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Large granular lymphocytic (LGL) leukemia in an adult with Down syndrome (47,XX,+21)
Leukemia Research 34 (2010) e125–e127
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor
Large granular lymphocytic (LGL) leukemia in an adult with Down syndrome (47,XX,+21) Clonal disorders of large granular lymphocytic (LGL) origin can arise from either a CD3+ T-cell lineage or from a CD3− NK-cell lineage [1]. CD3+ T-LGL leukemia is the most frequent form of LGL leukemia. This rare syndrome is characterized by the presence of LGL cells in the bone marrow, spleen, lymph nodes and peripheral blood, and is thought to represent a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway [1,2]. The affected patients often present with neutropenia, anemia, splenomegaly and/or thrombocytopenia. Rheumatoid arthritis and other autoimmune conditions, including Felty syndrome, have been described in association with this disease. Despite harboring monoclonal cells, most patients follow an indolent clinical course [2]. In some cases, LGL leukemia was shown to evolve into overt acute leukemia or undergo Richter transformation that responds poorly to standard anti-leukemia/lymphoma therapy. The aggressive T-LGL leukemia cells frequently express NK-cell markers such as CD16 and CD56. Herein, we report the first case of LGL leukemia in a patient with trisomy 21. A 38-year-old female was referred to us in consultation in the fall of 2007 with a persistently increased white blood cell (WBC) count. She had no fever, night sweats or weight loss. Furthermore, there was no history of recent infections, fatigue, shortness of breath, mucosal or cutaneous bleeding. Her medical history was significant for Down syndrome (DS), a related ventricular septal defect that was surgically repaired in childhood and mild hand osteoarthritis. She was severely mentally retarded, and had been institutionalized for most of her life. Physical examination revealed oblique eye fissures, a protruding tongue, somewhat shorter limbs, with single palmar creases, and a soft systolic murmur heard best at the left lower sternal border. A modest splenomegaly was also appreciated, but no enlarged lymph nodes were identified. A complete blood count showed a WBC count of 17,000 mcl−1 , with absolute lymphocytosis, a hemoglobin of 11 g/dl and a hematocrit of 33%. The platelet count was normal. A peripheral smear showed the presence of unusually large monuclear cells with condensed oval nuclei, abundant cytoplasm and azurophilic granules, comprising circa 50% of the WBCs [Fig. 1A]. Peripheral blood flow cytometry identified them as CD3+ CD4− CD8+ CD16+ CD27− CD45R0− CD57+ CD94+ T cells. Polymerase chain reaction (PCR) analysis of T-cell receptor gene rearrangements identified a clonal T-lymphocyte population. The bone marrow aspiration and biopsy procedure showed a hypercellular marrow, featuring a diffuse large granular T-lymphocytic infiltrate, somewhat decreased erythroid precursors, but normal megakaryocyte numbers and morphologies [Fig. 1B–D]. Flow cytometry readily confirmed the lymphocytic proliferation to represent 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.11.022
clonal T-lymphocytes. The cytogenetic studies showed trisomy 21 (47,XX, + 21[17]) as the sole abnormality. Serology was positive for rheumatoid factor, but antinuclear antibody titer and serum protein electrophoresis were normal. As the patient remains completely asymptomatic, she is currently being observed as an outpatient at 3-month intervals. Noteworthy, there has been no significant change in her peripheral blood counts over the last 2 years. The incidence of DS is estimated at 1 per 800–1000 births and most persons with this syndrome have trisomy 21 as a result of a meiotic nondisjunction event. The DS patients present abnormalities of all major organ systems including the immune, bone, central nervous and cardiovascular systems. Since the pathological features of DS also occur in the general population, albeit less severely and later in life, elucidation of the function of chromosome 21 genes has important implications for major human diseases. The subjects with DS have demonstrated an important reduction in various thymocyte subpopulations, including the thymocyte pool able to differentiate into functionally mature T cells [3]. The thymic hypoplasia and the resulting imbalance in the proportions of peripheral T-cell subpopulations in DS patients could not only lead to the splenic hypoplasia and increased susceptibility to infection, but also signal an inherent dysregulation of T-cell development in the DS thymus [4]. In addition, patients with DS were shown to display a unique spectrum of malignancies, with a 10- to 20-fold higher risk of acute leukemias, and a significantly lower incidence of solid tumors than in general population [5]. Deaths from leukemia, in part, account for the excess mortality associated with DS [6]. Such conditions as transient myeloproliferative disorder (TMD), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) are well-known to affect DS individuals. AML in persons with DS is often preceded by TMD. However, TMD disappears spontaneously in most cases and only about 20% of subjects with TMD go on to develop AML. The most common subtype of AML in children with DS is acute megakaryoblastic leukemia (DS-AMKL, M7). This transition from TMD to AML in DS offers a unique model for investigation of the stepwise development of leukemia and the gene dosage effects mediated by aneuploidy [7]. Children with TMD and those who subsequently develop DS-AMKL were shown to have acquired mutations in one allele of the GATA-1 gene, involving small deletions or insertions in sequences encoding exon 2 [8]. Furthermore, older children and adults with DS have an increased incidence of ALL. The ALL presenting features in DS differ from those in non-DS patients. They are almost invariably characterized by B-cell precursor (pre-B) immunophenotype, and are often TEL/AML1 negative [9]. The general outcomes in these patients also appear to be worse than in non-DS patients with ALL [9].
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Letter to the Editor / Leukemia Research 34 (2010) e125–e127
Fig. 1. Morphological appearance of peripheral blood, bone marrow aspirate and bone marrow biopsy in the patient. (A) Peripheral blood, original magnification 100×: Large granular lymphocytosis in the periphery. (B) Bone marrow aspirate, original magnification 100×: Lymphoid aggregate composed predominantly of large granular lymphocytes. (C) Bone marrow biopsy, original magnification 40×: Lymphoid aggregate/infiltrate featuring large granular lymphocytes. (D) CD3 stain of bone marrow biopsy, original magnification 40×: Predominance of CD3+ T cells is shown in the bone biopsy specimen. A similar pattern was obtained with CD57 anti-sera.
We realize that the T-LGL leukemia in an adult DS patient may represent a simple coincidence and, therefore, we cannot dismiss altogether the possibility that our patient could have developed it anyway, independent of the genetic abnormalities. However, the presence of a +21 karyotype, known to be associated with T-cell abnormalities and an increased incidence of other lymphoid and myeloid leukemias in patients with DS, could also suggest that this association may not be random. Recent use of transgenic mice to study the specific genes in the DS critical region has yielded some interesting results. The ETS2 gene is also known as the Avian Erythroblastosis Virus E26 Oncogene Homolog 2. ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiology of DS. It is believed to have important implications in cancer, bone development and immune responses. Its over-expression could therefore contribute to the features of Down syndrome related to these functions. Wolvetang et al. have demonstrated that over-expression of ETS2 results in apoptosis [10]. In their study, transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to the features observed in Down syndrome [10]. These results may have important implications in understanding leukemogenesis in DS. Currently, an array of genetic and molecular investigations is under way to explain the relationship between trisomy 21 and the origin of various leukemias. In the interim, the present case of T-LGL leukemic proliferation in an adult DS patient might offer additional insights to this widely discussed and captivating topic, which in
turn may yield new tools for the evolving therapeutic strategies of leukemia. Conflict of interest We do not have any commercial or proprietary interest in any drug, device, or equipment mentioned in the article below. Acknowledgements We certify that we do not have any affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, honoraria, and expert testimony). No financial support was used for this work. Contributions. We certify sufficient participation of each author in the conception, design, analysis, interpretation, writing, revising, and approval of the manuscript. References [1] Lamy T, Loughran Jr TP. Current concepts: large granular lymphocyte leukemia. Blood Rev 1999;13(December (4)):230–40. [2] Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004;9(3):247–58. [3] Larocca LM, Piantelli M, Valitutti S, Castellino F, Maggiano N, Musiani P. Alterations in thymocyte subpopulations in Down’s syndrome (trisomy 21). Clin Immunol Immunopathol 1988;49(November (2)):175–86.
Letter to the Editor / Leukemia Research 34 (2010) e125–e127 [4] Murphy M, Epstein LB. Down syndrome (DS) peripheral blood contains phenotypically mature CD3+TCR alpha, beta+ cells but abnormal proportions of TCR alpha, beta+, TCR gamma, delta+, and CD4+ CD45RA+ cells: evidence for an inefficient release of mature T cells by the DS thymus. Clin Immunol Immunopathol 1992;62(February (2)):245–51. [5] Rabin KR, Whitlock JA. Malignancy in children with trisomy 21. Oncologist 2009;14(February (2)):164–73. [6] Webb D, Roberts I, Vyas P. Haematology of Down syndrome. Arch Dis Child Fetal Neonatal Ed 2007;92(November (6)):F503–7. [7] Zwaan MC, Reinhardt D, Hitzler J, Vyas P. Acute leukemias in children with Down syndrome. Pediatr Clin North Am 2008;55(February (1)):53–70. [8] Gurbuxani S, Vyas P, Crispino JD. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 2004;103(January (2)):399–406. [9] Arico M, Ziino O, Valsecchi MG, Cazzaniga G, Baronci C, Messina C, et al. Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 2008;113(August (3)):515–21. [10] Wolvetang EJ, Wilson TJ, Sanij E, Busciglio J, Hatzistavrou T, Seth A, et al. ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Hum Mol Genet 2003;12(February (3)):247–55.
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Constantin A. Dasanu ∗ Department of Hematology and Oncology, Saint Francis Hospital and Medical Center, Gothic Park, 43 Woodland Street, Suite G-80, Hartford, CT 06105, USA Frank Bauer Department of Anatomic and Clinical Pathology, Saint Francis Hospital and Medical Center, Hartford, CT, USA ∗ Corresponding
author. Tel.: +1 347 679 9455; fax: +1 860 430 5603. E-mail address: c [email protected] (C.A. Dasanu) 27 September 2009 Available online 21 December 2009
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor
Large granular lymphocytic (LGL) leukemia in an adult with Down syndrome (47,XX,+21) Clonal disorders of large granular lymphocytic (LGL) origin can arise from either a CD3+ T-cell lineage or from a CD3− NK-cell lineage [1]. CD3+ T-LGL leukemia is the most frequent form of LGL leukemia. This rare syndrome is characterized by the presence of LGL cells in the bone marrow, spleen, lymph nodes and peripheral blood, and is thought to represent a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway [1,2]. The affected patients often present with neutropenia, anemia, splenomegaly and/or thrombocytopenia. Rheumatoid arthritis and other autoimmune conditions, including Felty syndrome, have been described in association with this disease. Despite harboring monoclonal cells, most patients follow an indolent clinical course [2]. In some cases, LGL leukemia was shown to evolve into overt acute leukemia or undergo Richter transformation that responds poorly to standard anti-leukemia/lymphoma therapy. The aggressive T-LGL leukemia cells frequently express NK-cell markers such as CD16 and CD56. Herein, we report the first case of LGL leukemia in a patient with trisomy 21. A 38-year-old female was referred to us in consultation in the fall of 2007 with a persistently increased white blood cell (WBC) count. She had no fever, night sweats or weight loss. Furthermore, there was no history of recent infections, fatigue, shortness of breath, mucosal or cutaneous bleeding. Her medical history was significant for Down syndrome (DS), a related ventricular septal defect that was surgically repaired in childhood and mild hand osteoarthritis. She was severely mentally retarded, and had been institutionalized for most of her life. Physical examination revealed oblique eye fissures, a protruding tongue, somewhat shorter limbs, with single palmar creases, and a soft systolic murmur heard best at the left lower sternal border. A modest splenomegaly was also appreciated, but no enlarged lymph nodes were identified. A complete blood count showed a WBC count of 17,000 mcl−1 , with absolute lymphocytosis, a hemoglobin of 11 g/dl and a hematocrit of 33%. The platelet count was normal. A peripheral smear showed the presence of unusually large monuclear cells with condensed oval nuclei, abundant cytoplasm and azurophilic granules, comprising circa 50% of the WBCs [Fig. 1A]. Peripheral blood flow cytometry identified them as CD3+ CD4− CD8+ CD16+ CD27− CD45R0− CD57+ CD94+ T cells. Polymerase chain reaction (PCR) analysis of T-cell receptor gene rearrangements identified a clonal T-lymphocyte population. The bone marrow aspiration and biopsy procedure showed a hypercellular marrow, featuring a diffuse large granular T-lymphocytic infiltrate, somewhat decreased erythroid precursors, but normal megakaryocyte numbers and morphologies [Fig. 1B–D]. Flow cytometry readily confirmed the lymphocytic proliferation to represent 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.11.022
clonal T-lymphocytes. The cytogenetic studies showed trisomy 21 (47,XX, + 21[17]) as the sole abnormality. Serology was positive for rheumatoid factor, but antinuclear antibody titer and serum protein electrophoresis were normal. As the patient remains completely asymptomatic, she is currently being observed as an outpatient at 3-month intervals. Noteworthy, there has been no significant change in her peripheral blood counts over the last 2 years. The incidence of DS is estimated at 1 per 800–1000 births and most persons with this syndrome have trisomy 21 as a result of a meiotic nondisjunction event. The DS patients present abnormalities of all major organ systems including the immune, bone, central nervous and cardiovascular systems. Since the pathological features of DS also occur in the general population, albeit less severely and later in life, elucidation of the function of chromosome 21 genes has important implications for major human diseases. The subjects with DS have demonstrated an important reduction in various thymocyte subpopulations, including the thymocyte pool able to differentiate into functionally mature T cells [3]. The thymic hypoplasia and the resulting imbalance in the proportions of peripheral T-cell subpopulations in DS patients could not only lead to the splenic hypoplasia and increased susceptibility to infection, but also signal an inherent dysregulation of T-cell development in the DS thymus [4]. In addition, patients with DS were shown to display a unique spectrum of malignancies, with a 10- to 20-fold higher risk of acute leukemias, and a significantly lower incidence of solid tumors than in general population [5]. Deaths from leukemia, in part, account for the excess mortality associated with DS [6]. Such conditions as transient myeloproliferative disorder (TMD), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) are well-known to affect DS individuals. AML in persons with DS is often preceded by TMD. However, TMD disappears spontaneously in most cases and only about 20% of subjects with TMD go on to develop AML. The most common subtype of AML in children with DS is acute megakaryoblastic leukemia (DS-AMKL, M7). This transition from TMD to AML in DS offers a unique model for investigation of the stepwise development of leukemia and the gene dosage effects mediated by aneuploidy [7]. Children with TMD and those who subsequently develop DS-AMKL were shown to have acquired mutations in one allele of the GATA-1 gene, involving small deletions or insertions in sequences encoding exon 2 [8]. Furthermore, older children and adults with DS have an increased incidence of ALL. The ALL presenting features in DS differ from those in non-DS patients. They are almost invariably characterized by B-cell precursor (pre-B) immunophenotype, and are often TEL/AML1 negative [9]. The general outcomes in these patients also appear to be worse than in non-DS patients with ALL [9].
e126
Letter to the Editor / Leukemia Research 34 (2010) e125–e127
Fig. 1. Morphological appearance of peripheral blood, bone marrow aspirate and bone marrow biopsy in the patient. (A) Peripheral blood, original magnification 100×: Large granular lymphocytosis in the periphery. (B) Bone marrow aspirate, original magnification 100×: Lymphoid aggregate composed predominantly of large granular lymphocytes. (C) Bone marrow biopsy, original magnification 40×: Lymphoid aggregate/infiltrate featuring large granular lymphocytes. (D) CD3 stain of bone marrow biopsy, original magnification 40×: Predominance of CD3+ T cells is shown in the bone biopsy specimen. A similar pattern was obtained with CD57 anti-sera.
We realize that the T-LGL leukemia in an adult DS patient may represent a simple coincidence and, therefore, we cannot dismiss altogether the possibility that our patient could have developed it anyway, independent of the genetic abnormalities. However, the presence of a +21 karyotype, known to be associated with T-cell abnormalities and an increased incidence of other lymphoid and myeloid leukemias in patients with DS, could also suggest that this association may not be random. Recent use of transgenic mice to study the specific genes in the DS critical region has yielded some interesting results. The ETS2 gene is also known as the Avian Erythroblastosis Virus E26 Oncogene Homolog 2. ETS2 is a transcription factor encoded by a gene on human chromosome 21 and alterations in its expression have been implicated in the pathophysiology of DS. It is believed to have important implications in cancer, bone development and immune responses. Its over-expression could therefore contribute to the features of Down syndrome related to these functions. Wolvetang et al. have demonstrated that over-expression of ETS2 results in apoptosis [10]. In their study, transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to the features observed in Down syndrome [10]. These results may have important implications in understanding leukemogenesis in DS. Currently, an array of genetic and molecular investigations is under way to explain the relationship between trisomy 21 and the origin of various leukemias. In the interim, the present case of T-LGL leukemic proliferation in an adult DS patient might offer additional insights to this widely discussed and captivating topic, which in
turn may yield new tools for the evolving therapeutic strategies of leukemia. Conflict of interest We do not have any commercial or proprietary interest in any drug, device, or equipment mentioned in the article below. Acknowledgements We certify that we do not have any affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in the manuscript (e.g., employment, consultancies, stock ownership, honoraria, and expert testimony). No financial support was used for this work. Contributions. We certify sufficient participation of each author in the conception, design, analysis, interpretation, writing, revising, and approval of the manuscript. References [1] Lamy T, Loughran Jr TP. Current concepts: large granular lymphocyte leukemia. Blood Rev 1999;13(December (4)):230–40. [2] Rose MG, Berliner N. T-cell large granular lymphocyte leukemia and related disorders. Oncologist 2004;9(3):247–58. [3] Larocca LM, Piantelli M, Valitutti S, Castellino F, Maggiano N, Musiani P. Alterations in thymocyte subpopulations in Down’s syndrome (trisomy 21). Clin Immunol Immunopathol 1988;49(November (2)):175–86.
Letter to the Editor / Leukemia Research 34 (2010) e125–e127 [4] Murphy M, Epstein LB. Down syndrome (DS) peripheral blood contains phenotypically mature CD3+TCR alpha, beta+ cells but abnormal proportions of TCR alpha, beta+, TCR gamma, delta+, and CD4+ CD45RA+ cells: evidence for an inefficient release of mature T cells by the DS thymus. Clin Immunol Immunopathol 1992;62(February (2)):245–51. [5] Rabin KR, Whitlock JA. Malignancy in children with trisomy 21. Oncologist 2009;14(February (2)):164–73. [6] Webb D, Roberts I, Vyas P. Haematology of Down syndrome. Arch Dis Child Fetal Neonatal Ed 2007;92(November (6)):F503–7. [7] Zwaan MC, Reinhardt D, Hitzler J, Vyas P. Acute leukemias in children with Down syndrome. Pediatr Clin North Am 2008;55(February (1)):53–70. [8] Gurbuxani S, Vyas P, Crispino JD. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 2004;103(January (2)):399–406. [9] Arico M, Ziino O, Valsecchi MG, Cazzaniga G, Baronci C, Messina C, et al. Acute lymphoblastic leukemia and Down syndrome: presenting features and treatment outcome in the experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP). Cancer 2008;113(August (3)):515–21. [10] Wolvetang EJ, Wilson TJ, Sanij E, Busciglio J, Hatzistavrou T, Seth A, et al. ETS2 overexpression in transgenic models and in Down syndrome predisposes to apoptosis via the p53 pathway. Hum Mol Genet 2003;12(February (3)):247–55.
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Constantin A. Dasanu ∗ Department of Hematology and Oncology, Saint Francis Hospital and Medical Center, Gothic Park, 43 Woodland Street, Suite G-80, Hartford, CT 06105, USA Frank Bauer Department of Anatomic and Clinical Pathology, Saint Francis Hospital and Medical Center, Hartford, CT, USA ∗ Corresponding
author. Tel.: +1 347 679 9455; fax: +1 860 430 5603. E-mail address: c [email protected] (C.A. Dasanu) 27 September 2009 Available online 21 December 2009