, by Contrafatto [5], more recent studies [6-9] failed to confirm the presence of any specific marker chromoseme in cases studied. Several suggestions have been made about the role of structural and numerical abnormalities of chromosomes 1 [6], 10, 11, 12 [7, 9], and 14 [4, 8] in this disorder. CASE REPORT
The propositus was a 62-year-old Spanish man admitted to our center in August 1992. A diagnosis of macroglobulinemia was made in another center in 1990 after a routine examination that showed monoclonal gammapathy (3.68 g/dl) with IgM: 12,000 mg/dl. Immunoelectrophoresis showed implication of the X-chain, and BM aspirate showed 22% infiltration by small lymphocytes and some loci of plasmatic cells. He was initially treated with chlorambucil which was changed to CVP (cyclophosphamide, vincristine, and pred-
From the Departments of Genetics (J. C. C., M. ]. C., C. E, A. G.) Hematology (J. R., B. C.), University af Navarro, Pamp|oma, Spain. Address reprint requests to: Dra. Maria Jos~ Calasanz, Department of Genetics, University of Navarra. Apdo. 273. 31080 Pamplona, Spain. Received May 10, 1993; accepted October 5, 1993.
nisone) because of the lack of reduction in the M-component and development of intense pancytopenia after six courses. At the time he was admitted to our center, the patient was extremely pale. Physical examination showed no other remarkable signs. Complete blood count showed red blood cell (RBC) count of 3.3 x 1012/L;hemoglobin level 10.8 g/dl; hematocrit 33.2; white blood cell (WBC) count 0.6 x 109/L, and platelet count 13 x 109. The serum IgM values were 7,270 mg/dl. BM biopsy showed massive infiltration by lymphocytes characterized by intense pyroninophilia. In November 1992, he received a new polychemotherapy course with vincristine, cyclophosphamide, melfalan, and prednisone associated with plasmapheresis. Clinical evolution was unfavorable, and the patient died 1 month later. CYTOGENETIC STUDIES We used the same BM sample to establish two different cultures: one with a B-cell mitogen (pokeweed) and one without mitogens. Metaphases were studied with GTG-banding. The International System for Human Cytogenetic Nomenclature was used to describe the karyotypes. Cytogenetic analysis of both B-cell-stimulated and unstimulated cultured showed normal metaphases (five of 70) and the following chromosome changes: 48,XY,der(2)del(2)(p12) t(2;11)(q32;q11),del(6)(q15q21),add(7p),i(8q),add(14q),, add (17p),.mar [29]/49,idem,+4 [36]. The abnormal chromosomes are shown in Figure 1.
DISCUSSION From the limited number of published cases of WM with chromosome abnormalities [1, 10], and the useful discussions of their nature stated by some authors [1, 3, 4, 8, 9], the information can be summarized as follows: First, no chromosome abnormality is specifically associated with this disorder, but t(8;14) and other alterations of 14q32 band may play a role, as in other lymphoproliferative disorders, in the genesis of 169
© 1994 Elsevier Science Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Cancer Genet Cytogenet 73:169-170 (1994) 0165-4608/94/$07.00
170
J . C . Cigudosa et al.
mality with the presence of a lymphoproliferative disorder (chronic l y m p h o c y t i c leukemia, m u l t i p l e myeloma); thus, WM is i n c l u d e d in this cytogenetic group. Secondary chromosome changes were either similar to those described by other investigators, such as add(Tp) [6], and add(17p) [4], or those newly reported such as trisomy 4, i(8q) or del(6q). The prognostic value of cytogenetic analysis was also confirmed by the short survival of this patient. It is unfortunate that the patient was referred to our center 2 years after initial diagnosis and that we could not perform the cytogenetic analysis in the early phase of the disease. We believe that an early cytogenetic study is the more desirable method to establish the primary chromosome changes in WM and the true meaning of such changes.
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2
REFERENCES
7
8
8m 14
17
mar
Figure 1 Partial G-banded karyotype showing der(2), del(6q), add(Tp), i(Sq), add(14q), add(17p), and marker chromosome. Arrows indicate abnormal chromosomes.
the disease [4, 8]. Second, the appearance of m u l t i p l e chromosome aberrations, probably associated with disease progression, correlates with poor prognosis and unfavorable outcome for the patient [9]. Our case confirms the above statements. A add(14q) marker indicates the putative relation of this chromosome abnor-
1. Sandberg AA (1990): The Chromosomes in Human Cancer and Leukemia, 2nd Ed. Elsevier Science Publishing Co., New York, pp. 658-659. 2. Sandberg AA (1980): The Chromosomes in Human Cancer and Leukemia. Elsevier North Holland, New York, pp. 377-425. 3. Heim S, Mitelman F (1987): Cancer Cytogenetics. Alan R. Liss, New York, pp. 188-189. 4. Nishida K, Taniwaki M, Misawa S, Abe T (1989): Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res 49:1275-1281. 5. Contrafatto G (1977): Marker chromosome of macroglobulinemia identified by G-banding. Cytogenet Cell Genet 18:370-373. 6. Ueshima Y, Fukerhara S, Nagai K, Uchino H (1983): Cytogenetics studies and clinical aspects of patients with plasma cell leukemia and leukemic macroglobulinemia. Cancer Res 43:905-912. 7. Han T, Emrich LJ, Ozer H, Sandberg AA (1985): Prognostic implication of trisomy 12 and non trisomy 12 karyotypes in B cell chronic lymphocytic leukemia. Blood 66:470-473. 8. San Roman C, Ferro T, Guzmfin M, Odriozola J (1985): Clonal abnormalities in patients with Waldenstr6m's macroglobulinemia with special reference to a Burkitt-type t(8;14). Cancer Genet Cytogenet 18:155-158. 9. Palka G, Spadano A, Geraci L, Horitoni G, Dragani A, Calabrese G, Guanciali Franchi P, and Stuppia L (1987): Chromosome changes in 19 patients with WaldenstrOm's macroglobulinemia. Cancer Genet Cytogenet 29:261-269. 10. Mitelman F (1991): Catalog of Chromosome Aberrations in Cancer, 4th ed. Wiley-Liss. New York.
ABSTRACT: We describe a case of WaldenstrSm's macroglobulinemia with a complex karyotype includ•ng a 14q + marker. Secondary changes affected chromosomes 2, 4, 6, 7, 8, and 17. The cytogenetic significance ef the changes and their prognostic value, as compared with these described in previous reperts, are discussed.
INTRODUCTION Waldenstr6m's macroglobulinemia (WM) is a proliferative disorder of lymphoid elements that have both surface and cytoplasmic IgM and also secrete substantial amounts of IgM. Other features of the disease are diffuse bone marrow (BM) infiltration by lymphoplasmatic cells, anemia, hepatosplenomegaly, and a hyperviscosity syndrome [1]. During the prebanding era, a large marker chromosome, similar in size to a group A chromosome, was detected in about 70% of reported patients with WM [2]. Since then, a few cytogenetic descriptions with banding techniques in WM have been reported [1, 3, 4]. After identification of the large marker chromosome as a deleted chromosome 3, by Contrafatto [5], more recent studies [6-9] failed to confirm the presence of any specific marker chromoseme in cases studied. Several suggestions have been made about the role of structural and numerical abnormalities of chromosomes 1 [6], 10, 11, 12 [7, 9], and 14 [4, 8] in this disorder. CASE REPORT
The propositus was a 62-year-old Spanish man admitted to our center in August 1992. A diagnosis of macroglobulinemia was made in another center in 1990 after a routine examination that showed monoclonal gammapathy (3.68 g/dl) with IgM: 12,000 mg/dl. Immunoelectrophoresis showed implication of the X-chain, and BM aspirate showed 22% infiltration by small lymphocytes and some loci of plasmatic cells. He was initially treated with chlorambucil which was changed to CVP (cyclophosphamide, vincristine, and pred-
From the Departments of Genetics (J. C. C., M. ]. C., C. E, A. G.) Hematology (J. R., B. C.), University af Navarro, Pamp|oma, Spain. Address reprint requests to: Dra. Maria Jos~ Calasanz, Department of Genetics, University of Navarra. Apdo. 273. 31080 Pamplona, Spain. Received May 10, 1993; accepted October 5, 1993.
nisone) because of the lack of reduction in the M-component and development of intense pancytopenia after six courses. At the time he was admitted to our center, the patient was extremely pale. Physical examination showed no other remarkable signs. Complete blood count showed red blood cell (RBC) count of 3.3 x 1012/L;hemoglobin level 10.8 g/dl; hematocrit 33.2; white blood cell (WBC) count 0.6 x 109/L, and platelet count 13 x 109. The serum IgM values were 7,270 mg/dl. BM biopsy showed massive infiltration by lymphocytes characterized by intense pyroninophilia. In November 1992, he received a new polychemotherapy course with vincristine, cyclophosphamide, melfalan, and prednisone associated with plasmapheresis. Clinical evolution was unfavorable, and the patient died 1 month later. CYTOGENETIC STUDIES We used the same BM sample to establish two different cultures: one with a B-cell mitogen (pokeweed) and one without mitogens. Metaphases were studied with GTG-banding. The International System for Human Cytogenetic Nomenclature was used to describe the karyotypes. Cytogenetic analysis of both B-cell-stimulated and unstimulated cultured showed normal metaphases (five of 70) and the following chromosome changes: 48,XY,der(2)del(2)(p12) t(2;11)(q32;q11),del(6)(q15q21),add(7p),i(8q),add(14q),, add (17p),.mar [29]/49,idem,+4 [36]. The abnormal chromosomes are shown in Figure 1.
DISCUSSION From the limited number of published cases of WM with chromosome abnormalities [1, 10], and the useful discussions of their nature stated by some authors [1, 3, 4, 8, 9], the information can be summarized as follows: First, no chromosome abnormality is specifically associated with this disorder, but t(8;14) and other alterations of 14q32 band may play a role, as in other lymphoproliferative disorders, in the genesis of 169
© 1994 Elsevier Science Inc. 655 A v e n u e of the Americas, N e w York, NY 10010
Cancer Genet Cytogenet 73:169-170 (1994) 0165-4608/94/$07.00
170
J . C . Cigudosa et al.
mality with the presence of a lymphoproliferative disorder (chronic l y m p h o c y t i c leukemia, m u l t i p l e myeloma); thus, WM is i n c l u d e d in this cytogenetic group. Secondary chromosome changes were either similar to those described by other investigators, such as add(Tp) [6], and add(17p) [4], or those newly reported such as trisomy 4, i(8q) or del(6q). The prognostic value of cytogenetic analysis was also confirmed by the short survival of this patient. It is unfortunate that the patient was referred to our center 2 years after initial diagnosis and that we could not perform the cytogenetic analysis in the early phase of the disease. We believe that an early cytogenetic study is the more desirable method to establish the primary chromosome changes in WM and the true meaning of such changes.
'hi" b6
2
REFERENCES
7
8
8m 14
17
mar
Figure 1 Partial G-banded karyotype showing der(2), del(6q), add(Tp), i(Sq), add(14q), add(17p), and marker chromosome. Arrows indicate abnormal chromosomes.
the disease [4, 8]. Second, the appearance of m u l t i p l e chromosome aberrations, probably associated with disease progression, correlates with poor prognosis and unfavorable outcome for the patient [9]. Our case confirms the above statements. A add(14q) marker indicates the putative relation of this chromosome abnor-
1. Sandberg AA (1990): The Chromosomes in Human Cancer and Leukemia, 2nd Ed. Elsevier Science Publishing Co., New York, pp. 658-659. 2. Sandberg AA (1980): The Chromosomes in Human Cancer and Leukemia. Elsevier North Holland, New York, pp. 377-425. 3. Heim S, Mitelman F (1987): Cancer Cytogenetics. Alan R. Liss, New York, pp. 188-189. 4. Nishida K, Taniwaki M, Misawa S, Abe T (1989): Nonrandom rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Res 49:1275-1281. 5. Contrafatto G (1977): Marker chromosome of macroglobulinemia identified by G-banding. Cytogenet Cell Genet 18:370-373. 6. Ueshima Y, Fukerhara S, Nagai K, Uchino H (1983): Cytogenetics studies and clinical aspects of patients with plasma cell leukemia and leukemic macroglobulinemia. Cancer Res 43:905-912. 7. Han T, Emrich LJ, Ozer H, Sandberg AA (1985): Prognostic implication of trisomy 12 and non trisomy 12 karyotypes in B cell chronic lymphocytic leukemia. Blood 66:470-473. 8. San Roman C, Ferro T, Guzmfin M, Odriozola J (1985): Clonal abnormalities in patients with Waldenstr6m's macroglobulinemia with special reference to a Burkitt-type t(8;14). Cancer Genet Cytogenet 18:155-158. 9. Palka G, Spadano A, Geraci L, Horitoni G, Dragani A, Calabrese G, Guanciali Franchi P, and Stuppia L (1987): Chromosome changes in 19 patients with WaldenstrOm's macroglobulinemia. Cancer Genet Cytogenet 29:261-269. 10. Mitelman F (1991): Catalog of Chromosome Aberrations in Cancer, 4th ed. Wiley-Liss. New York.