- Email: [email protected]
Tetraploid Acute Promyelocytic Leukemia with Large Bizarre Blast Cell Morphology
SHORT COMMUNICATIONS
Tetraploid Acute Promyelocytic Leukemia with Large Bizarre Blast Cell Morphology W. Y. Au, S. K. Ma, C. C. K. Lam, L. C. Chan, and Y. L. Kwong
ABSTRACT: We describe a case of atypical acute promyelocytic leukemia (APL) with a tetraploid clone and multiple karyotypic abnormalities in addition to the translocation (15;17)(q22;q21). Microscopically, the leukemic cells were highly heterogeneous in morphology and granularity, being bizarre and large in size compared with classical APL blasts. The patient responded to treatment with chemotherapy and all-trans-retinoic acid, at diagnosis and at relapse 10 months later. He is currently in clinical and molecular remission, 3 years after initial diagnosis. Tetraploidy in association with large and bizarre blasts has not been previously reported in APL. Although tetraploidy and complex karyotypic aberrations confer a poor prognosis in other types of acute myeloid leukemia, in the presence of t(15;17) they did not appear to affect the prognosis, inasmuch as the clinical features and treatment outcome in our case followed those of APL in general. © 1999 Elsevier Science, Inc. All rights reserved. INTRODUCTION Acute promyelocytic leukemia (APL) is specifically associated with the translocation (15;17)(q22;q21) and the PML/RAR gene fusion [1]. Previously, disseminated intravascular coagulopathy (DIC) during induction chemotherapy was a major cause of death, curtailing the overall treatment results of this leukemia. However, the use of alltrans retinoic acid (ATRA) and arsenic trioxide for induction therapy has made DIC an uncommon event, so APL has become one of the most curable leukemias [2, 3]. Tetraploidy in acute myeloid leukemia (AML) is uncommon and, except in APL, has been reported in all French– American–British (FAB) subclasses. Tetraploidy in AML is often associated with poor prognosis [4]. We report a unique case of APL with tetraploidy and bizarre blast morphology. The leukemia responded to ATRA and chemotherapy, both at diagnosis and at relapse. MATERIALS AND METHODS Case Report A 24-year-old Chinese man presented with gum bleeding and fever. Initial complete blood count showed hemogloFrom the Department of Medicine (W. Y. A., Y. L. K.), and the Department of Pathology (S. K. M., C. C. K. L., L. C. C.), University of Hong Kong, Queen Mary Hospital, Hong Kong, People’s Republic of China. Address reprint requests to: Dr. Y. L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, People’s Republic of China. Received November 10, 1998; accepted March 30, 1999. Cancer Genet Cytogenet 115:52–55 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
bin, 7.9g/dL; white cell count, 1.6 3 109/L; and platelet count, 32 3 109/L; with deranged clotting profile suggestive of DIC. Bone marrow biopsy showed APL. The patient was started on ATRA (45 mg/m2 3 6 weeks), which was complicated by severe ATRA syndrome requiring 4 weeks of mechanical ventilation. However, a complete remission (CR) was obtained, which was consolidated with two courses of chemotherapy (daunorubicin, 50 mg/m2 3 2 days; cytosine arabinoside (Ara-C), 100 mg/m2 3 5 days). He relapsed 10 months afterward and was induced into a second CR with ATRA and chemotherapy (Ara-C 1 g/m2 3 4 days, mitoxantrone 12 mg/m2 3 3 days), which was consolidated with two courses of Ara-C/mitoxantrone and three courses of Ara-C (6 g/m2 3 2 days). He is currently still in the second CR, 14 months after the last course of chemotherapy. Morphologic, Karyotypic, and Molecular Analyses Morphologic, cytochemical, and immunophenotypic analyses by the alkaline phosphatase anti-alkaline phosphatase method were performed according to standard protocols. Cytogenetic analysis was performed on Giemsabanded metaphases from overnight marrow cell culture. Reverse transcription–polymerase chain reaction (RTPCR) for the PML/RAR fusion transcript with two pairs of nested PML and RAR primers was performed as previously described [5]. RESULTS Morphologic, Karyotypic, and Molecular Analyses The blast cells were large, with a low nuclear/cytoplasmic ratio, bizarre nuclear configuration, and multiple nucleoli
0165-4608/99/$–see front matter PII S0165-4608(99)00066-7
53
Atypical Acute Promyelocytic Leukemia (Fig. 1). The cytoplasm showed a range of granulation, some being rather hypergranular, but Auer rods were rarely seen. The blasts were moderately positive for Sudan Black B and weakly positive for myeloperoxidase, and they expressed CD2, CD13, and CD33. The features were consistent with an atypical case of the microgranular variant of APL. Karyotypic analysis showed a tetraploid clone with a modal chromosome number of more than 80. A t(15;17) was present in all abnormal cells analyzed, in addition to multiple monosomies and marker chromosomes (Fig. 2). The complete karyotype was: 73z89,XXY,2Y[3], 23[10],25[9],27[4],29[7],211[9],214[10],215[9],t(15;17) (q22;q21)[10],t(15;17)(q22;q21)[4],der(15)t(15;17)(q22;q21) [4],217[8],218[7],19[9],220[3],1mar1[9],1mar232[10], 1mar3[7][cp10]/46,XY[6]. RT-PCR showed a PCR product of 87 b.p., consistent with fusion of the PML exon 3 to RARA exon 3 (results not shown). Repeated RT-PCR monitoring of the peripheral blood after the second remission had been achieved remained persistently negative.
DISCUSSION Although aneuploidy is often detected in AML with sensitive techniques such as flow cytometry [6], tetraploidy is seldom observed in conventional karyotypic analysis.
Cases of tetraploid AML were previously reported in FAB subtypes of M0 [7], M1 [8], M2 [9], M4/5 [6, 10], M6 [11], and M7 [12] but not in M3. Association of tetraploidy with leukemia-specific translocations, especially t(8;21), has also been reported [9, 13, 14]. Morphologically, tetraploidy is associated with large and bizarre blasts, probably due to the increased nucleic acid content [6, 15, 16]. Tetraploidy has been more extensively studied in pediatric acute lymphoblastic leukemia, although its prognostic significance is still uncertain [17]. In adult AML cases, however, tetraploidy is typically associated with a poor response to treatment [6]. An association with granulocytic sarcoma has also been reported [4]. This is the only tetraploid case among 45 consecutive cases of APL analyzed in our hospital. To our knowledge, it is the first reported case of tetraploid APL. In addition, there are some interesting findings. First, although the diagnosis of APL is often based on microscopic features, the morphology in some cases might be different from the classical and microgranular variant subtypes [18]. Our tetraploid case is probably a further variant of the FAB microgranular category, with the large and bizarre blasts making a morphologic diagnosis of APL difficult. This case therefore emphasizes the importance of cytogenetic and molecular confirmation of suspicious cases [19–21]. Second, our patient showed a good response to ATRA induction de-
Figure 1 (A) Bone marrow smear showing abnormal blasts that are large in size (note comparison with the size of red cells in the background) with low nuclear cytoplasmic ratio, bizarre and highly convoluted nuclear configuration, open chromatin, and multiple nucleoli. Cytoplasmic granulation is variable and Auer rods are very infrequently encountered. The mean cell size is 29 mm (range 23–32 mm) as measured by a micrometer (Wright Giemsa). (B) Trephine biopsy showing hypercellular marrow that is replaced by large blasts with marked nuclear lobulation (hematoxylin/eosin).
54
W. Y. Au et al.
Figure 2 Tetraploid karyotype with t(15;17) (shown by arrows).
spite multiple secondary karyotypic abnormalities. The absence of RT-PCR-detectable disease at follow-up is highly predictive of cure [22]. The favorable prognostic effect of the PML-RAR gene fusion seemed to override other poor clinical (e.g., secondary AML) and cytogenetic prognostic factors in leukemia [23, 24]. Tetraploidy in APL, as in other AML, is probably a secondary phenomenon after the initial leukemogenic event [13]. The frequency of secondary cytogenetic abnormalities in APL, mostly trisomies, is about 30% [24] and may be higher if assessed by more sensitive techniques [5]. Their prognostic significance remains to be clarified [25, 26]. In our case, neither the tetraploidy nor the additional karyotypic aberrations appeared to have affected the response to treatment or the prognosis.
REFERENCES 1. Huang W, Sun GL, Li XS, Cao Q, Lu Y, Jang GS, Zhang, FQ, Chai JR, Wang ZY, Waxman S (1993): Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood 82:1264–1269. 2. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F (1996): AIDA (alltrans retinoic acid 1 idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) pilot study. Blood 88:1390–1398. 3. Shen Z, Chen G, Ni J, Li X, Xiong S, Qiu Q, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhao L, Fang ZW, Wang YT, Ma J,
Zhang, P, Zhang TD, Chen SJ, Chen Z, Wang ZY (1997): Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL) II: clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360. 4. Au WY, Ma SK, Chan AC, Liang R, Lam CC, Kwong YL (1998): Near tetraploidy in three cases of acute myeloid leukemia associated with mediastinal granulocytic sarcoma. Cancer Genet Cytogenet 102:50–53. 5. Kwong YL, Wong KF, Chan TK (1995): Trisomy 8 in acute promyelocytic leukaemia: an interphase study by fluorescence in situ hybridization. Br J Haematol 90:697–700. 6. Clarke MR, Lynch EF, Contis LC, Sherer ME, Shekhter Levin S. (1996): Near-tetraploidy in adult acute myelogenous leukemia. Cancer Genet Cytogenet 86:107–115. 7. Lemez P, Jelinek J, Michalova K, Koubek K, Schwarz J, Malaskova V, Rypackova B, Jirasek A, Brezinova J, Hrabenek J (1994): Near-tetraploid poorly differentiated acute myeloid leukemia M0 diagnosed by short-term cultures with a phorbol ester TPA. Leuk Res 18:493–497. 8. Zelante L, Perla G, Bodenizza C, Greco M, Carotenuto M, Dallapiccola B (1988): Tetraploidy (92,XXYY) in acute nonlymphocytic leukemia (M1) patient following autologous bone marrow transplantation. Cancer Genet Cytogenet 36:69–75. 9. Abe R, Raza A, Preisler HD, Tebbi CK, Sandberg AA (1985): Chromosomes and causation of human cancer and leukemia LIV: near-tetraploidy in acute leukemia. Cancer Genet Cytogenet 14:45–59. 10. Weh HJ, von Paleske A, Hossfeld DK (1983): Disappearance of hypotetraploid clones after short-term culture of leukemic cells: a case report. Cancer Genet Cytogenet 10:237–240. 11. Kocova M, Sandberg A (1985): Major karyotypic abnormalities in a near-tetraploid erythroleukemia. Cancer Genet Cytogenet 17:143–150.
55
Atypical Acute Promyelocytic Leukemia 12. Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic M, Fink FM, Stojimirovic A, Hermann J, Riehm HJ (1992): The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood 79:3325–3330. 13. Kohler M, Johansson B, Ludvigsson J, Aman P, Heim S, Mitelman F (1994): Acute myeloid leukemia (AML-M1) with multiple trisomies and t(8;21)(q22;q22). Cancer Genet Cytogenet 73:79–81.
21.
22.
14. Xue Y, Pan Y, Liu Z, Li J, Guo Y, Xie X (1996): Tetraploid or near-tetraploid clones characterized by two 8;21 translocations and other chromosomal abnormalities in two patients with acute myeloblastic leukemia. Cancer Genet Cytogenet 92:18–23. 15. Kwong YL, Wong KF (1995): Hyperdiploid acute myeloid leukemia: relationship between blast size and karyotype demonstrated by fluorescence in situ hybridization. Cancer Genet Cytogenet 83:1–4.
23.
16. Testa J, Oguma N, Pollak A, Wiernik P (1983): Near-tetraploid clones in acute leukemia. Blood 61:71–78.
24.
17. Pui C, Carroll A, Head D, Raimondi S, Shuster J, Crist W, Link MP, Borowitz MJ, Behm FG, Land VJ, Nash MB, Pullen DJ, Look AT (1990): Near triploid and near tetraploid acute lymphoblastic leukemia of childhood. Blood 76:590–596.
25.
18. Neame PB, Soamboonsrup P, Leber B, Carter RF, Sunisloe L, Patterson W, Orzel A, Bates S, McBride JA (1997): Morphology of acute promyelocytic leukemia with cytogenetic or molecular evidence for the diagnosis: characterization of additional microgranular variants. Am J Hematol 56:131– 142. 19. Diverio D, Pandolfi PP, Rossi V, Biondi A, Pelicci PG, Lo Coco F (1994): Monitoring of treatment outcome in acute promyelocytic leukemia by RT-PCR. Leukemia 8:1105–1107. 20. Acar H, Dundar M, Stewart J (1997): Identification of classic
26.
and complex t(15;17) and/or RAR alpha/PML gene fusion in APL by cytogenetic and dual color-FISH techniques. Proc Natl Sci Counc Repub China B 21:54–60. Mancini M, Nanni M, Cedrone M, Diverio D, Avvisati G, Riccioni R, De Cuia MR, Fenu S, Alimena G (1995): Combined cytogenetic, FISH and molecular analysis in acute promyelocytic leukaemia at diagnosis and in complete remission. Br J Haematol 91:878–884. Martinelli G, Remiddi C, Visani G, Farabegoli P, Testoni N, Zaccaria A, Manfroi S, Cenacchi A, Russo D, Bandini G (1995): Molecular analysis of PML-RAR alpha fusion mRNA detected by reverse transcription-polymerase chain reaction assay in long-term disease-free acute promyelocytic leukaemia patients. Br J Haematol 90:966–968. Wiernik PH, Dutcher JP, Paietta E, Hittelman WN, Vyas R, Strack M, Castaigne S, Degos L, Gallagher RE (1991): Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid. Leukemia 5:504–509. Pollicardo N, O’Brien S, Estey EH, al Bitar M, Pierce S, Keating M, Kantarjian HM (1996): Secondary acute promyelocytic leukemia: characteristics and prognosis of 14 patients from a single institution. Leukemia 10:27–31. Slack JL, Arthur DC, Lawrence D, Mrozek K, Mayer RJ, Davey FR, Tantravahi R, Pattenati MJ, Bigner S, Carroll AJ, Rao KW, Schiffer CA, Bloomfield CD (1997): Secondary cytogenetic changes in acute promyelocytic leukemia: prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene; a Cancer and Leukemia Group B study. J Clin Oncol 15:1786– 1795. Hiorns LR, Swansbury GJ, Mehta J, Min T, Dainton MG, Treleaven J, Powles RL, Catovsky D (1997): Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia. Br J Haematol 96:314–321.
Tetraploid Acute Promyelocytic Leukemia with Large Bizarre Blast Cell Morphology W. Y. Au, S. K. Ma, C. C. K. Lam, L. C. Chan, and Y. L. Kwong
ABSTRACT: We describe a case of atypical acute promyelocytic leukemia (APL) with a tetraploid clone and multiple karyotypic abnormalities in addition to the translocation (15;17)(q22;q21). Microscopically, the leukemic cells were highly heterogeneous in morphology and granularity, being bizarre and large in size compared with classical APL blasts. The patient responded to treatment with chemotherapy and all-trans-retinoic acid, at diagnosis and at relapse 10 months later. He is currently in clinical and molecular remission, 3 years after initial diagnosis. Tetraploidy in association with large and bizarre blasts has not been previously reported in APL. Although tetraploidy and complex karyotypic aberrations confer a poor prognosis in other types of acute myeloid leukemia, in the presence of t(15;17) they did not appear to affect the prognosis, inasmuch as the clinical features and treatment outcome in our case followed those of APL in general. © 1999 Elsevier Science, Inc. All rights reserved. INTRODUCTION Acute promyelocytic leukemia (APL) is specifically associated with the translocation (15;17)(q22;q21) and the PML/RAR gene fusion [1]. Previously, disseminated intravascular coagulopathy (DIC) during induction chemotherapy was a major cause of death, curtailing the overall treatment results of this leukemia. However, the use of alltrans retinoic acid (ATRA) and arsenic trioxide for induction therapy has made DIC an uncommon event, so APL has become one of the most curable leukemias [2, 3]. Tetraploidy in acute myeloid leukemia (AML) is uncommon and, except in APL, has been reported in all French– American–British (FAB) subclasses. Tetraploidy in AML is often associated with poor prognosis [4]. We report a unique case of APL with tetraploidy and bizarre blast morphology. The leukemia responded to ATRA and chemotherapy, both at diagnosis and at relapse. MATERIALS AND METHODS Case Report A 24-year-old Chinese man presented with gum bleeding and fever. Initial complete blood count showed hemogloFrom the Department of Medicine (W. Y. A., Y. L. K.), and the Department of Pathology (S. K. M., C. C. K. L., L. C. C.), University of Hong Kong, Queen Mary Hospital, Hong Kong, People’s Republic of China. Address reprint requests to: Dr. Y. L. Kwong, University Department of Medicine, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, People’s Republic of China. Received November 10, 1998; accepted March 30, 1999. Cancer Genet Cytogenet 115:52–55 (1999) Elsevier Science Inc., 1999. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
bin, 7.9g/dL; white cell count, 1.6 3 109/L; and platelet count, 32 3 109/L; with deranged clotting profile suggestive of DIC. Bone marrow biopsy showed APL. The patient was started on ATRA (45 mg/m2 3 6 weeks), which was complicated by severe ATRA syndrome requiring 4 weeks of mechanical ventilation. However, a complete remission (CR) was obtained, which was consolidated with two courses of chemotherapy (daunorubicin, 50 mg/m2 3 2 days; cytosine arabinoside (Ara-C), 100 mg/m2 3 5 days). He relapsed 10 months afterward and was induced into a second CR with ATRA and chemotherapy (Ara-C 1 g/m2 3 4 days, mitoxantrone 12 mg/m2 3 3 days), which was consolidated with two courses of Ara-C/mitoxantrone and three courses of Ara-C (6 g/m2 3 2 days). He is currently still in the second CR, 14 months after the last course of chemotherapy. Morphologic, Karyotypic, and Molecular Analyses Morphologic, cytochemical, and immunophenotypic analyses by the alkaline phosphatase anti-alkaline phosphatase method were performed according to standard protocols. Cytogenetic analysis was performed on Giemsabanded metaphases from overnight marrow cell culture. Reverse transcription–polymerase chain reaction (RTPCR) for the PML/RAR fusion transcript with two pairs of nested PML and RAR primers was performed as previously described [5]. RESULTS Morphologic, Karyotypic, and Molecular Analyses The blast cells were large, with a low nuclear/cytoplasmic ratio, bizarre nuclear configuration, and multiple nucleoli
0165-4608/99/$–see front matter PII S0165-4608(99)00066-7
53
Atypical Acute Promyelocytic Leukemia (Fig. 1). The cytoplasm showed a range of granulation, some being rather hypergranular, but Auer rods were rarely seen. The blasts were moderately positive for Sudan Black B and weakly positive for myeloperoxidase, and they expressed CD2, CD13, and CD33. The features were consistent with an atypical case of the microgranular variant of APL. Karyotypic analysis showed a tetraploid clone with a modal chromosome number of more than 80. A t(15;17) was present in all abnormal cells analyzed, in addition to multiple monosomies and marker chromosomes (Fig. 2). The complete karyotype was: 73z89,XXY,2Y[3], 23[10],25[9],27[4],29[7],211[9],214[10],215[9],t(15;17) (q22;q21)[10],t(15;17)(q22;q21)[4],der(15)t(15;17)(q22;q21) [4],217[8],218[7],19[9],220[3],1mar1[9],1mar232[10], 1mar3[7][cp10]/46,XY[6]. RT-PCR showed a PCR product of 87 b.p., consistent with fusion of the PML exon 3 to RARA exon 3 (results not shown). Repeated RT-PCR monitoring of the peripheral blood after the second remission had been achieved remained persistently negative.
DISCUSSION Although aneuploidy is often detected in AML with sensitive techniques such as flow cytometry [6], tetraploidy is seldom observed in conventional karyotypic analysis.
Cases of tetraploid AML were previously reported in FAB subtypes of M0 [7], M1 [8], M2 [9], M4/5 [6, 10], M6 [11], and M7 [12] but not in M3. Association of tetraploidy with leukemia-specific translocations, especially t(8;21), has also been reported [9, 13, 14]. Morphologically, tetraploidy is associated with large and bizarre blasts, probably due to the increased nucleic acid content [6, 15, 16]. Tetraploidy has been more extensively studied in pediatric acute lymphoblastic leukemia, although its prognostic significance is still uncertain [17]. In adult AML cases, however, tetraploidy is typically associated with a poor response to treatment [6]. An association with granulocytic sarcoma has also been reported [4]. This is the only tetraploid case among 45 consecutive cases of APL analyzed in our hospital. To our knowledge, it is the first reported case of tetraploid APL. In addition, there are some interesting findings. First, although the diagnosis of APL is often based on microscopic features, the morphology in some cases might be different from the classical and microgranular variant subtypes [18]. Our tetraploid case is probably a further variant of the FAB microgranular category, with the large and bizarre blasts making a morphologic diagnosis of APL difficult. This case therefore emphasizes the importance of cytogenetic and molecular confirmation of suspicious cases [19–21]. Second, our patient showed a good response to ATRA induction de-
Figure 1 (A) Bone marrow smear showing abnormal blasts that are large in size (note comparison with the size of red cells in the background) with low nuclear cytoplasmic ratio, bizarre and highly convoluted nuclear configuration, open chromatin, and multiple nucleoli. Cytoplasmic granulation is variable and Auer rods are very infrequently encountered. The mean cell size is 29 mm (range 23–32 mm) as measured by a micrometer (Wright Giemsa). (B) Trephine biopsy showing hypercellular marrow that is replaced by large blasts with marked nuclear lobulation (hematoxylin/eosin).
54
W. Y. Au et al.
Figure 2 Tetraploid karyotype with t(15;17) (shown by arrows).
spite multiple secondary karyotypic abnormalities. The absence of RT-PCR-detectable disease at follow-up is highly predictive of cure [22]. The favorable prognostic effect of the PML-RAR gene fusion seemed to override other poor clinical (e.g., secondary AML) and cytogenetic prognostic factors in leukemia [23, 24]. Tetraploidy in APL, as in other AML, is probably a secondary phenomenon after the initial leukemogenic event [13]. The frequency of secondary cytogenetic abnormalities in APL, mostly trisomies, is about 30% [24] and may be higher if assessed by more sensitive techniques [5]. Their prognostic significance remains to be clarified [25, 26]. In our case, neither the tetraploidy nor the additional karyotypic aberrations appeared to have affected the response to treatment or the prognosis.
REFERENCES 1. Huang W, Sun GL, Li XS, Cao Q, Lu Y, Jang GS, Zhang, FQ, Chai JR, Wang ZY, Waxman S (1993): Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood 82:1264–1269. 2. Avvisati G, Lo Coco F, Diverio D, Falda M, Ferrara F, Lazzarino M, Russo D, Petti MC, Mandelli F (1996): AIDA (alltrans retinoic acid 1 idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) pilot study. Blood 88:1390–1398. 3. Shen Z, Chen G, Ni J, Li X, Xiong S, Qiu Q, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhao L, Fang ZW, Wang YT, Ma J,
Zhang, P, Zhang TD, Chen SJ, Chen Z, Wang ZY (1997): Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL) II: clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360. 4. Au WY, Ma SK, Chan AC, Liang R, Lam CC, Kwong YL (1998): Near tetraploidy in three cases of acute myeloid leukemia associated with mediastinal granulocytic sarcoma. Cancer Genet Cytogenet 102:50–53. 5. Kwong YL, Wong KF, Chan TK (1995): Trisomy 8 in acute promyelocytic leukaemia: an interphase study by fluorescence in situ hybridization. Br J Haematol 90:697–700. 6. Clarke MR, Lynch EF, Contis LC, Sherer ME, Shekhter Levin S. (1996): Near-tetraploidy in adult acute myelogenous leukemia. Cancer Genet Cytogenet 86:107–115. 7. Lemez P, Jelinek J, Michalova K, Koubek K, Schwarz J, Malaskova V, Rypackova B, Jirasek A, Brezinova J, Hrabenek J (1994): Near-tetraploid poorly differentiated acute myeloid leukemia M0 diagnosed by short-term cultures with a phorbol ester TPA. Leuk Res 18:493–497. 8. Zelante L, Perla G, Bodenizza C, Greco M, Carotenuto M, Dallapiccola B (1988): Tetraploidy (92,XXYY) in acute nonlymphocytic leukemia (M1) patient following autologous bone marrow transplantation. Cancer Genet Cytogenet 36:69–75. 9. Abe R, Raza A, Preisler HD, Tebbi CK, Sandberg AA (1985): Chromosomes and causation of human cancer and leukemia LIV: near-tetraploidy in acute leukemia. Cancer Genet Cytogenet 14:45–59. 10. Weh HJ, von Paleske A, Hossfeld DK (1983): Disappearance of hypotetraploid clones after short-term culture of leukemic cells: a case report. Cancer Genet Cytogenet 10:237–240. 11. Kocova M, Sandberg A (1985): Major karyotypic abnormalities in a near-tetraploid erythroleukemia. Cancer Genet Cytogenet 17:143–150.
55
Atypical Acute Promyelocytic Leukemia 12. Lion T, Haas OA, Harbott J, Bannier E, Ritterbach J, Jankovic M, Fink FM, Stojimirovic A, Hermann J, Riehm HJ (1992): The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children. Blood 79:3325–3330. 13. Kohler M, Johansson B, Ludvigsson J, Aman P, Heim S, Mitelman F (1994): Acute myeloid leukemia (AML-M1) with multiple trisomies and t(8;21)(q22;q22). Cancer Genet Cytogenet 73:79–81.
21.
22.
14. Xue Y, Pan Y, Liu Z, Li J, Guo Y, Xie X (1996): Tetraploid or near-tetraploid clones characterized by two 8;21 translocations and other chromosomal abnormalities in two patients with acute myeloblastic leukemia. Cancer Genet Cytogenet 92:18–23. 15. Kwong YL, Wong KF (1995): Hyperdiploid acute myeloid leukemia: relationship between blast size and karyotype demonstrated by fluorescence in situ hybridization. Cancer Genet Cytogenet 83:1–4.
23.
16. Testa J, Oguma N, Pollak A, Wiernik P (1983): Near-tetraploid clones in acute leukemia. Blood 61:71–78.
24.
17. Pui C, Carroll A, Head D, Raimondi S, Shuster J, Crist W, Link MP, Borowitz MJ, Behm FG, Land VJ, Nash MB, Pullen DJ, Look AT (1990): Near triploid and near tetraploid acute lymphoblastic leukemia of childhood. Blood 76:590–596.
25.
18. Neame PB, Soamboonsrup P, Leber B, Carter RF, Sunisloe L, Patterson W, Orzel A, Bates S, McBride JA (1997): Morphology of acute promyelocytic leukemia with cytogenetic or molecular evidence for the diagnosis: characterization of additional microgranular variants. Am J Hematol 56:131– 142. 19. Diverio D, Pandolfi PP, Rossi V, Biondi A, Pelicci PG, Lo Coco F (1994): Monitoring of treatment outcome in acute promyelocytic leukemia by RT-PCR. Leukemia 8:1105–1107. 20. Acar H, Dundar M, Stewart J (1997): Identification of classic
26.
and complex t(15;17) and/or RAR alpha/PML gene fusion in APL by cytogenetic and dual color-FISH techniques. Proc Natl Sci Counc Repub China B 21:54–60. Mancini M, Nanni M, Cedrone M, Diverio D, Avvisati G, Riccioni R, De Cuia MR, Fenu S, Alimena G (1995): Combined cytogenetic, FISH and molecular analysis in acute promyelocytic leukaemia at diagnosis and in complete remission. Br J Haematol 91:878–884. Martinelli G, Remiddi C, Visani G, Farabegoli P, Testoni N, Zaccaria A, Manfroi S, Cenacchi A, Russo D, Bandini G (1995): Molecular analysis of PML-RAR alpha fusion mRNA detected by reverse transcription-polymerase chain reaction assay in long-term disease-free acute promyelocytic leukaemia patients. Br J Haematol 90:966–968. Wiernik PH, Dutcher JP, Paietta E, Hittelman WN, Vyas R, Strack M, Castaigne S, Degos L, Gallagher RE (1991): Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all trans-retinoic acid. Leukemia 5:504–509. Pollicardo N, O’Brien S, Estey EH, al Bitar M, Pierce S, Keating M, Kantarjian HM (1996): Secondary acute promyelocytic leukemia: characteristics and prognosis of 14 patients from a single institution. Leukemia 10:27–31. Slack JL, Arthur DC, Lawrence D, Mrozek K, Mayer RJ, Davey FR, Tantravahi R, Pattenati MJ, Bigner S, Carroll AJ, Rao KW, Schiffer CA, Bloomfield CD (1997): Secondary cytogenetic changes in acute promyelocytic leukemia: prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene; a Cancer and Leukemia Group B study. J Clin Oncol 15:1786– 1795. Hiorns LR, Swansbury GJ, Mehta J, Min T, Dainton MG, Treleaven J, Powles RL, Catovsky D (1997): Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia. Br J Haematol 96:314–321.