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Isolated trisomy 2 in bone marrows of patients with suspected hematopoietic malignancies
Cancer Genetics
-
(2014)
-
Isolated trisomy 2 in bone marrows of patients with suspected hematopoietic malignancies Umut Aypar a, Kaaren K. Reichard a, Lindsey A. Waltman b, a, * Daniel L. Van Dyke a b
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Genetic Counselor, Ambry Genetics, Aliso Viejo, CA, USA Isolated trisomy 2 in hematopoietic malignancies is rare, having been reported in only eight cases. Of these cases, the majority are older males. The underlying hematologic malignancies range from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). The molecular pathogenesis and prognostic significance of isolated trisomy 2 remains unknown. Herein, we report 11 cases of isolated trisomy 2 in hematologic disorders seen in the Mayo Clinic Cytogenetics laboratory from 1996e2012. The majority were older males between the ages of 6393 years. The underlying bone marrow pathologic diagnoses ranged from no diagnostic features of malignancy to AML. Our data suggest that isolated trisomy 2 could represent an agerelated phenomenon since all 11 cases were age 63 and over. It appears that isolated trisomy 2 harbors little prognostic significance and that, instead, the prognostic significance is driven by the underlying pathologic diagnosis. For example, whereas 3 of the cases with AML survived only 710 weeks postbone marrow biopsy, 1 of the cases without diagnostic features of malignancy survived 10 additional years. Therefore, trisomy 2 as a sole abnormality should not be considered as definitive evidence for a myeloid neoplasm in the absence of diagnostic morphologic criteria. Keywords Trisomy 2, MDS, AML, PMF ª 2014 Elsevier Inc. All rights reserved.
Isolated trisomy 2 in hematopoietic malignancies is a rare finding that has been reported in eight cases in the literature (1e7). These cases are typically older males ranging from 6484 years old, presenting with various myeloid neoplasms including myelodysplastic syndrome (MDS), refractory anemia (RA) subtype; MDS, RA with excess blasts (RAEB-II) subtype; MDS, RAEB in transformation (RAEB-t) subtype; chronic myelomonocytic leukemia in transformation (CMMLt); acute myeloid leukemia (AML) arising out of prior MDS; acute monoblastic and monocytic leukemia (AMoL; FAB (French-American-British classification system) M5); and relapsed AML (Table 1). The significance of isolated trisomy 2 is not known, but has been postulated to be an age-related phenomenon (3). To further investigate the possible diagnostic and prognostic significance of isolated trisomy 2 in hematologic
Received January 16, 2014; received in revised form February 25, 2014; accepted February 27, 2014. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2014.02.011
malignancies, we report the hematopathologic and genetic studies from 11 cases seen at our institution.
Materials and methods Cases with isolated trisomy 2 in bone marrow specimens were identified from 1996 to 2012 in our cytogenetics laboratory. G-banding was performed according to standard cytogenetic methods using trypsin and Leishman stain. Although 20 metaphases are routinely examined, only 9 and 15 metaphases were identified in cases 8 and 4, respectively.
Results We identified 11 cases with isolated trisomy 2 in bone marrow specimens. The specimens were all from older patients, ranging from 6393 years old, and 7 of 11 were male. Their hematopathologic evaluations represent a range of findings including two without diagnostic features of malignancy (Table 2).
2
U. Aypar et al.
Table 1 Cases of isolated trisomy 2 in bone marrow hematopoietic disorders reported in the literature
Table 2 List of the patients with isolated trisomy 2 seen in the Mayo Clinic cytogenetics laboratory between 1996 and 2012
Age Patient (y) Sex Result
Reference
Age Patient (y) Sex Result
Pathology report
(1)
1
87
M
47,XY,þ2[4]/45, X,-Y[3]/46,XY[13]
(2) (3)
2
84
M
47,XY,þ2[11]/46, XY[9]
(3)
3
78
M
47,XY,þ2[17]/46, XY[3]
(4)
4
82
M
47,XY,þ2[6]/46, XY[9]
(5)
5
72
F
47,XX,þ2[2]/46, XX[18]
(6)
6
93
F
47,XX,þ2[19]/46, XX[1]
(7)
7 8 9 10 11
67 82 75 69 63
F M M M F
47,XX,þ2[3]/46, XX[17] 47,XY,þ2[9] 47,XY,þ2[20] 47,XY,þ2[13]/46, XY[7] 47,XX,þ2[17]/46,X, idic(X)(q13)[1]/46,XX[2]
No diagnostic features of malignancy No diagnostic features of malignancy MDS, RCMD subtype MDS, RCMD subtype MDS, RAEB-1 subtype MDS, RAEB-1 subtype PMF AML, NOS AML, NOS AML, MRC AML, MRC
1
74
M
2 3
75 87
M M
4
80
F
5
64
M
6
73
M
7
84
M
8
N/A M
47,XY,þ2a
Pathology report
MDS, RA subtype MDS, RAEB-t 47,XY,þ2a 47,XY,þ2[5]/ MDS 46, XY[35] transformed into AML 47,XX,þ2[22]/ CMML-t 46, XX[8] 47,XY,þ2/46, MDS, RA subtype XYa 47,XY,þ2[5]/ MDS, RAEB-II 46, XY[8] subtype 47,XY,þ2[8]/ AMoL; 46, XY[8] FAB M5 47,XY,þ2[19] AML in relapse
Abbreviation: MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transformation; AML, acute myeloid leukemia; CMML-t, chronic myelomonocytic leukemia in transformation; AMoL, acute monoblastic and monocytic leukemia; FAB, French-American-British classification system; N/A, not available. a Number of metaphases not reported.
Case 1, 47,XY,þ2[4]/45,X,-Y[3]/46,XY[13], was an 87year-old male who had mild thrombocytopenia and mild anemia. The bone marrow was normocellular (30%; M:E ratio 1.7:1.0) with intact trilineage hematopoiesis and no increase in blasts. Erythropoiesis was mildly megaloblastoid without convincing evidence of myelodysplasia. The patient did not receive any treatment. He survived 10 years after the identification of the trisomy 2. His chromosome study also showed an absence of the Y chromosome in 3 of 20 metaphasesda known age-related phenomenon (8). Case 2, 47,XY,þ2[11]/46,XY[9], was an 84-year-old male with thrombocytopenia. The bone marrow was mildly hypercellular (50%) with mild panhyperplasia and no increase in blasts. Overall findings were compatible with peripheral sequestration and/or destruction of platelets (M:E ratio 3:1). Additional clinical information was not available. Case 3, 47,XY,þ2[17]/46,XY[3], was a 78-year-old male with severe anemia, neutropenia, and thrombocytopenia. The bone marrow showed a hypercellular bone marrow (80e90%) with myeloid maturation arrest at the myelocyte stage, megaloblastoid erythropoiesis, and dysplastic megakaryocytes. The abnormal megakaryocytes were characterized by distinctly separate nuclear lobes. There was 3% blasts. The findings were most suggestive of MDS. No additional clinical information was available; however, a bone marrow specimen collected 11 weeks after this study showed similar findings, except for an increase in blasts to 8%. Case 4, 47,XY,þ2[6]/46,XY[9], was an 82-year-old male with anemia and neutropenia. The bone marrow was mildly hypercellular (40%; M:E ratio 0.3:1) with erythroid hyperplasia and megaloblastoid erythropoiesis, mild dysgranulopoiesis, and increased dysplastic megakaryocytes that consisted of mononuclear forms and micromegakaryocytes.
Abbreviations:MDS, myelodysplastic syndrome; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; PMF, primary myelofibrosis; AML, acute myeloid leukemia; NOS, not otherwise specified; MRC, myelodysplasiarelated changes.
Blasts were <3%. The overall findings were consistent with MDS, refractory cytopenia with multilineage dyspoiesis subtype. Additional clinical information was not available. Case 5, 47,XX,þ2[2]/46,XX[18], was a 72-year-old female whose initial bone marrow showed moderate to marked hypercellularity (70e75%) with a slightly increased myeloblast percentage (5e6%), granulocytic and erythroid dysplasia, normal-appearing megakaryocytes and ring sideroblasts. The findings were consistent with a diagnosis of MDS, RAEB-1 subtype. No further clinical information was available. A follow-up bone marrow 4 years later showed persistent MDS with a borderline increase in blasts (5e6%) and development of monocytosis. Chromosomes were normal at that time. Case 6, 47,XX,þ2[19]/46,XX[1], was a 93-year-old female whose bone marrow was slightly hypercellular (40%) with mild panhyperplasia, dyserythropoiesis, dysplastic megakaryocytes, and a borderline increase in blasts (5%). The findings were consistent with MDS, RAEB-1 subtype. No additional clinical information was available. Case 7, a female, was initially diagnosed with a myeloproliferative neoplasm for which the pathology and cytogenetics reports were not available for our review. The clinical notes indicated that multiple interval bone marrow biopsies showed a similar pathologic picture, with trisomy 2 in all metaphases. She was treated with hydroxyurea for about 5 years, and after becoming transfusion dependent, she received four cycles of Dacogen. She was then admitted on a clinical trial treatment of pomalidomide; however, no clinical improvement was seen. At this time, her fluorescence in situ hybridization (FISH) test for BCR-ABL1 was normal, and
Isolated trisomy 2 in hematopoietic malignancies chromosomes showed add(3)(q21) in 6 of 20 metaphases. Six months later, the now 67-year-old female, was diagnosed with JAK2 V617Fpositive primary myelofibrosis and a karyotype of 47,XX,þ2[3]/46,XX[17]. The bone marrow core biopsy was 90% cellular with increased megakaryocytes and marked reticulin fibrosis. The touch preparation revealed increased blasts (7%). Eighteen weeks after the cytogenetic study at Mayo Clinic, the patient passed away. Case 8, 47,XY,þ2[9], was an 82-year-old male who had an aparticulate bone marrow sample that was hypocellular. Granulocytes were decreased and left shifted, showing occasional dyspoietic morphology including variable cytoplasmic granulation. Maturing forms of erythrocytes were identified, occasionally with irregular nuclear contours and megaloblastoid nuclear features. Blasts were increased (7%), and a final diagnosis of persistent AML was made. Additional clinical information was not available for this patient. His bone marrow specimen was studied in the laboratory about 9 months earlier, with possible MDS noted as the reason for testing. The results showed trisomy 8 in 2 of 20 metaphases, 47,XY,þ8[2]/46,XY[18]. Case 9, 47,XY,þ2[20], was a 75-year-old male who was originally diagnosed with cytogenetically normal AML (25% blasts in the bone marrow). He was treated with one cycle of decitabine; however, the treatment was stopped due to elevation of circulating blasts. Two months later, a bone marrow specimen showed AML with 50% blasts, trilineage dysplasia, and ring sideroblasts. A FLT3 gene mutation was not identified. The patient passed away after 7 weeks. Case 10 was initially diagnosed with anemia and chromosome studies were performed 3 and 6 years before the current study, which showed that there was no evidence for trisomy 2. The bone marrow specimen collected 3 years earlier was hypercellular with features of MDS, refractory cytopenia with multilineage dysplasia (RCMD) subtype. Blasts were not increased, and no ring sideroblasts were present. The peripheral blood smear showed mild normochromic/normocytic anemia and moderate thrombocytopenia. Three years later, the now 69-year-old male had a bone marrow cytogenetic study that revealed 47,XY,þ2[13]/ 46,XY[7]. The bone marrow pathology demonstrated AML with MDS-related changes (54% blasts/promonocytes). Although the chromosome analysis showed isolated trisomy 2, FISH identified four intact copies of the MLL region at 11q23. FISH analysis of three abnormal metaphases indicated that an intact copy of MLL was cryptically translocated to the long arm (q-arm) of two of the chromosomes 2, verifying the presence of two copies of a cryptic 2;11 translocation. About 7 weeks after this study, FISH for MLL was normal. The patient received 7 cycles of cytarabine, which ended at the time of this study, and the patient passed away 10 weeks later. Case 11 was a 55-year-old female who presented with a chromosome study that revealed idic(X)(q13) in 5 of 20 metaphases, 46,X,idic(X)(q13)[5]/46,XX[15]. At that time, the bone marrow biopsy revealed 55% cellularity with 3% myeloblasts and megakaryocytic dysplasia. It was decided that the patient would be observed clinically without treatment. A year later, a cytogenetic study revealed two apparently independent clones: trisomy 2 in 4 of 20 metaphases, and idic(X)(q13) in 13 metaphases, 46,X,idic(X)(q13)[11]/ 47-48,idem,þidic(X)(q13),þ1mar[cp2]/47,XX,þ2[4]/46,XX
3 [3]. Bone marrow biopsy revealed a cellularity of 60% with 6% myeloblasts, which indicated a diagnosis of MDS, RAEB-1 subtype. She received two cycles of hypomethylating therapy with 5-azacitidine, followed by observation. Six years later, she had progressive cytopenias and circulating blasts. A CBC revealed hemoglobin of 12.6, WBC 1.86, and a platelet count of 35,000, with 12% circulating blasts. A bone marrow biopsy was hypercellular (60%) with approximately 17% blasts, which indicated progression to MDS, RAEB-II subtype. Cytogenetics revealed an isodicentric Xq13 in two metaphases and trisomy 2 in eight metaphases. She underwent nine cycles of hypomethylating therapy with decitabine. The last five cycles were administered with a dose reduction due to persistent leukopenia. One year later, she had a bone marrow biopsy that was normocellular (40%) with less than 5% blasts. Cytogenetics identified trisomy 2 in seven metaphases. Four months later, the now 63-year-old female had a cytogenetics study with findings of 47,XX,þ2 [17]/46,X,idic(X)(q13)[1]/46,XX[2]. Bone marrow biopsy showed a hypocellular bone marrow (20%). The bone marrow aspirate revealed slightly decreased erythroid precursors with mild megaloblastoid maturation (M:E ratio 4:1). Maturing forms of granulocytic precursors were virtually absent. Blasts were increased (54%). A diagnosis of AML with MDS-related changes was rendered. She received induction chemotherapy with idarubicin and cytarabine. Her day 14 marrow had a cellularity of 10% with 20% blasts, and her day 21 bone marrow had a cellularity of 57% with 10% blasts. At this point, she required re-induction chemotherapy; however, she developed febrile neutropenia with pneumonia. Seven weeks later, she passed away from cardiorespiratory arrest. Of note, her constitutional cytogenetics analysis was not performed to exclude Turner syndrome with an isochromosome X; however, she gave birth to three healthy children, making a diagnosis of Turner syndrome highly unlikely.
Discussion Isolated trisomies are observed in bone marrow studies. In particular, trisomy 8 is a common finding in myeloid malignancies (9). Although many other trisomies have been observed, they are not as common, as per the 2013 Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/ Mitelman). Trisomy 2 has been reported in eight cases in the literature; however, its significance is not well understood. Herein, we describe 11 cases of trisomy 2 as a sole abnormality in bone marrow studies. These patients’ hematopathologic evaluations represent a range of findings including hypercellular bone marrow without diagnostic features of malignancy (cases 1 and 2); MDS, RCMD subtype (cases 3 and 4); MDS, RAEB-1 subtype (cases 5 and 6); JAK2 V617Fpositive primary myelofibrosis with 7% bone marrow blasts (case 7); AML, not otherwise specified (cases 8 and 9); and AML with myelodysplasia-related changes (cases 10 and 11). The majority of our cases showed a myeloid neoplasm (9 of 11). The patient population was predominantly male (7 of 11) and above age 60 (11 of 11). Molecular pathogenesis and prognostic significance of this abnormality is unknown due to the small number of cases. It has been suggested that trisomy 2 is an age-related
4 phenomenon since the ages of the patients reported in the literature range from 6484 years. This could be a potential explanation since the cases reported in our study have a similar age range (6393 years). One possibility is that trisomy 2 is unrelated to the pathogenesis. Case 7 had trisomy 2 throughout the disease, which was stable for 6 years. Trisomy 2 was found in all of the metaphases in previous studies, with only 3 of 20 metaphases showing trisomy 2 in the final study, which was 18 weeks before the patient passed away. A similar stable disease was seen in case 5. Initially, 2 of 20 metaphases had trisomy 2; however, 4 years later, a normal chromosome study was observed. In fact, the MDS had evolved since trilineage dysplasia was more obvious and monocytosis was present. Finally, case 1 showed trisomy 2 in 4 of 20 metaphases without features diagnostic of a bone marrow disorder. The patient did not receive any treatment and survived 10 years. Thus, this set of cases would suggest that trisomy 2 may be independent from the type of disease, severity of the disease, and disease progression. Conversely, it could be suggested that trisomy 2 is a secondary hit after a primary submicroscopic and/or molecular abnormality. Cases 8, 9, 10, and 11 had disease progression to AML with acquisition of trisomy 2. For case 8, initial cytogenetic testing showed trisomy 8 in only two metaphases in MDS; however, when the disease progressed into AML, the chromosomes showed trisomy 2 in all nine available metaphases. Cases 9 and 10 had normal chromosome studies at initial diagnosis; however, trisomy 2 was later identified with disease progression. Case 11 acquired trisomy 2 early in the disease; however, the percentage of trisomy 2 metaphases was highest (17 of 20 metaphases) at the latest stage of disease upon evolution to AML. Patients 9, 10, and 11 passed away at 7, 10, and 7 weeks following the identification of trisomy 2, respectively. In regard to these conclusions, caution is advised because the clinical information available for some of the cases was limited, such as unavailable diagnostic cytogenetic results and variations in the time frame of follow-up studies. Further case reports and studies are necessary to understand the prognostic significance of trisomy 2. Although
U. Aypar et al. the majority of our cases showed a hematologic malignancy in the bone marrow, given that only a limited number of cases are available, trisomy 2 as a sole abnormality should not be considered as definitive evidence for MDS or another myeloid neoplasm in the absence of diagnostic morphological criteria. Trisomy 2 may, in some cases, be associated with an unidentified primary submicroscopic and/or molecular abnormalities that might be driving disease progression.
References F, Prieto F, Badia L, et al. Cytogenetic studies in 112 cases 1. Sole of untreated myelodysplastic syndromes. Cancer Genet Cytogenet 1992;64:12e20. 2. Cytogenetic analysis in patients with primary myelodysplastic syndromes in leukaemic transformation. A report on 94 cases. ne tique He matologique (GFCH). Groupe Franc‚ais de Cytoge Hematol Cell Ther 1996;38:177e181. 3. Czepulkowski B, Saunders K, Pocock C, et al. Mosaic trisomy 2 in myelodysplastic syndromes and acute myeloblastic leukemias. Cancer Genet Cytogenet 2003;145:78e81. €rk S, Palanduz S, Cefle K, et al. Genotoxicity and sister 4. Oztu chromatid exchange in patients with myelodysplastic disorders. Cancer Genet Cytogenet 2005;159:148e150. 5. Heller M, Provan D, Amess JA, et al. Myelodysplastic syndrome associated with trisomy 2. Clin Lab Haematol 2005;27:270e273. 6. Bao L, Wang X, Ryder J, et al. Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations. Eur J Haematol 2006;77:35e45. 7. Wang ES, Sait SN, Gold D, et al. Genomic, immunophenotypic, and NPM1/FLT3 mutational studies on 17 patients with normal karyotype acute myeloid leukemia (AML) followed by aberrant karyotype AML at relapse. Cancer Genet Cytogenet 2010;202: 101e107. 8. Wiktor A, Rybicki BA, Piao ZS, et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000;27:11e16. 9. Swerdlow SH, Campo E, Harris NL, et al., editors. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer (IARC); 2008.
-
(2014)
-
Isolated trisomy 2 in bone marrows of patients with suspected hematopoietic malignancies Umut Aypar a, Kaaren K. Reichard a, Lindsey A. Waltman b, a, * Daniel L. Van Dyke a b
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Genetic Counselor, Ambry Genetics, Aliso Viejo, CA, USA Isolated trisomy 2 in hematopoietic malignancies is rare, having been reported in only eight cases. Of these cases, the majority are older males. The underlying hematologic malignancies range from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). The molecular pathogenesis and prognostic significance of isolated trisomy 2 remains unknown. Herein, we report 11 cases of isolated trisomy 2 in hematologic disorders seen in the Mayo Clinic Cytogenetics laboratory from 1996e2012. The majority were older males between the ages of 6393 years. The underlying bone marrow pathologic diagnoses ranged from no diagnostic features of malignancy to AML. Our data suggest that isolated trisomy 2 could represent an agerelated phenomenon since all 11 cases were age 63 and over. It appears that isolated trisomy 2 harbors little prognostic significance and that, instead, the prognostic significance is driven by the underlying pathologic diagnosis. For example, whereas 3 of the cases with AML survived only 710 weeks postbone marrow biopsy, 1 of the cases without diagnostic features of malignancy survived 10 additional years. Therefore, trisomy 2 as a sole abnormality should not be considered as definitive evidence for a myeloid neoplasm in the absence of diagnostic morphologic criteria. Keywords Trisomy 2, MDS, AML, PMF ª 2014 Elsevier Inc. All rights reserved.
Isolated trisomy 2 in hematopoietic malignancies is a rare finding that has been reported in eight cases in the literature (1e7). These cases are typically older males ranging from 6484 years old, presenting with various myeloid neoplasms including myelodysplastic syndrome (MDS), refractory anemia (RA) subtype; MDS, RA with excess blasts (RAEB-II) subtype; MDS, RAEB in transformation (RAEB-t) subtype; chronic myelomonocytic leukemia in transformation (CMMLt); acute myeloid leukemia (AML) arising out of prior MDS; acute monoblastic and monocytic leukemia (AMoL; FAB (French-American-British classification system) M5); and relapsed AML (Table 1). The significance of isolated trisomy 2 is not known, but has been postulated to be an age-related phenomenon (3). To further investigate the possible diagnostic and prognostic significance of isolated trisomy 2 in hematologic
Received January 16, 2014; received in revised form February 25, 2014; accepted February 27, 2014. * Corresponding author. E-mail address: [email protected] 2210-7762/$ - see front matter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cancergen.2014.02.011
malignancies, we report the hematopathologic and genetic studies from 11 cases seen at our institution.
Materials and methods Cases with isolated trisomy 2 in bone marrow specimens were identified from 1996 to 2012 in our cytogenetics laboratory. G-banding was performed according to standard cytogenetic methods using trypsin and Leishman stain. Although 20 metaphases are routinely examined, only 9 and 15 metaphases were identified in cases 8 and 4, respectively.
Results We identified 11 cases with isolated trisomy 2 in bone marrow specimens. The specimens were all from older patients, ranging from 6393 years old, and 7 of 11 were male. Their hematopathologic evaluations represent a range of findings including two without diagnostic features of malignancy (Table 2).
2
U. Aypar et al.
Table 1 Cases of isolated trisomy 2 in bone marrow hematopoietic disorders reported in the literature
Table 2 List of the patients with isolated trisomy 2 seen in the Mayo Clinic cytogenetics laboratory between 1996 and 2012
Age Patient (y) Sex Result
Reference
Age Patient (y) Sex Result
Pathology report
(1)
1
87
M
47,XY,þ2[4]/45, X,-Y[3]/46,XY[13]
(2) (3)
2
84
M
47,XY,þ2[11]/46, XY[9]
(3)
3
78
M
47,XY,þ2[17]/46, XY[3]
(4)
4
82
M
47,XY,þ2[6]/46, XY[9]
(5)
5
72
F
47,XX,þ2[2]/46, XX[18]
(6)
6
93
F
47,XX,þ2[19]/46, XX[1]
(7)
7 8 9 10 11
67 82 75 69 63
F M M M F
47,XX,þ2[3]/46, XX[17] 47,XY,þ2[9] 47,XY,þ2[20] 47,XY,þ2[13]/46, XY[7] 47,XX,þ2[17]/46,X, idic(X)(q13)[1]/46,XX[2]
No diagnostic features of malignancy No diagnostic features of malignancy MDS, RCMD subtype MDS, RCMD subtype MDS, RAEB-1 subtype MDS, RAEB-1 subtype PMF AML, NOS AML, NOS AML, MRC AML, MRC
1
74
M
2 3
75 87
M M
4
80
F
5
64
M
6
73
M
7
84
M
8
N/A M
47,XY,þ2a
Pathology report
MDS, RA subtype MDS, RAEB-t 47,XY,þ2a 47,XY,þ2[5]/ MDS 46, XY[35] transformed into AML 47,XX,þ2[22]/ CMML-t 46, XX[8] 47,XY,þ2/46, MDS, RA subtype XYa 47,XY,þ2[5]/ MDS, RAEB-II 46, XY[8] subtype 47,XY,þ2[8]/ AMoL; 46, XY[8] FAB M5 47,XY,þ2[19] AML in relapse
Abbreviation: MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-t, refractory anemia with excess blasts in transformation; AML, acute myeloid leukemia; CMML-t, chronic myelomonocytic leukemia in transformation; AMoL, acute monoblastic and monocytic leukemia; FAB, French-American-British classification system; N/A, not available. a Number of metaphases not reported.
Case 1, 47,XY,þ2[4]/45,X,-Y[3]/46,XY[13], was an 87year-old male who had mild thrombocytopenia and mild anemia. The bone marrow was normocellular (30%; M:E ratio 1.7:1.0) with intact trilineage hematopoiesis and no increase in blasts. Erythropoiesis was mildly megaloblastoid without convincing evidence of myelodysplasia. The patient did not receive any treatment. He survived 10 years after the identification of the trisomy 2. His chromosome study also showed an absence of the Y chromosome in 3 of 20 metaphasesda known age-related phenomenon (8). Case 2, 47,XY,þ2[11]/46,XY[9], was an 84-year-old male with thrombocytopenia. The bone marrow was mildly hypercellular (50%) with mild panhyperplasia and no increase in blasts. Overall findings were compatible with peripheral sequestration and/or destruction of platelets (M:E ratio 3:1). Additional clinical information was not available. Case 3, 47,XY,þ2[17]/46,XY[3], was a 78-year-old male with severe anemia, neutropenia, and thrombocytopenia. The bone marrow showed a hypercellular bone marrow (80e90%) with myeloid maturation arrest at the myelocyte stage, megaloblastoid erythropoiesis, and dysplastic megakaryocytes. The abnormal megakaryocytes were characterized by distinctly separate nuclear lobes. There was 3% blasts. The findings were most suggestive of MDS. No additional clinical information was available; however, a bone marrow specimen collected 11 weeks after this study showed similar findings, except for an increase in blasts to 8%. Case 4, 47,XY,þ2[6]/46,XY[9], was an 82-year-old male with anemia and neutropenia. The bone marrow was mildly hypercellular (40%; M:E ratio 0.3:1) with erythroid hyperplasia and megaloblastoid erythropoiesis, mild dysgranulopoiesis, and increased dysplastic megakaryocytes that consisted of mononuclear forms and micromegakaryocytes.
Abbreviations:MDS, myelodysplastic syndrome; RCMD, refractory cytopenia with multilineage dysplasia; RAEB, refractory anemia with excess blasts; PMF, primary myelofibrosis; AML, acute myeloid leukemia; NOS, not otherwise specified; MRC, myelodysplasiarelated changes.
Blasts were <3%. The overall findings were consistent with MDS, refractory cytopenia with multilineage dyspoiesis subtype. Additional clinical information was not available. Case 5, 47,XX,þ2[2]/46,XX[18], was a 72-year-old female whose initial bone marrow showed moderate to marked hypercellularity (70e75%) with a slightly increased myeloblast percentage (5e6%), granulocytic and erythroid dysplasia, normal-appearing megakaryocytes and ring sideroblasts. The findings were consistent with a diagnosis of MDS, RAEB-1 subtype. No further clinical information was available. A follow-up bone marrow 4 years later showed persistent MDS with a borderline increase in blasts (5e6%) and development of monocytosis. Chromosomes were normal at that time. Case 6, 47,XX,þ2[19]/46,XX[1], was a 93-year-old female whose bone marrow was slightly hypercellular (40%) with mild panhyperplasia, dyserythropoiesis, dysplastic megakaryocytes, and a borderline increase in blasts (5%). The findings were consistent with MDS, RAEB-1 subtype. No additional clinical information was available. Case 7, a female, was initially diagnosed with a myeloproliferative neoplasm for which the pathology and cytogenetics reports were not available for our review. The clinical notes indicated that multiple interval bone marrow biopsies showed a similar pathologic picture, with trisomy 2 in all metaphases. She was treated with hydroxyurea for about 5 years, and after becoming transfusion dependent, she received four cycles of Dacogen. She was then admitted on a clinical trial treatment of pomalidomide; however, no clinical improvement was seen. At this time, her fluorescence in situ hybridization (FISH) test for BCR-ABL1 was normal, and
Isolated trisomy 2 in hematopoietic malignancies chromosomes showed add(3)(q21) in 6 of 20 metaphases. Six months later, the now 67-year-old female, was diagnosed with JAK2 V617Fpositive primary myelofibrosis and a karyotype of 47,XX,þ2[3]/46,XX[17]. The bone marrow core biopsy was 90% cellular with increased megakaryocytes and marked reticulin fibrosis. The touch preparation revealed increased blasts (7%). Eighteen weeks after the cytogenetic study at Mayo Clinic, the patient passed away. Case 8, 47,XY,þ2[9], was an 82-year-old male who had an aparticulate bone marrow sample that was hypocellular. Granulocytes were decreased and left shifted, showing occasional dyspoietic morphology including variable cytoplasmic granulation. Maturing forms of erythrocytes were identified, occasionally with irregular nuclear contours and megaloblastoid nuclear features. Blasts were increased (7%), and a final diagnosis of persistent AML was made. Additional clinical information was not available for this patient. His bone marrow specimen was studied in the laboratory about 9 months earlier, with possible MDS noted as the reason for testing. The results showed trisomy 8 in 2 of 20 metaphases, 47,XY,þ8[2]/46,XY[18]. Case 9, 47,XY,þ2[20], was a 75-year-old male who was originally diagnosed with cytogenetically normal AML (25% blasts in the bone marrow). He was treated with one cycle of decitabine; however, the treatment was stopped due to elevation of circulating blasts. Two months later, a bone marrow specimen showed AML with 50% blasts, trilineage dysplasia, and ring sideroblasts. A FLT3 gene mutation was not identified. The patient passed away after 7 weeks. Case 10 was initially diagnosed with anemia and chromosome studies were performed 3 and 6 years before the current study, which showed that there was no evidence for trisomy 2. The bone marrow specimen collected 3 years earlier was hypercellular with features of MDS, refractory cytopenia with multilineage dysplasia (RCMD) subtype. Blasts were not increased, and no ring sideroblasts were present. The peripheral blood smear showed mild normochromic/normocytic anemia and moderate thrombocytopenia. Three years later, the now 69-year-old male had a bone marrow cytogenetic study that revealed 47,XY,þ2[13]/ 46,XY[7]. The bone marrow pathology demonstrated AML with MDS-related changes (54% blasts/promonocytes). Although the chromosome analysis showed isolated trisomy 2, FISH identified four intact copies of the MLL region at 11q23. FISH analysis of three abnormal metaphases indicated that an intact copy of MLL was cryptically translocated to the long arm (q-arm) of two of the chromosomes 2, verifying the presence of two copies of a cryptic 2;11 translocation. About 7 weeks after this study, FISH for MLL was normal. The patient received 7 cycles of cytarabine, which ended at the time of this study, and the patient passed away 10 weeks later. Case 11 was a 55-year-old female who presented with a chromosome study that revealed idic(X)(q13) in 5 of 20 metaphases, 46,X,idic(X)(q13)[5]/46,XX[15]. At that time, the bone marrow biopsy revealed 55% cellularity with 3% myeloblasts and megakaryocytic dysplasia. It was decided that the patient would be observed clinically without treatment. A year later, a cytogenetic study revealed two apparently independent clones: trisomy 2 in 4 of 20 metaphases, and idic(X)(q13) in 13 metaphases, 46,X,idic(X)(q13)[11]/ 47-48,idem,þidic(X)(q13),þ1mar[cp2]/47,XX,þ2[4]/46,XX
3 [3]. Bone marrow biopsy revealed a cellularity of 60% with 6% myeloblasts, which indicated a diagnosis of MDS, RAEB-1 subtype. She received two cycles of hypomethylating therapy with 5-azacitidine, followed by observation. Six years later, she had progressive cytopenias and circulating blasts. A CBC revealed hemoglobin of 12.6, WBC 1.86, and a platelet count of 35,000, with 12% circulating blasts. A bone marrow biopsy was hypercellular (60%) with approximately 17% blasts, which indicated progression to MDS, RAEB-II subtype. Cytogenetics revealed an isodicentric Xq13 in two metaphases and trisomy 2 in eight metaphases. She underwent nine cycles of hypomethylating therapy with decitabine. The last five cycles were administered with a dose reduction due to persistent leukopenia. One year later, she had a bone marrow biopsy that was normocellular (40%) with less than 5% blasts. Cytogenetics identified trisomy 2 in seven metaphases. Four months later, the now 63-year-old female had a cytogenetics study with findings of 47,XX,þ2 [17]/46,X,idic(X)(q13)[1]/46,XX[2]. Bone marrow biopsy showed a hypocellular bone marrow (20%). The bone marrow aspirate revealed slightly decreased erythroid precursors with mild megaloblastoid maturation (M:E ratio 4:1). Maturing forms of granulocytic precursors were virtually absent. Blasts were increased (54%). A diagnosis of AML with MDS-related changes was rendered. She received induction chemotherapy with idarubicin and cytarabine. Her day 14 marrow had a cellularity of 10% with 20% blasts, and her day 21 bone marrow had a cellularity of 57% with 10% blasts. At this point, she required re-induction chemotherapy; however, she developed febrile neutropenia with pneumonia. Seven weeks later, she passed away from cardiorespiratory arrest. Of note, her constitutional cytogenetics analysis was not performed to exclude Turner syndrome with an isochromosome X; however, she gave birth to three healthy children, making a diagnosis of Turner syndrome highly unlikely.
Discussion Isolated trisomies are observed in bone marrow studies. In particular, trisomy 8 is a common finding in myeloid malignancies (9). Although many other trisomies have been observed, they are not as common, as per the 2013 Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer (http://cgap.nci.nih.gov/Chromosomes/ Mitelman). Trisomy 2 has been reported in eight cases in the literature; however, its significance is not well understood. Herein, we describe 11 cases of trisomy 2 as a sole abnormality in bone marrow studies. These patients’ hematopathologic evaluations represent a range of findings including hypercellular bone marrow without diagnostic features of malignancy (cases 1 and 2); MDS, RCMD subtype (cases 3 and 4); MDS, RAEB-1 subtype (cases 5 and 6); JAK2 V617Fpositive primary myelofibrosis with 7% bone marrow blasts (case 7); AML, not otherwise specified (cases 8 and 9); and AML with myelodysplasia-related changes (cases 10 and 11). The majority of our cases showed a myeloid neoplasm (9 of 11). The patient population was predominantly male (7 of 11) and above age 60 (11 of 11). Molecular pathogenesis and prognostic significance of this abnormality is unknown due to the small number of cases. It has been suggested that trisomy 2 is an age-related
4 phenomenon since the ages of the patients reported in the literature range from 6484 years. This could be a potential explanation since the cases reported in our study have a similar age range (6393 years). One possibility is that trisomy 2 is unrelated to the pathogenesis. Case 7 had trisomy 2 throughout the disease, which was stable for 6 years. Trisomy 2 was found in all of the metaphases in previous studies, with only 3 of 20 metaphases showing trisomy 2 in the final study, which was 18 weeks before the patient passed away. A similar stable disease was seen in case 5. Initially, 2 of 20 metaphases had trisomy 2; however, 4 years later, a normal chromosome study was observed. In fact, the MDS had evolved since trilineage dysplasia was more obvious and monocytosis was present. Finally, case 1 showed trisomy 2 in 4 of 20 metaphases without features diagnostic of a bone marrow disorder. The patient did not receive any treatment and survived 10 years. Thus, this set of cases would suggest that trisomy 2 may be independent from the type of disease, severity of the disease, and disease progression. Conversely, it could be suggested that trisomy 2 is a secondary hit after a primary submicroscopic and/or molecular abnormality. Cases 8, 9, 10, and 11 had disease progression to AML with acquisition of trisomy 2. For case 8, initial cytogenetic testing showed trisomy 8 in only two metaphases in MDS; however, when the disease progressed into AML, the chromosomes showed trisomy 2 in all nine available metaphases. Cases 9 and 10 had normal chromosome studies at initial diagnosis; however, trisomy 2 was later identified with disease progression. Case 11 acquired trisomy 2 early in the disease; however, the percentage of trisomy 2 metaphases was highest (17 of 20 metaphases) at the latest stage of disease upon evolution to AML. Patients 9, 10, and 11 passed away at 7, 10, and 7 weeks following the identification of trisomy 2, respectively. In regard to these conclusions, caution is advised because the clinical information available for some of the cases was limited, such as unavailable diagnostic cytogenetic results and variations in the time frame of follow-up studies. Further case reports and studies are necessary to understand the prognostic significance of trisomy 2. Although
U. Aypar et al. the majority of our cases showed a hematologic malignancy in the bone marrow, given that only a limited number of cases are available, trisomy 2 as a sole abnormality should not be considered as definitive evidence for MDS or another myeloid neoplasm in the absence of diagnostic morphological criteria. Trisomy 2 may, in some cases, be associated with an unidentified primary submicroscopic and/or molecular abnormalities that might be driving disease progression.
References F, Prieto F, Badia L, et al. Cytogenetic studies in 112 cases 1. Sole of untreated myelodysplastic syndromes. Cancer Genet Cytogenet 1992;64:12e20. 2. Cytogenetic analysis in patients with primary myelodysplastic syndromes in leukaemic transformation. A report on 94 cases. ne tique He matologique (GFCH). Groupe Franc‚ais de Cytoge Hematol Cell Ther 1996;38:177e181. 3. Czepulkowski B, Saunders K, Pocock C, et al. Mosaic trisomy 2 in myelodysplastic syndromes and acute myeloblastic leukemias. Cancer Genet Cytogenet 2003;145:78e81. €rk S, Palanduz S, Cefle K, et al. Genotoxicity and sister 4. Oztu chromatid exchange in patients with myelodysplastic disorders. Cancer Genet Cytogenet 2005;159:148e150. 5. Heller M, Provan D, Amess JA, et al. Myelodysplastic syndrome associated with trisomy 2. Clin Lab Haematol 2005;27:270e273. 6. Bao L, Wang X, Ryder J, et al. Prospective study of 174 de novo acute myelogenous leukemias according to the WHO classification: subtypes, cytogenetic features and FLT3 mutations. Eur J Haematol 2006;77:35e45. 7. Wang ES, Sait SN, Gold D, et al. Genomic, immunophenotypic, and NPM1/FLT3 mutational studies on 17 patients with normal karyotype acute myeloid leukemia (AML) followed by aberrant karyotype AML at relapse. Cancer Genet Cytogenet 2010;202: 101e107. 8. Wiktor A, Rybicki BA, Piao ZS, et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000;27:11e16. 9. Swerdlow SH, Campo E, Harris NL, et al., editors. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer (IARC); 2008.