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Deletion of the long arm of chromosome 20 in a patient with small cell lymphocytic lymphoma
Deletion of the Long Arm of Chromosome 20 in a Patient with Small Cell Lymphocytic Lymphoma Philip D. Cotter, Paul Tumewu, and Peter J. Browett
ABSTRACT: Cytogenetic analysis of bone marrow from an 80-year-old woman with small cell lymphocytic l y m p h o m a revealed o del(20)(q11.2) as the sole cytogenetic abnormality. Del(2Oq) is found almost exclusively in myeloid disorders and this case represents a rare occurrence in a non-myeloid disorder.
INTRODUCTION Small cell lymphocytic lymphoma (SCLL) is a low-grade nonHodgkin's lymphoma characterized by the clonal proliferation of small cells that resemble resting, mature lymphocytes in appearance [1]. In the majority of cases, the lymphocytes are of B-cell origin with an immunophenotype similar to that documented in chronic lymphocytic leukemia [2]. Characteristic cytogenetic abnormalities in SCLL include loss of chromosome 9, trisomy 12, and translocations and rearrangements involving chromosome bands 14q32 and 11q21-22 [3-5]. CASE REPORT An 80-year-old woman, with a 6-year history of an IgG paraprotein, was noted to have generalized lymphoadenopathy when admitted with gastro-intestinal tract bleeding and left ventricular failure. A full blood count revealed hemoglobin 7.4 g/dL, white blood cell count 5.9 x 109/L (normal differential), and platelets 91 × 109/L. The IgG kappa paraprotein was quantitated at 33 g/L. Serum calcium and creatinine were both normal and urine examination was negative for Bence-Jones protein. A chest radiograph showed cardiomegaly and early left ventricular failure; compression fractures of the 7th and 10th thoracic vertebrae were also noted. Ultrasound of the abdomen and pelvis revealed the spleen to be at the upper limit of normal, measuring 13 cm in length. No significant intraabdominal lymphadenopathy was seen, Bone marrow biopsy showed infiltration by small welldifferentiated lymphocytes, some of which showed plasmacytold features. Cell marker studies by indirect immunofluo-
rescence confirmed a B-cell immunophenotype (CD19 = 73%, CD20 = 76%, IgG = 80%) with kappa light-chain restriction. Fine needle aspirate of a left axillary lymph node showed infiltration by lymphocytes with a similar morphology and immunophenotype. The patient received red cell transfusions to maintain her hemoglobin and general supportive care. She died 12 months later from bilateral bronchopneumonia and left ventricular failure secondary to ischemic heart disease. Cytogenetics Cytogenetic analysis was performed on GTG-banded metaphases derived from 24-hour and fluorodeoxyuridine-synchronized bone marrow cultures. An abnormal clone, 46,XX, del(20)(q11.2), (Fig. 1) was found in 29 of 30 cells examined. One cell was 46,XX. DISCUSSION Deletions of the long arm of chromosome 20 are most often associated with hematologic disorders of the myeloid lineage. Del(20q) is a common finding in polycythemia vera [6] and is also frequently encountered in acute myeloid leukemia and myelodysplasia [7]. Reports of del(20q) and rearrangements involving 20q in lymphoproliferative disorders are uncommon [8]. A number of isolated cases of del(20q) in non-Hodgkin's lymphomas have been reported in the literature, including: a diffused
F i g u r e 1 Partial karyotype showing the normal and del(20q) chromosomes from bone marrow of a patient with SCLL.
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i:: :
i~i!/ili:i/:~
From the Cytogenetics Department, Princess Mary Childrens'Hos-
pital (P. D. C., P. T.), and Department of Haematology, Auckland Hospital (P. ]. B.), Auckland, New Zealand. Address reprint requests to: Philip D. Cotter, Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, 100th Street & 5th Avenue, New York, N.Y. 10029. Received April 27, 1993; accepted June Z 1993.
142 Cancer Genet Cytogenet 70:142-143 [1993} 0165-4608/93/$06.00
© 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Del(20q) in SCLL large cell (histiocytic) l y m p h o m a w i t h m u l t i p l e cytogenetic a b n o r m a l i t i e s i n c l u d i n g two del(20)(q12) [9]; del(20q) w i t h m u l t i p l e cytogenetic abnormalities from bone marrow of a patient w i t h a T-cell l y m p h o m a [10]; and del(20q) and t(8;14) in a m a l i g n a n t l y m p h o m a [11]. Of interest, del(2Oq) was nonr a n d o m l y associated with diffuse small cleaved cell lymphomas a n d correlated w i t h the histiologic subtype in six cases [12]. This case is the first report of del(20q) associated w i t h small cell (well-differentiated) l y m p h o c y t i c l y m p h o m a . Alt h o u g h cytogenetic analysis was performed on bone marrow from our patient, the high percentage of B cells in the marrow (80%) a n d that the abnormal clone accounted for almost all cells a n a l y z e d leads us to believe that the del(20q) clone r e p r e s e n t e d the clonal m a l i g n a n c y derived from the lymphoma. Previous reports, based on cytogenetic and molecular evidence, have suggested that the a b n o r m a l i t y in 2 0 q - chrom o s o m e s may be an interstitial deletion rather t h a n a terminal deletion [13, 14]. At the r e s o l u t i o n used, we were unable to determine w h e t h e r the d e l e t i o n was interstitial in our patient. Heterogeneity has been noted for the loss of the c-src proto-oncogene on 20q in patients w i t h the del(20q) chrom o s o m e , l e a d i n g to s p e c u l a t i o n that deletions or rearrangements of c-src may be involved in the pathogenesis of the n e o p l a s i a in some patients w i t h del(20q) [13, 14]. Alternatively, loss of heterozygosity or rearrangements of the hematopoietic cell kinase gene, w h i c h m a p p e d to the region 20q11-*q12 [15], or of some other gene in that region, could p o t e n t i a l l y be involved. In summary, reported is a case of an 80-year-old w o m a n with a well-differentiated small cell lymphocytic lymphoma. Del(20)(q11.2) was the sole cytogenetic a b n o r m a l i t y found in bone marrow from this patient. This represents one of only a few cases of del(20q) in a l y m p h o i d disorder a n d the first report of del(20q] in a patient with SCLL. Prospective studies w i l l be required to determine w h e t h e r the del(20q) abnorm a l i t y is of diagnostic or prognostic significance in lymphomas. However, it is interesting to speculate that abnormalities of either the proto-oncogene c-src or the hematopoietic cell k i n a s e gene may be implicated in the pathogenesis of this t y p e of l y m p h o m a .
REFERENCES 1. Non-Hodgkin's lymphoma pathologic classification project (1982): National Cancer Institute sponsored study of classifica-
143
2.
3.
4. 5.
6.
7.
8. 9.
10.
11.
12.
13.
tion of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135. Spier CM, Grogan TM, Fielder K, Richter L, Rangel C (1986): Immunophenotypes in "well-differentiated" lymphoproliferative disorders, with emphasis on small lymphocytic lymphoma. Hum Pathol 17:1126-1136. Fifth International Workshop on Chromosome in LeukemiaLymphoma (1987): Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Blood 70:1554-1564. Speaks SL, Sanger WG, Linder J, Johnson DR, Armitage JO, Weisenburger D, Purtilo D (1967): Chromosomal abnormalities in indolent lymphoma. Cancer Genet Cytogenet 27:335-344. Offit K, Jhanwar SC, Ladanyi M, Filippa DA, Chaganti RSK (1991): Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: Correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment. Genes Chrom Cancer 3:189-201. Diez-Martin JL, Graham DL, Petitt RM, Dewald GW (1991): Chromosome studies in 104 patients with polycythemia vera. Mayo Clin Proc 66:287-299. Davis MP, Dewald GW, Pierre RV, Hoagland HC (1984): Hematologic manifestations associated with deletions of the long arm of chromosome 20. Cancer Genet Cytogenet 12:63-71. Mitelman F (1988): Catalog of Chromosome Aberrations in Cancer, 4th ed. Wiley-Liss, New York. Mark J, Dahlenfors R, Ekedahl C (1979): Recurrent chromosomal aberrations in non-Hodgkins and non-Burkitt lymphomas. Cancer Genet Cytogenet 1:39-56. Ueshima Y, Rowley JD, Varikojis D, Winter J, Gordon L (1984): Cytogenetic studies on patients with chronic T cell leukemia/lymphoma. Blood 63:1028-1038. Maseki N, Kaneko Y, Sakurai M, Kurihara M, Sampi K, Shimamura K, Takayama S (1987): Chromosome abnormalities in malignant lymphoma in patients from Saitama. Cancer Res 47:6767-6775. Kodum PRK, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RSK (1987): Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97-102. Le Beau MM, Westbrook CA, Diaz MO, Rowley JD (1985): c-src is consistently conserved in the chromosome deletion (20q) observed in myeloid disorders. Proc Natl Acad Sci USA 82:66926696.
14. Morris CM, Honeybone LM, Hollings PE, Fitzgerald PH (1989): Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 74:1768-1773. 15. Quintrell N, Lebo R, Varmus H, Bishop JM, Pettenati MJ, LeBeau M, Diaz MO, Rowley JD (1967): Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol Cell Biol 7:2267-2275.
ABSTRACT: Cytogenetic analysis of bone marrow from an 80-year-old woman with small cell lymphocytic l y m p h o m a revealed o del(20)(q11.2) as the sole cytogenetic abnormality. Del(2Oq) is found almost exclusively in myeloid disorders and this case represents a rare occurrence in a non-myeloid disorder.
INTRODUCTION Small cell lymphocytic lymphoma (SCLL) is a low-grade nonHodgkin's lymphoma characterized by the clonal proliferation of small cells that resemble resting, mature lymphocytes in appearance [1]. In the majority of cases, the lymphocytes are of B-cell origin with an immunophenotype similar to that documented in chronic lymphocytic leukemia [2]. Characteristic cytogenetic abnormalities in SCLL include loss of chromosome 9, trisomy 12, and translocations and rearrangements involving chromosome bands 14q32 and 11q21-22 [3-5]. CASE REPORT An 80-year-old woman, with a 6-year history of an IgG paraprotein, was noted to have generalized lymphoadenopathy when admitted with gastro-intestinal tract bleeding and left ventricular failure. A full blood count revealed hemoglobin 7.4 g/dL, white blood cell count 5.9 x 109/L (normal differential), and platelets 91 × 109/L. The IgG kappa paraprotein was quantitated at 33 g/L. Serum calcium and creatinine were both normal and urine examination was negative for Bence-Jones protein. A chest radiograph showed cardiomegaly and early left ventricular failure; compression fractures of the 7th and 10th thoracic vertebrae were also noted. Ultrasound of the abdomen and pelvis revealed the spleen to be at the upper limit of normal, measuring 13 cm in length. No significant intraabdominal lymphadenopathy was seen, Bone marrow biopsy showed infiltration by small welldifferentiated lymphocytes, some of which showed plasmacytold features. Cell marker studies by indirect immunofluo-
rescence confirmed a B-cell immunophenotype (CD19 = 73%, CD20 = 76%, IgG = 80%) with kappa light-chain restriction. Fine needle aspirate of a left axillary lymph node showed infiltration by lymphocytes with a similar morphology and immunophenotype. The patient received red cell transfusions to maintain her hemoglobin and general supportive care. She died 12 months later from bilateral bronchopneumonia and left ventricular failure secondary to ischemic heart disease. Cytogenetics Cytogenetic analysis was performed on GTG-banded metaphases derived from 24-hour and fluorodeoxyuridine-synchronized bone marrow cultures. An abnormal clone, 46,XX, del(20)(q11.2), (Fig. 1) was found in 29 of 30 cells examined. One cell was 46,XX. DISCUSSION Deletions of the long arm of chromosome 20 are most often associated with hematologic disorders of the myeloid lineage. Del(20q) is a common finding in polycythemia vera [6] and is also frequently encountered in acute myeloid leukemia and myelodysplasia [7]. Reports of del(20q) and rearrangements involving 20q in lymphoproliferative disorders are uncommon [8]. A number of isolated cases of del(20q) in non-Hodgkin's lymphomas have been reported in the literature, including: a diffused
F i g u r e 1 Partial karyotype showing the normal and del(20q) chromosomes from bone marrow of a patient with SCLL.
::
i:: :
i~i!/ili:i/:~
From the Cytogenetics Department, Princess Mary Childrens'Hos-
pital (P. D. C., P. T.), and Department of Haematology, Auckland Hospital (P. ]. B.), Auckland, New Zealand. Address reprint requests to: Philip D. Cotter, Division of Medical and Molecular Genetics, Mount Sinai School of Medicine, 100th Street & 5th Avenue, New York, N.Y. 10029. Received April 27, 1993; accepted June Z 1993.
142 Cancer Genet Cytogenet 70:142-143 [1993} 0165-4608/93/$06.00
© 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010
Del(20q) in SCLL large cell (histiocytic) l y m p h o m a w i t h m u l t i p l e cytogenetic a b n o r m a l i t i e s i n c l u d i n g two del(20)(q12) [9]; del(20q) w i t h m u l t i p l e cytogenetic abnormalities from bone marrow of a patient w i t h a T-cell l y m p h o m a [10]; and del(20q) and t(8;14) in a m a l i g n a n t l y m p h o m a [11]. Of interest, del(2Oq) was nonr a n d o m l y associated with diffuse small cleaved cell lymphomas a n d correlated w i t h the histiologic subtype in six cases [12]. This case is the first report of del(20q) associated w i t h small cell (well-differentiated) l y m p h o c y t i c l y m p h o m a . Alt h o u g h cytogenetic analysis was performed on bone marrow from our patient, the high percentage of B cells in the marrow (80%) a n d that the abnormal clone accounted for almost all cells a n a l y z e d leads us to believe that the del(20q) clone r e p r e s e n t e d the clonal m a l i g n a n c y derived from the lymphoma. Previous reports, based on cytogenetic and molecular evidence, have suggested that the a b n o r m a l i t y in 2 0 q - chrom o s o m e s may be an interstitial deletion rather t h a n a terminal deletion [13, 14]. At the r e s o l u t i o n used, we were unable to determine w h e t h e r the d e l e t i o n was interstitial in our patient. Heterogeneity has been noted for the loss of the c-src proto-oncogene on 20q in patients w i t h the del(20q) chrom o s o m e , l e a d i n g to s p e c u l a t i o n that deletions or rearrangements of c-src may be involved in the pathogenesis of the n e o p l a s i a in some patients w i t h del(20q) [13, 14]. Alternatively, loss of heterozygosity or rearrangements of the hematopoietic cell kinase gene, w h i c h m a p p e d to the region 20q11-*q12 [15], or of some other gene in that region, could p o t e n t i a l l y be involved. In summary, reported is a case of an 80-year-old w o m a n with a well-differentiated small cell lymphocytic lymphoma. Del(20)(q11.2) was the sole cytogenetic a b n o r m a l i t y found in bone marrow from this patient. This represents one of only a few cases of del(20q) in a l y m p h o i d disorder a n d the first report of del(20q] in a patient with SCLL. Prospective studies w i l l be required to determine w h e t h e r the del(20q) abnorm a l i t y is of diagnostic or prognostic significance in lymphomas. However, it is interesting to speculate that abnormalities of either the proto-oncogene c-src or the hematopoietic cell k i n a s e gene may be implicated in the pathogenesis of this t y p e of l y m p h o m a .
REFERENCES 1. Non-Hodgkin's lymphoma pathologic classification project (1982): National Cancer Institute sponsored study of classifica-
143
2.
3.
4. 5.
6.
7.
8. 9.
10.
11.
12.
13.
tion of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 49:2112-2135. Spier CM, Grogan TM, Fielder K, Richter L, Rangel C (1986): Immunophenotypes in "well-differentiated" lymphoproliferative disorders, with emphasis on small lymphocytic lymphoma. Hum Pathol 17:1126-1136. Fifth International Workshop on Chromosome in LeukemiaLymphoma (1987): Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Blood 70:1554-1564. Speaks SL, Sanger WG, Linder J, Johnson DR, Armitage JO, Weisenburger D, Purtilo D (1967): Chromosomal abnormalities in indolent lymphoma. Cancer Genet Cytogenet 27:335-344. Offit K, Jhanwar SC, Ladanyi M, Filippa DA, Chaganti RSK (1991): Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: Correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment. Genes Chrom Cancer 3:189-201. Diez-Martin JL, Graham DL, Petitt RM, Dewald GW (1991): Chromosome studies in 104 patients with polycythemia vera. Mayo Clin Proc 66:287-299. Davis MP, Dewald GW, Pierre RV, Hoagland HC (1984): Hematologic manifestations associated with deletions of the long arm of chromosome 20. Cancer Genet Cytogenet 12:63-71. Mitelman F (1988): Catalog of Chromosome Aberrations in Cancer, 4th ed. Wiley-Liss, New York. Mark J, Dahlenfors R, Ekedahl C (1979): Recurrent chromosomal aberrations in non-Hodgkins and non-Burkitt lymphomas. Cancer Genet Cytogenet 1:39-56. Ueshima Y, Rowley JD, Varikojis D, Winter J, Gordon L (1984): Cytogenetic studies on patients with chronic T cell leukemia/lymphoma. Blood 63:1028-1038. Maseki N, Kaneko Y, Sakurai M, Kurihara M, Sampi K, Shimamura K, Takayama S (1987): Chromosome abnormalities in malignant lymphoma in patients from Saitama. Cancer Res 47:6767-6775. Kodum PRK, Filippa DA, Richardson ME, Jhanwar SC, Chaganti SR, Koziner B, Clarkson BD, Lieberman PH, Chaganti RSK (1987): Cytogenetic and histologic correlations in malignant lymphoma. Blood 69:97-102. Le Beau MM, Westbrook CA, Diaz MO, Rowley JD (1985): c-src is consistently conserved in the chromosome deletion (20q) observed in myeloid disorders. Proc Natl Acad Sci USA 82:66926696.
14. Morris CM, Honeybone LM, Hollings PE, Fitzgerald PH (1989): Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood 74:1768-1773. 15. Quintrell N, Lebo R, Varmus H, Bishop JM, Pettenati MJ, LeBeau M, Diaz MO, Rowley JD (1967): Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. Mol Cell Biol 7:2267-2275.