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Cerebellar granulocytic sarcoma in an infant with CD56+ acute monoblastic leukemia
Leukemia Research 25 (2001) 1019– 1021 www.elsevier.com/locate/leukres
Case report
Cerebellar granulocytic sarcoma in an infant with CD56+ acute monoblastic leukemia Elene Psiachou-Leonard a,*, Georgios Paterakis b, Kalliopi Stefanaki c, Vasiliki Mikraki-Christou a, Stavros Haidas a a
Department of Haematology –Oncology, Aghia Sophia Children’s Hospital, Thi6on & Papadiamanto-poulou, Athens 11527, Greece b Department of Immunology and Histocompatibility, General Hospital ‘G. Gennimatas’, Athens, Greece c Department of Pathology, Aghia Sophia Children’s Hospital, Athens, Greece Received 1 October 2000; accepted 10 March 2001
Abstract Granulocytic sarcoma (GS) is a form of extramedullary leukaemia (EML). The presence of the neural cell adhesion molecule (NCAM) on the surface of the blasts, which is recognized by the CD56 monoclonal antibody, enhances their propensity for tissue penetration. GS within the central nervous system (CNS), in particular within the cerebellum, is extremely uncommon. We review the literature and describe an infant with isolated cerebellar GS relapse, which antedated a CD56 + acute monoblastic leukaemia bone marrow (BM) relapse. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Acute myeloid leukaemia; Cerebellum; Granulocytic sarcoma; NCAM
1. Case report An 11 month boy was diagnosed with AML M5 without CNS disease, leucocytosis or organomegaly. A difficult BM aspiration yielded a poor sample, infiltrated by monoblasts, inadequate for cytogenetic analysis or immunophenotyping. A BM trephine biopsy showed 90% infiltration by monoblasts, grade 2–3 fibrosis and focal haemophagocytosis. Immunohistochemistry of the BM trephine biopsy sections showed CD15 +, CD45R/LCA +, CD68 / PGM1 + , CD68/ KP-1 + , lysozyme+, CD34 − , CD61 − , CD56 − , glycophorin c- and focal positivity for myeloperoxidase. He was treated according to BFM AML 98 and Abbre6iations: AML, acute myeloid leukaemia; BM, bone marrow; CNS, central nervous system; CR, complete remission; CSF, cerebrospinal fluid; EML, extramedullary leukaemia; GS, granulocytic sarcoma; IT, intrathecal; LC, leukaemia cutis; ML, meningeal leukaemia; MRI, magnetic resonance imaging; NCAM, neural cell adhesion molecule. * Corresponding author. E-mail address: [email protected] (E. Psiachou-Leonard).
achieved complete remission (CR). At the end of the consolidation phase, he presented with a few hours’ history of vomiting, lethargy and opisthotonus, but no fever. On magnetic resonance imaging (MRI) of the brain, there was hyperattenuated and isoattenuated infiltration of the left cerebellum on T2- and T1weighted images, respectively. Contrast-enhancement studies demonstrated no enhancement ring around the lesion and pathological uptake over the cerebellar meninges. His clinical condition deteriorated rapidly due to obstructive hydrocephalus, which was managed with external ventricular drainage. On several occasions, the CSF chemical, cytological and immunophenotypic profile was normal. Infectious causes were excluded. He was in morphological and immunophenotypic BM remission. With the presumptive diagnosis of cerebellar GS, he was commenced on triple intrathecal chemotherapy on alternate days through the drainage tube. He remained afebrile with slowly deteriorating sensorium, and 12 days later, he developed fever with thrombocytopenia and laboratory signs of DIC. A BM aspirate revealed infiltration with CD15+ , CD33 +,
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 1 ) 0 0 0 6 8 - 6
E. Psiachou-Leonard et al. / Leukemia Research 25 (2001) 1019–1021
1020
CD64 +, HLA-DR +, CD14 +, CD56 + , CD68 + , monoblasts. Systemic chemotherapy was commenced, but he succumbed from multiorgan failure. There was no parental consent for post-mortem examination.
2. Discussion Extramedullary leukaemia (EML) represents leukemia cells outside the bone marrow and includes granulocytic sarcomas (GS) at any anatomical site, leukaemia cutis (LC) and meningeal leukaemia (ML) [1]. It can be a presenting feature of evolving AML or an antedating/concomitant feature of medullary relapse [1]. The incidence in adult AML was reported to be between 2.9 and 8% during the non-intensive chemotherapy era [1]. Pui et al. found a 4.7% incidence in children with AML. [3]. Suggested predisposing factors include FAB M4/M5 morphology [4,5], CD56 + blasts [1,2,12], cytogenetic abnormalities like t(8;21), inv (16), [1] and infant AML [6]. The commonest sites of occurrence are the orbit and skin followed by bones, paranasal sinuses and epidural areas [1]. The cerebellum is a rare site of infiltration. To our knowledge, there have been four cases of cerebellar GS with AML, described (Table 1). Three of those cases were adults, and the fourth a 7 year old boy [7–10]. Pathological diagnosis is particularly problematic in CNS GS. Pui et al. [3] assessed the CT and MRI findings of 33 children with CNS GS. They concluded that homogeneously isoattenuated or slightly hyperattenuated masses are compatible with leukaemia infiltration and that CT and MRI studies may allow the distinction of intracranial GS from haematomas and abscesses, reserving biopsy for selected cases. In our case, the MRI findings (Fig. 1) met the criteria of this study, and the deterioration of the CNS condition along with the evolution of the BM relapse supports the diagnosis. This case was classified as monoblastic AML. One of the reported cases was of myelomonocytic subtype, while the others were not specified. Clinical and pathological analysis of a relatively large cohort of
patients with AML M5 showed that about half of the patients manifest GS at diagnosis, during BM remission or relapse [4]. Immunohistochemistry at diagnosis showed that the blasts were CD15+ , CD68 + , CD45R/LCA + and CD56 − . The blasts at the time of BM relapse were CD15 + , CD68 + and in addition were CD56+. In a recent report, the results of immunotyping on BM trephine paraffin sections correlated accurately with the flow-cytometric findings [11]. NCAM, a surface glycoprotein, belongs to the cell adhesion group of molecules, which play an important role in the metastasis of tumours [1]. Seymour et al. reported an 83% incidence of CD56+ in a cohort of patients with AML M5, whereas in another report, the incidence was 36% [12–14]. CD56+ blasts seem to have a tendency for EML especially intracranial infiltration [2], but Seymour et al. suggested that the presence of CD56 + blasts alone cannot account for tissue infiltration and in particular for CNS disease unless there are other predisposing factors present [12]. In this case, monoblastic type and the evolution of a new, aggressive CD56+ clone may have acted synergistically for the development of the cerebellar GS [12,14]. Two of the reported cases had blasts in the CSF. We assessed CSF repeatedly. The absence of blasts could be explained by the physical properties of blasts bearing the NCAM molecule, which binds homophilically to neurons. It is likely that tight adherence of the blasts to neural cell prevents shedding of the blasts into CSF [1,2]. The management of cerebellar GS includes surgical excision, radiotherapy, IT and/or systemic chemotherapy [1]. In this case, the surgical excision was not feasible. IT chemotherapy did not affect the GS and was eventually supervened by the fulminant course of the medullary disease. In conclusion, this case provides further evidence that patients with CD56+ AML and monoblastic subtype are predisposed to EML formation. The expression of CD56 antigen in EML has been correlated with dismal prognosis and short remission
Table 1 Reported cases of cerebellar granulocytic sarcoma in AML Patient
Age/sex
Diagnosis
BM
CSF
Management
Outcome
Reference
1 2 3 4
26 years/F 7 years/M 29 years/F 60 years/F
AML AML AML/M4 AML
+ve −ve −ve NR
+ve NR +ve NR
S, CNS RT, IT-MTX S, CNS RT, S-chemo CNS-RT, IT-MTX RT
NR Death BMR 1 year later NR
[8] [9] [10] [11]
NR: not reported; S: surgery; RT: radiotherapy; IT-MTX: intrathecal methotrexate; S-chemo: systemic chemotherapy; BMR: bone marrow relapse; +ve: positive; −ve: negative.
E. Psiachou-Leonard et al. / Leukemia Research 25 (2001) 1019–1021
1021
Street Hospital London, and Dr. BJ. Bain for their invaluable comments during the preparation of the manuscripts.
References
Fig. 1. MR images of the brain: (a) isoattenuated mass in the L cerebellum on T1-weighted image; (b) hyperattenuated mass on T2weighted image.
duration even in the presence of good prognosis cytogenetic markers [15].
Acknowledgements The authors would like to thank Dr. I.M. Hann, Consultant Haematologist, Great Ormond
[1] Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumours in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13(7):1800. [2] Iizuka Y, Aiso M, Oshimi K, Kanemarou M, Kawamura M, Takeuchi J, Horikoshi A, Ohshima T, Mizoguchi H, Horie T. Myeloblastoma formation in acute myeloid leukemia. Leukemia Res 1992;16(67):665. [3] Pui MH, Fletcher BD, Langston JW. Granulocytic sarcoma in childhood leukemia: imaging features. Radiology 1993;190:698. [4] Tobelem G, Jaquillat C, Chastang C, Auclerc MF, Lechevallier T, Weil M, Daniel MT, Flandrin G, Harrousseau JL, Boiron M, Shalson G, Bernard J. Acute monoblastic leukemia: a clinical and biologic study of 74 cases. Blood 1980;55(1):71. [5] Peterson L, Dehner LP, Brunning RD. Extramedullary masses as presenting feature of acute monoblastic leukemia. Am J Clin Pathol 1981;75(2):140. [6] Pui CH, Raimondi SC, Srivastava DK, et al. Prognostic factors in infants with acute myeloid leukemia. Leukemia 2000;14:684. [7] Demaray MJ, Coladonato JP, Parker JC, Rosomoff HL. Intracerebellar chloroma (granulocytic sarcoma): a neurosurgical complication of acute myelocytic leukemia. Surg Neurol 1976;6:353. [8] Nickels J, Koivuniemi A, Heiskanen O. Granulocytic sarcoma (chloroma) of the cerebellum and meninges, a case report. Acta Neurochirurg 1979;46(3/4):297. [9] Saper CB, Jarowski CI. Leukemic infiltration of the cerebellum in acute myelomonocytic leukemia. Neurology 1982;32:77. [10] Wang AM, Lin JCT, Power TC, Haykal HA, Zamani AA. Chloroma of the cerebellum, tentorium and occipital bone in acute myelogenous leukemia. Neuroradiology 1987;29:590. [11] Junela S, Trute L, Westman D, Venter D, et al. Paraffin section immunotyping of leukaemias. Br J Haematol 2000;109:267. [12] Seymour JF, Pierce SA, Kantarjian HM, Keating MJ, Estey EH. Investigation of karyotypic, morphologic and clinical features in patients with acute myeloid leukaemia blast cells expressing the neural cell adhesion molecule (CD56). Leukemia 1994;8(5):823. [13] Baer MR, Stewart CC, Lawrence BL, Powell BL, Schiffer CA, Davey FR, Arthur DC, Bloomfield CD. Multiparameter flow cytometry (MFC) analysis of de novo acute myeloid leukemia (AML) reveals low frequencies of lymphoid antigen expression and strong associations between immunophenotype and karyotype (GALGB 8361). Blood 1995;86(10) (Suppl. 1):439. [14] Daniels JT, Davis BJ, Houde-McGrail L, Byrd JC. Clonal selection of CD56 + t(8;21) AML blasts: further suggestion of the adverse clinical significance of this biologic marker? Br J Haematol 1999;107:381. [15] Baer MR, Stewart CC, Lawrence D, Arthur DC, Byrd JC, Davey FR, Schiffer CA, Bloomfield CD. Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 1997;90(4):1643.
Case report
Cerebellar granulocytic sarcoma in an infant with CD56+ acute monoblastic leukemia Elene Psiachou-Leonard a,*, Georgios Paterakis b, Kalliopi Stefanaki c, Vasiliki Mikraki-Christou a, Stavros Haidas a a
Department of Haematology –Oncology, Aghia Sophia Children’s Hospital, Thi6on & Papadiamanto-poulou, Athens 11527, Greece b Department of Immunology and Histocompatibility, General Hospital ‘G. Gennimatas’, Athens, Greece c Department of Pathology, Aghia Sophia Children’s Hospital, Athens, Greece Received 1 October 2000; accepted 10 March 2001
Abstract Granulocytic sarcoma (GS) is a form of extramedullary leukaemia (EML). The presence of the neural cell adhesion molecule (NCAM) on the surface of the blasts, which is recognized by the CD56 monoclonal antibody, enhances their propensity for tissue penetration. GS within the central nervous system (CNS), in particular within the cerebellum, is extremely uncommon. We review the literature and describe an infant with isolated cerebellar GS relapse, which antedated a CD56 + acute monoblastic leukaemia bone marrow (BM) relapse. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Acute myeloid leukaemia; Cerebellum; Granulocytic sarcoma; NCAM
1. Case report An 11 month boy was diagnosed with AML M5 without CNS disease, leucocytosis or organomegaly. A difficult BM aspiration yielded a poor sample, infiltrated by monoblasts, inadequate for cytogenetic analysis or immunophenotyping. A BM trephine biopsy showed 90% infiltration by monoblasts, grade 2–3 fibrosis and focal haemophagocytosis. Immunohistochemistry of the BM trephine biopsy sections showed CD15 +, CD45R/LCA +, CD68 / PGM1 + , CD68/ KP-1 + , lysozyme+, CD34 − , CD61 − , CD56 − , glycophorin c- and focal positivity for myeloperoxidase. He was treated according to BFM AML 98 and Abbre6iations: AML, acute myeloid leukaemia; BM, bone marrow; CNS, central nervous system; CR, complete remission; CSF, cerebrospinal fluid; EML, extramedullary leukaemia; GS, granulocytic sarcoma; IT, intrathecal; LC, leukaemia cutis; ML, meningeal leukaemia; MRI, magnetic resonance imaging; NCAM, neural cell adhesion molecule. * Corresponding author. E-mail address: [email protected] (E. Psiachou-Leonard).
achieved complete remission (CR). At the end of the consolidation phase, he presented with a few hours’ history of vomiting, lethargy and opisthotonus, but no fever. On magnetic resonance imaging (MRI) of the brain, there was hyperattenuated and isoattenuated infiltration of the left cerebellum on T2- and T1weighted images, respectively. Contrast-enhancement studies demonstrated no enhancement ring around the lesion and pathological uptake over the cerebellar meninges. His clinical condition deteriorated rapidly due to obstructive hydrocephalus, which was managed with external ventricular drainage. On several occasions, the CSF chemical, cytological and immunophenotypic profile was normal. Infectious causes were excluded. He was in morphological and immunophenotypic BM remission. With the presumptive diagnosis of cerebellar GS, he was commenced on triple intrathecal chemotherapy on alternate days through the drainage tube. He remained afebrile with slowly deteriorating sensorium, and 12 days later, he developed fever with thrombocytopenia and laboratory signs of DIC. A BM aspirate revealed infiltration with CD15+ , CD33 +,
0145-2126/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 1 ) 0 0 0 6 8 - 6
E. Psiachou-Leonard et al. / Leukemia Research 25 (2001) 1019–1021
1020
CD64 +, HLA-DR +, CD14 +, CD56 + , CD68 + , monoblasts. Systemic chemotherapy was commenced, but he succumbed from multiorgan failure. There was no parental consent for post-mortem examination.
2. Discussion Extramedullary leukaemia (EML) represents leukemia cells outside the bone marrow and includes granulocytic sarcomas (GS) at any anatomical site, leukaemia cutis (LC) and meningeal leukaemia (ML) [1]. It can be a presenting feature of evolving AML or an antedating/concomitant feature of medullary relapse [1]. The incidence in adult AML was reported to be between 2.9 and 8% during the non-intensive chemotherapy era [1]. Pui et al. found a 4.7% incidence in children with AML. [3]. Suggested predisposing factors include FAB M4/M5 morphology [4,5], CD56 + blasts [1,2,12], cytogenetic abnormalities like t(8;21), inv (16), [1] and infant AML [6]. The commonest sites of occurrence are the orbit and skin followed by bones, paranasal sinuses and epidural areas [1]. The cerebellum is a rare site of infiltration. To our knowledge, there have been four cases of cerebellar GS with AML, described (Table 1). Three of those cases were adults, and the fourth a 7 year old boy [7–10]. Pathological diagnosis is particularly problematic in CNS GS. Pui et al. [3] assessed the CT and MRI findings of 33 children with CNS GS. They concluded that homogeneously isoattenuated or slightly hyperattenuated masses are compatible with leukaemia infiltration and that CT and MRI studies may allow the distinction of intracranial GS from haematomas and abscesses, reserving biopsy for selected cases. In our case, the MRI findings (Fig. 1) met the criteria of this study, and the deterioration of the CNS condition along with the evolution of the BM relapse supports the diagnosis. This case was classified as monoblastic AML. One of the reported cases was of myelomonocytic subtype, while the others were not specified. Clinical and pathological analysis of a relatively large cohort of
patients with AML M5 showed that about half of the patients manifest GS at diagnosis, during BM remission or relapse [4]. Immunohistochemistry at diagnosis showed that the blasts were CD15+ , CD68 + , CD45R/LCA + and CD56 − . The blasts at the time of BM relapse were CD15 + , CD68 + and in addition were CD56+. In a recent report, the results of immunotyping on BM trephine paraffin sections correlated accurately with the flow-cytometric findings [11]. NCAM, a surface glycoprotein, belongs to the cell adhesion group of molecules, which play an important role in the metastasis of tumours [1]. Seymour et al. reported an 83% incidence of CD56+ in a cohort of patients with AML M5, whereas in another report, the incidence was 36% [12–14]. CD56+ blasts seem to have a tendency for EML especially intracranial infiltration [2], but Seymour et al. suggested that the presence of CD56 + blasts alone cannot account for tissue infiltration and in particular for CNS disease unless there are other predisposing factors present [12]. In this case, monoblastic type and the evolution of a new, aggressive CD56+ clone may have acted synergistically for the development of the cerebellar GS [12,14]. Two of the reported cases had blasts in the CSF. We assessed CSF repeatedly. The absence of blasts could be explained by the physical properties of blasts bearing the NCAM molecule, which binds homophilically to neurons. It is likely that tight adherence of the blasts to neural cell prevents shedding of the blasts into CSF [1,2]. The management of cerebellar GS includes surgical excision, radiotherapy, IT and/or systemic chemotherapy [1]. In this case, the surgical excision was not feasible. IT chemotherapy did not affect the GS and was eventually supervened by the fulminant course of the medullary disease. In conclusion, this case provides further evidence that patients with CD56+ AML and monoblastic subtype are predisposed to EML formation. The expression of CD56 antigen in EML has been correlated with dismal prognosis and short remission
Table 1 Reported cases of cerebellar granulocytic sarcoma in AML Patient
Age/sex
Diagnosis
BM
CSF
Management
Outcome
Reference
1 2 3 4
26 years/F 7 years/M 29 years/F 60 years/F
AML AML AML/M4 AML
+ve −ve −ve NR
+ve NR +ve NR
S, CNS RT, IT-MTX S, CNS RT, S-chemo CNS-RT, IT-MTX RT
NR Death BMR 1 year later NR
[8] [9] [10] [11]
NR: not reported; S: surgery; RT: radiotherapy; IT-MTX: intrathecal methotrexate; S-chemo: systemic chemotherapy; BMR: bone marrow relapse; +ve: positive; −ve: negative.
E. Psiachou-Leonard et al. / Leukemia Research 25 (2001) 1019–1021
1021
Street Hospital London, and Dr. BJ. Bain for their invaluable comments during the preparation of the manuscripts.
References
Fig. 1. MR images of the brain: (a) isoattenuated mass in the L cerebellum on T1-weighted image; (b) hyperattenuated mass on T2weighted image.
duration even in the presence of good prognosis cytogenetic markers [15].
Acknowledgements The authors would like to thank Dr. I.M. Hann, Consultant Haematologist, Great Ormond
[1] Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumours in acute nonlymphocytic leukemia: a clinical review. J Clin Oncol 1995;13(7):1800. [2] Iizuka Y, Aiso M, Oshimi K, Kanemarou M, Kawamura M, Takeuchi J, Horikoshi A, Ohshima T, Mizoguchi H, Horie T. Myeloblastoma formation in acute myeloid leukemia. Leukemia Res 1992;16(67):665. [3] Pui MH, Fletcher BD, Langston JW. Granulocytic sarcoma in childhood leukemia: imaging features. Radiology 1993;190:698. [4] Tobelem G, Jaquillat C, Chastang C, Auclerc MF, Lechevallier T, Weil M, Daniel MT, Flandrin G, Harrousseau JL, Boiron M, Shalson G, Bernard J. Acute monoblastic leukemia: a clinical and biologic study of 74 cases. Blood 1980;55(1):71. [5] Peterson L, Dehner LP, Brunning RD. Extramedullary masses as presenting feature of acute monoblastic leukemia. Am J Clin Pathol 1981;75(2):140. [6] Pui CH, Raimondi SC, Srivastava DK, et al. Prognostic factors in infants with acute myeloid leukemia. Leukemia 2000;14:684. [7] Demaray MJ, Coladonato JP, Parker JC, Rosomoff HL. Intracerebellar chloroma (granulocytic sarcoma): a neurosurgical complication of acute myelocytic leukemia. Surg Neurol 1976;6:353. [8] Nickels J, Koivuniemi A, Heiskanen O. Granulocytic sarcoma (chloroma) of the cerebellum and meninges, a case report. Acta Neurochirurg 1979;46(3/4):297. [9] Saper CB, Jarowski CI. Leukemic infiltration of the cerebellum in acute myelomonocytic leukemia. Neurology 1982;32:77. [10] Wang AM, Lin JCT, Power TC, Haykal HA, Zamani AA. Chloroma of the cerebellum, tentorium and occipital bone in acute myelogenous leukemia. Neuroradiology 1987;29:590. [11] Junela S, Trute L, Westman D, Venter D, et al. Paraffin section immunotyping of leukaemias. Br J Haematol 2000;109:267. [12] Seymour JF, Pierce SA, Kantarjian HM, Keating MJ, Estey EH. Investigation of karyotypic, morphologic and clinical features in patients with acute myeloid leukaemia blast cells expressing the neural cell adhesion molecule (CD56). Leukemia 1994;8(5):823. [13] Baer MR, Stewart CC, Lawrence BL, Powell BL, Schiffer CA, Davey FR, Arthur DC, Bloomfield CD. Multiparameter flow cytometry (MFC) analysis of de novo acute myeloid leukemia (AML) reveals low frequencies of lymphoid antigen expression and strong associations between immunophenotype and karyotype (GALGB 8361). Blood 1995;86(10) (Suppl. 1):439. [14] Daniels JT, Davis BJ, Houde-McGrail L, Byrd JC. Clonal selection of CD56 + t(8;21) AML blasts: further suggestion of the adverse clinical significance of this biologic marker? Br J Haematol 1999;107:381. [15] Baer MR, Stewart CC, Lawrence D, Arthur DC, Byrd JC, Davey FR, Schiffer CA, Bloomfield CD. Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 1997;90(4):1643.