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Small noncleaved cell lymphoma in an adolescent with the XYY syndrome
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Small Noncleaved Cell Lymphoma in an Adolescent with the XYY Syndrome J. T. Sandlund and S. C. Raimondi
ABSTRACT: A 19-year-old male was diagnosed with stage Ill abdominal small noncleaved cell (SNCC)
non-Hodgkin lymphoma (NHL). Cytogenetic evaluation of the tumor revealed a complex karyotype which included the t(8;14)(q24;q32), classically associated with this lymphoma histotype, and an extra Y chromosome. After remission was obtained, cytogenetic analysis of bone marrow cells and PHA-stimulated peripheral blood lymphocytes disclosed a normal karyotype except for the persistence of an extra Y chromosome, diagnostic of the X Y Y syndrome. This is the first reported case of SNCC NHL in an adolescent with the X Y Y syndrome. @ Elsevier Science Inc., 1997
INTRODUCTION
The XYY syndrome is a constitutional chromosomal abnormality occurring in one of 1000 live male births [1], It has been associated with increased stature, propensity for acne, and learning disabilities in some cases [1]. Although acute lymphoblastic and myeloid leukemias have been reported in patients with XYY [2-15], the risk of these malignancies does not appear to be significantly higher in this population than in the general population [15]. To our knowledge, small noncleaved cell (SNCC) non-Hodgkin lymphoma has not been reported in patients with the XYY syndrome. CASE REPORT
A 19-year-old male presented with a large abdominal mass extending into the pelvis with testicular involvement. Biopsy of the mass revealed a SNCC NHL as defined by the National Cancer Institute (NCI) Working Formulation [16]. The cytogenetic evaluation of the tumor sample had the following karyotypes (Fig. 1): 47,XYYc,t(8;14)(q24;q32), der(10)t(1;10)(q12;q26),dup(13)(q32q12),del(17)(p11.1)[4]/ 47,XYYc,dup(1)(q3 lq21),der(8)t(8;14)(q24;q34),dup (13) (q32q12),der(14)t(8;14)(q24;q34)del(14)(q22q23),del(17)(p11.1) [14]/47,XYYc [2].
From the Departments of Hematology-Oncology (J. T. S) and Pathology and Laboratory Medicine (S. C. R.), St. Jude Children's Research Hospital, and the Department of Pediatrics, University of Tennessee, Memphis, College of Medicine (J. T. S.), Tennessee, U.S.A. Address reprint requests to: John T. Sandlund, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38101. Received April 27, 1996; accepted July 9, 1996. Cancer Genet Cytogenet 9 4 : 8 8 - 9 0 (1997) @ Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
As the patient had no evidence of bone marrow or central nervous system involvement, he was considered to have stage III disease, according to the St. Jude system [17]. He was treated according to the French (SFOP) LMB89 regimen [18]. Upon attaining complete remission, cytogenetic analysis of bone marrow cells and PHA-stimulated peripheral blood lymphocytes revealed a karyotype with an extra Y chromosome, diagnostic of the originally suspected constitutional XYY syndrome (Fig. 1). Four months after completion of therapy, the patient developed a CNS relapse with a right third cranial nerve palsy and FAB L3 lymphoblasts in the cerebrospinal fluid. Complete workup demonstrated an additional site of recurrence in the left levator scapulae muscle. He was treated with two courses of multiagent cheinotherapy, including high-dose methotrexate (8 grams/m2), ifosfamide, etoposide, and dexamethasone. CNS-directed therapy included methotrexate, cytarabine, and hydrocortisone delivered via an Ommaya reservoir, followed by craniospinal irradiation. He tolerated this therapy well and achieved a second complete remission. Subsequently, he received an allogeneic bone marrow transplant which was complicated by fatal hepatic veno-occlusive disease. The patient expired 11 months after initial diagnosis. DISCUSSION
A spectrum of primarily hematopoietic neoplasms has been reported to occur in children and adults with the XYY syndrome, including acute lymphoblastic leukemia, acute myeloid leukemia, and one case each of medulloblastoma and mycosis fungoides [2-15, 19, 20]. Our patient represents, to our knowledge, the first reported case of SNCC NHL in a male with XYY syndrome. Thus, children and adolescents with XYY syndrome do not appear to be at increased risk of developing SNCC NHL on the basis of the literature
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Small Noncleaved Cell Lymphoma in an Adolescent
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Figure I G-banded karyotype of two leukemic blasts. (A) Representative stemline karyotype: 47,XYYc,t(8;14)(q24;q34), der(10)t(1;10)(q12;q26),dup(13)(q32q12),del(17)(p11.1). (B) Representative sideline karyatype: 47,XYYc,dup(1)(q31q21), der(8)t(8;14)(q24;q34)•dup(13)(q32q12)'der(14)t(8;14)(q24;q34)de•(14)(q22q23)•de•(17)(11.1).
90
review; however, this finding may simply be a reflection of a small n u m b e r of tumors studied and/or reported. Additionally, it is r e c o m m e n d e d that if an extra Y is identified in a tumor cell karyotype, PHA-stimulated peripheral blood lymphocytes be studied during remission, to accurately diagnose the XYY syndrome. That our patient tolerated two very intensive treatment regimens prior to bone marrow transplantation suggests that young patients with the XYY constitutional abnormality are not predisposed to increased treatment-associated toxicity, in contrast to children with Down's syndrome, who require modification in dosage of certain drugs such as high-dose methotrexate [21]. In this regard, we have previously reported two children with the XYY syndrome who tolerated an intensive multiagent treatment for ALL without untoward acute toxicity [15]. Nonetheless, long-term followup is needed to determine if these patients are at increased risk of developing long-term sequelae. The authors want to thank Peggy Vandiveer for typing the manuscript, and J. Dalton for excellent technical assistance. This work was supported in part by grants CA20180 and CA21765 from the National Cancer Institute and by American Lebanese Syrian Associated Charities (ALSAC).
REFERENCES 1. Moore CA, Weaver DD (1990): Chromosome XYY. In: Birth Defects Encyclopedia. Buyse ML, ed. Blackwell Scientific Publications, Inc., Boston, pp. 400-401. 2. Benitea J, Valcarcel E, Ramos C, Ayuso C, Sanchez Cascos A (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354. 3. Chaganti RSK, Jhanwar SC, Arlin ZA, Clarkson BD (1982): Chronic myelogenous leukemia in an XYY male. Cancer Genetics Cytogenet 5;223-226. 4. Atichartakarn V, Punyammalee B, Wongsasant B, Jootar S (1986): Acute nonlymphocytic leukemia with a translocation (1;3)(p36;q21) in an XYY man. Cancer Genet Cytogenet 21:79-83. 5. Midro AT, Wojtukiewica M, Bielawiec M, Sawicka A (1987): XYY syndrome and acute myeloblastic leukemia. Cancer Genet Cytogenet 24:363-365. 6. Ohyashiki JH, Ohyashiki K, Iwabuchi H, Lin K-Y, Toyama K (1987): Acute myelomonocytic leukemia with inv(16)(p13q22) in an XY/XYY male. Cancer Genet Cytogenet 29:331-332.
J.T. S a n d l u n d and S. C. Raimondi 7. Gilgenkrantz S (1988): XYY males and leukemia. Cancer Genet Cytogenet 30:337-338. 8. Perez de Oteyza J, Sureda A, Ferro T, Larafia JG, Odriozola J, Escribano L, Navarro JL (1990): Acute lymphoblastic leukemia in an XYY male. Cancer Genet Cytogenet 39:225-227. 9. Trivedi AH, Bakshi SR, Roy SK, Patel RK, Balar DB, Anand A, Shah PM (1995): An XYY male with acute lymphoblastic leukemia. Cancer Genet Cytogenet 83:178. 10. Gilgendrantz S, Lederlin P, Streiff F, Guerci O, Thibaut G, Houplon M, Herbeuval R (1969): Leucose aigue et aberration chromesomizue XYY. Ann Med Nancy 8:565-570. 11. Mouriquand C, Jalbert P, Chabanas A, Malka J, Bachelot A, Hadijan AJ (1973): Les Lec6mies de l'enfant: Doundes de la cytog~ndtique. Rev Med Alper Fr 2:341-351. 32. Deschamps M (1975): Constitution XYY et leuc~mies aigues. Th~se Med Paris, p. 41. 13. Ohyashiki K, Oshimura M, Toyoda T, Sakari N, Ito H, Yamamoto K, Tonomura A (1984): Chronic myelogenous leukemia with a complex Ph I translocation in an XYY male. Cancer Genet Cytogenet 11:215-219. 14. Tanb JW, Raviudranath Y, Mohamed AN, Wolman SR, Bawle EV (1993): ALL in 46,XY/47,XYY mosaic. The Pediatric Forum 147:1254-1255. 15. Sandlund JT, Krance R, Piu C-H, Hancock M, Crist WM, Filatov LV, Raimondi SC: XYY syndrome in children with acute lymphoblastic leukemia. Med Ped Oncol (in press). 16. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphoma (1982): Summary and description of a working formulation for clinical usage. Cancer 49:21122135. 17. Murphy SB (1980): Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities from lymphoma in adults. Sem Oncol 7:332-339. 18. Patte C, Leverger G, Michon J, Frappaz D, Robert A, Bertrand Y, Perel Y, Behrendt H, Gentel JC, Thyss A (1993): High survival rate of childhood B-cell lymphoma and leukemia (ALL) as result of the LMB89 protocol of the SFOP. Proceedings of the Fifth International Conference of Malignant Lymphoma (Abstract #63). 19. Rosario M, Delellis M, Massara B, Ditondo FU, Casini C (1974): Cariotipo XYY e medulloblastoma. Acta Genet Med Gemello 23:259-263. 20. Ohyashiki K, Yoshida MA, Ohyashiki JH, Block AW, Dabshi K, Sandberg AA (1985): Chromosome changes in mycosis fungoides in an XYY male. Cancer Genet Cytogenet 18:295-302. 21. Garre ML, Relling MV, Kalwinsky D, Dodge R, Crom WR, Abromowitch M, Pui C-H, Evans WE (1987): Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lylnphoblastic leukemia. J Pediatr 111:606-612.
Small Noncleaved Cell Lymphoma in an Adolescent with the XYY Syndrome J. T. Sandlund and S. C. Raimondi
ABSTRACT: A 19-year-old male was diagnosed with stage Ill abdominal small noncleaved cell (SNCC)
non-Hodgkin lymphoma (NHL). Cytogenetic evaluation of the tumor revealed a complex karyotype which included the t(8;14)(q24;q32), classically associated with this lymphoma histotype, and an extra Y chromosome. After remission was obtained, cytogenetic analysis of bone marrow cells and PHA-stimulated peripheral blood lymphocytes disclosed a normal karyotype except for the persistence of an extra Y chromosome, diagnostic of the X Y Y syndrome. This is the first reported case of SNCC NHL in an adolescent with the X Y Y syndrome. @ Elsevier Science Inc., 1997
INTRODUCTION
The XYY syndrome is a constitutional chromosomal abnormality occurring in one of 1000 live male births [1], It has been associated with increased stature, propensity for acne, and learning disabilities in some cases [1]. Although acute lymphoblastic and myeloid leukemias have been reported in patients with XYY [2-15], the risk of these malignancies does not appear to be significantly higher in this population than in the general population [15]. To our knowledge, small noncleaved cell (SNCC) non-Hodgkin lymphoma has not been reported in patients with the XYY syndrome. CASE REPORT
A 19-year-old male presented with a large abdominal mass extending into the pelvis with testicular involvement. Biopsy of the mass revealed a SNCC NHL as defined by the National Cancer Institute (NCI) Working Formulation [16]. The cytogenetic evaluation of the tumor sample had the following karyotypes (Fig. 1): 47,XYYc,t(8;14)(q24;q32), der(10)t(1;10)(q12;q26),dup(13)(q32q12),del(17)(p11.1)[4]/ 47,XYYc,dup(1)(q3 lq21),der(8)t(8;14)(q24;q34),dup (13) (q32q12),der(14)t(8;14)(q24;q34)del(14)(q22q23),del(17)(p11.1) [14]/47,XYYc [2].
From the Departments of Hematology-Oncology (J. T. S) and Pathology and Laboratory Medicine (S. C. R.), St. Jude Children's Research Hospital, and the Department of Pediatrics, University of Tennessee, Memphis, College of Medicine (J. T. S.), Tennessee, U.S.A. Address reprint requests to: John T. Sandlund, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38101. Received April 27, 1996; accepted July 9, 1996. Cancer Genet Cytogenet 9 4 : 8 8 - 9 0 (1997) @ Elsevier Science Inc., 1997 655 Avenue of the Americas, N e w York, NY 10010
As the patient had no evidence of bone marrow or central nervous system involvement, he was considered to have stage III disease, according to the St. Jude system [17]. He was treated according to the French (SFOP) LMB89 regimen [18]. Upon attaining complete remission, cytogenetic analysis of bone marrow cells and PHA-stimulated peripheral blood lymphocytes revealed a karyotype with an extra Y chromosome, diagnostic of the originally suspected constitutional XYY syndrome (Fig. 1). Four months after completion of therapy, the patient developed a CNS relapse with a right third cranial nerve palsy and FAB L3 lymphoblasts in the cerebrospinal fluid. Complete workup demonstrated an additional site of recurrence in the left levator scapulae muscle. He was treated with two courses of multiagent cheinotherapy, including high-dose methotrexate (8 grams/m2), ifosfamide, etoposide, and dexamethasone. CNS-directed therapy included methotrexate, cytarabine, and hydrocortisone delivered via an Ommaya reservoir, followed by craniospinal irradiation. He tolerated this therapy well and achieved a second complete remission. Subsequently, he received an allogeneic bone marrow transplant which was complicated by fatal hepatic veno-occlusive disease. The patient expired 11 months after initial diagnosis. DISCUSSION
A spectrum of primarily hematopoietic neoplasms has been reported to occur in children and adults with the XYY syndrome, including acute lymphoblastic leukemia, acute myeloid leukemia, and one case each of medulloblastoma and mycosis fungoides [2-15, 19, 20]. Our patient represents, to our knowledge, the first reported case of SNCC NHL in a male with XYY syndrome. Thus, children and adolescents with XYY syndrome do not appear to be at increased risk of developing SNCC NHL on the basis of the literature
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Small Noncleaved Cell Lymphoma in an Adolescent
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Figure I G-banded karyotype of two leukemic blasts. (A) Representative stemline karyotype: 47,XYYc,t(8;14)(q24;q34), der(10)t(1;10)(q12;q26),dup(13)(q32q12),del(17)(p11.1). (B) Representative sideline karyatype: 47,XYYc,dup(1)(q31q21), der(8)t(8;14)(q24;q34)•dup(13)(q32q12)'der(14)t(8;14)(q24;q34)de•(14)(q22q23)•de•(17)(11.1).
90
review; however, this finding may simply be a reflection of a small n u m b e r of tumors studied and/or reported. Additionally, it is r e c o m m e n d e d that if an extra Y is identified in a tumor cell karyotype, PHA-stimulated peripheral blood lymphocytes be studied during remission, to accurately diagnose the XYY syndrome. That our patient tolerated two very intensive treatment regimens prior to bone marrow transplantation suggests that young patients with the XYY constitutional abnormality are not predisposed to increased treatment-associated toxicity, in contrast to children with Down's syndrome, who require modification in dosage of certain drugs such as high-dose methotrexate [21]. In this regard, we have previously reported two children with the XYY syndrome who tolerated an intensive multiagent treatment for ALL without untoward acute toxicity [15]. Nonetheless, long-term followup is needed to determine if these patients are at increased risk of developing long-term sequelae. The authors want to thank Peggy Vandiveer for typing the manuscript, and J. Dalton for excellent technical assistance. This work was supported in part by grants CA20180 and CA21765 from the National Cancer Institute and by American Lebanese Syrian Associated Charities (ALSAC).
REFERENCES 1. Moore CA, Weaver DD (1990): Chromosome XYY. In: Birth Defects Encyclopedia. Buyse ML, ed. Blackwell Scientific Publications, Inc., Boston, pp. 400-401. 2. Benitea J, Valcarcel E, Ramos C, Ayuso C, Sanchez Cascos A (1987): Frequency of constitutional chromosome alterations in patients with hematologic neoplasias. Cancer Genet Cytogenet 24:345-354. 3. Chaganti RSK, Jhanwar SC, Arlin ZA, Clarkson BD (1982): Chronic myelogenous leukemia in an XYY male. Cancer Genetics Cytogenet 5;223-226. 4. Atichartakarn V, Punyammalee B, Wongsasant B, Jootar S (1986): Acute nonlymphocytic leukemia with a translocation (1;3)(p36;q21) in an XYY man. Cancer Genet Cytogenet 21:79-83. 5. Midro AT, Wojtukiewica M, Bielawiec M, Sawicka A (1987): XYY syndrome and acute myeloblastic leukemia. Cancer Genet Cytogenet 24:363-365. 6. Ohyashiki JH, Ohyashiki K, Iwabuchi H, Lin K-Y, Toyama K (1987): Acute myelomonocytic leukemia with inv(16)(p13q22) in an XY/XYY male. Cancer Genet Cytogenet 29:331-332.
J.T. S a n d l u n d and S. C. Raimondi 7. Gilgenkrantz S (1988): XYY males and leukemia. Cancer Genet Cytogenet 30:337-338. 8. Perez de Oteyza J, Sureda A, Ferro T, Larafia JG, Odriozola J, Escribano L, Navarro JL (1990): Acute lymphoblastic leukemia in an XYY male. Cancer Genet Cytogenet 39:225-227. 9. Trivedi AH, Bakshi SR, Roy SK, Patel RK, Balar DB, Anand A, Shah PM (1995): An XYY male with acute lymphoblastic leukemia. Cancer Genet Cytogenet 83:178. 10. Gilgendrantz S, Lederlin P, Streiff F, Guerci O, Thibaut G, Houplon M, Herbeuval R (1969): Leucose aigue et aberration chromesomizue XYY. Ann Med Nancy 8:565-570. 11. Mouriquand C, Jalbert P, Chabanas A, Malka J, Bachelot A, Hadijan AJ (1973): Les Lec6mies de l'enfant: Doundes de la cytog~ndtique. Rev Med Alper Fr 2:341-351. 32. Deschamps M (1975): Constitution XYY et leuc~mies aigues. Th~se Med Paris, p. 41. 13. Ohyashiki K, Oshimura M, Toyoda T, Sakari N, Ito H, Yamamoto K, Tonomura A (1984): Chronic myelogenous leukemia with a complex Ph I translocation in an XYY male. Cancer Genet Cytogenet 11:215-219. 14. Tanb JW, Raviudranath Y, Mohamed AN, Wolman SR, Bawle EV (1993): ALL in 46,XY/47,XYY mosaic. The Pediatric Forum 147:1254-1255. 15. Sandlund JT, Krance R, Piu C-H, Hancock M, Crist WM, Filatov LV, Raimondi SC: XYY syndrome in children with acute lymphoblastic leukemia. Med Ped Oncol (in press). 16. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphoma (1982): Summary and description of a working formulation for clinical usage. Cancer 49:21122135. 17. Murphy SB (1980): Classification, staging and end results of treatment of childhood non-Hodgkin's lymphomas: Dissimilarities from lymphoma in adults. Sem Oncol 7:332-339. 18. Patte C, Leverger G, Michon J, Frappaz D, Robert A, Bertrand Y, Perel Y, Behrendt H, Gentel JC, Thyss A (1993): High survival rate of childhood B-cell lymphoma and leukemia (ALL) as result of the LMB89 protocol of the SFOP. Proceedings of the Fifth International Conference of Malignant Lymphoma (Abstract #63). 19. Rosario M, Delellis M, Massara B, Ditondo FU, Casini C (1974): Cariotipo XYY e medulloblastoma. Acta Genet Med Gemello 23:259-263. 20. Ohyashiki K, Yoshida MA, Ohyashiki JH, Block AW, Dabshi K, Sandberg AA (1985): Chromosome changes in mycosis fungoides in an XYY male. Cancer Genet Cytogenet 18:295-302. 21. Garre ML, Relling MV, Kalwinsky D, Dodge R, Crom WR, Abromowitch M, Pui C-H, Evans WE (1987): Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lylnphoblastic leukemia. J Pediatr 111:606-612.