Primary plasma cell leukemia: morphologic, immunophenotypic, and cytogenetic features of 4 cases treated with chemotherapy and stem cell transplantation

Annals of Diagnostic Pathology 10 (2006) 263 – 268

Primary plasma cell leukemia: morphologic, immunophenotypic, and cytogenetic features of 4 cases treated with chemotherapy and stem cell transplantation Malisha R. Johnson, DOa, Daniel Del Carpio-Jayo, MDa, Pei Lin, MDa, Sergio Giralt, MDb, Paolo Anderlini, MDb, Richard E. Champlin, MDb, Issa F. Khouri, MDb, Saroj Vadhan-Raj, MDc, L. Jeffrey Medeiros, MDa, Carlos E. Bueso-Ramos, MD, PhDa,4 a Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Bone Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA c Department of Cytokine and Supportive Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA b

Abstract

Plasma cell leukemia (PCL) is a neoplastic disorder of plasma cells of which there are 2 forms, primary PCL and secondary PCL, the latter occurring in patients with a history of plasma cell myeloma. We describe 4 patients with primary PCL. In all cases, the bone marrow aspirate smears and biopsy specimens demonstrated a diffuse infiltrate of atypical plasma cells that were difficult to classify using morphologic criteria alone. Immunophenotypic studies showed that each case was positive for plasma cell–associated antigens (cytoplasmic immunoglobin, CD38, or CD138) and negative for CD20. Of 4 cases, 3 had complex karyotypes, including the t(11;14)(q13;q32) or del(11)(q13). Despite chemotherapy and the use of novel therapeutic agents and stem cell transplantation, all 4 patients had short survival. D 2006 Elsevier Inc. All rights reserved.

Keywords:

Plasma cell leukemia; Stem cell transplantation; Chemotherapy

1. Introduction Plasma cell leukemia (PCL) is a rare neoplastic disorder of plasma cells, accounting for approximately 1% to 2% of all plasma cell neoplasms [1]. These tumors can be further subdivided into 2 forms based on clinical presentation. Primary or de novo PCL occurs in individuals without a preceding diagnosis of plasma cell myeloma [2-4]. Secondary PCL arises in patients with a history of plasma cell myeloma who have progressed to leukemic phase [2-8]. The published criteria for the diagnosis of PCL are an absolute plasma cell count greater than 2  109/L or greater than 20% plasmacytosis in the peripheral blood [2-4,6-15]. The clinical findings in patients with primary PCL are well described. Weakness, fatigue, and bone pain are common symptoms. Laboratory findings include anemia

4 Corresponding author. Tel.: +1 713 792 6328; fax: +1 713 794 1800. E-mail address: [email protected] (C.E. Bueso-Ramos). 1092-9134/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.anndiagpath.2005.12.011

(90%), leukocytosis (80%), and thrombocytopenia (50%) and numerous metabolic abnormalities such as hypercalcemia and elevated lactate dehydrogenase (LDH) level [5-7,16]. Most patients with PCL have a poor prognosis, with a reported median survival of 6 to 8 months [6]. By contrast, the pathologic findings of primary PCL are not well described in the literature [3-6]. Most reports of primary PCL have appeared in the clinical literature, with emphasis placed on clinical findings and therapy. In some papers, a description of the bone marrow aspirate smears is included, but complete descriptions of bone marrow aspirate smears and biopsy specimens with immunophenotypic and cytogenetic analysis are rare. Furthermore, current therapy for patients with PCL is disappointing, and there are no recognized curative regimens [6,16]. Treatment is usually based on an intensive chemotherapy; however, high-dose chemotherapy followed by stem cell transplantation (SCT) is another option [6,13,14,16-20]. In this report, we describe the clinicopathologic, immunophenotypic, and cytogenetic findings of 4 patients with

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primary PCL. All patients were treated with high-dose chemotherapy followed by SCT. 2. Material and methods We searched the files of the Departments of Hematopathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center (MDACC) from 1995 to 2001 for patients with the diagnosis of PCL. We further narrowed the search to cases in which bone marrow aspiration and biopsy were performed with flow cytometry immunophenotypic and cytogenetic analysis. A total of 4 cases met all of the previous criteria. The clinical and laboratory information is summarized in the tables. The diagnosis of primary PCL was based on the presence of an absolute plasma cell count greater that 2  109/L or 20% or greater plasmacytosis in the peripheral blood in patients without a history of plasma cell myeloma [2-4,6,7,9]. Flow cytometry immunophenotypic analysis was performed on bone marrow aspirate material from all cases with an extensive panel of antibodies as previously described [21]. Conventional cytogenetic analysis was also performed on bone marrow aspirate material of each case as described [22]. 3. Case reports 3.1. Case 1 A 49-year-old white man was diagnosed with primary PCL in November of 1995. He initially had low-grade fevers, myalgias, and thrombocytopenia. Medical history included infectious mononucleosis in 1974. Physical examination was unremarkable. An abdominal computed tomographic scan showed mild splenomegaly, and a skeletal survey was negative for bone lesions. The patient was referred to our institution for treatment. Laboratory findings at the time of referral included white blood cell (WBC) count of 11.9  109/L (reference range, 5-10  109/L) with 49% plasma cells (absolute plasma cell count, 5.8  109/L) and hemoglobin level of 12.6 g/dL (126 g/L; reference range, 14-18.0 g/dL [140-180 g/L]), and platelet count was 82  109/L (reference range, 150-450  109/L). Other laboratory studies included serum creatinine of 1.2 mg/100 mL (106 l/L; reference range, 0.8-1.5 mg/ 100 mL [71-133 lL]); calcium, 10.0 mg/100 mL (2.5 mmol/L; reference range, 8.4-10.2 mg/100 mL [2.1-2.55 mmol/L); LDH, 450 IU/L (reference range, 313-618 IU/L); and b 2-microglobulin, 7.3 mg/L (621 nmol/L; reference range, 0.6-2.0 mg/L [51-170 nmol/L). Serum protein electrophoresis revealed moderate hypogammaglobulinemia with no evidence of a monoclonal spike. Urinalysis was negative for Bence Jones protein. Bone marrow examination demonstrated involvement by PCL. The first chemotherapy treatment began in January 1996 and consisted of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD)

with a course of methotrexate and ara-C. A follow-up bone marrow examination showed no increase in plasma cells, and cytogenetic analysis was negative. The peripheral blood was negative for plasma cells. In April 1996, the patient underwent autologous peripheral blood SCT. The conditioning regimen consisted of total body irradiation, etoposide, and cyclophosphamide. His early posttransplant course was uncomplicated, but 7 months after transplant, the patient presented with recurrent PCL and alveolar hemorrhage. A peripheral blood smear demonstrated 20% plasmablasts, and a bone marrow examination revealed extensive PCL. Cytogenetics revealed multiple abnormalities consistent with relapse. He was restarted on chemotherapy but developed sepsis from vancomycin-resistant enterococcus. The patient ultimately died from multiorgan failure and recurrent PCL 13 months after initial diagnosis. 3.2. Case 2 A 49-year-old man presented in May of 2000 with severe lumbar pain, renal failure, and profound anemia. He had a history of untreated hypertension. Laboratory studies revealed a WBC count of 12.8  109/L with 25% plasma cells (absolute plasma cell count, 3.2  109/L), hemoglobin of 8.0 g/dL (80 g/L), and a normal platelet count. Serum creatinine was 9.2 mg/100 mL (813 lmol/L), and calcium was 12.4 mg/100 mL (3.1 mmol/L). Bone marrow aspiration and biopsy revealed PCL. Chemotherapy was initiated with vincristine, doxorubicin, and dexamethasone (VAD). He completed a total of 7 courses of chemotherapy and was considered in partial remission. The patient’s paraprotein level decreased; no plasma cells were identified in the peripheral blood smear, and a repeat bone marrow examination showed a 50% reduction in plasma cells. He was then started on interferon alfa and referred to our institution for further management in March 2001. Laboratory studies at time of referral showed WBC of 10.6  109/L, hemoglobin of 12.9 g/dL (129 g/L), and platelet count of 372  109/L (150-450  109/L). Other laboratory studies included serum LDH of 354 IU/L and a b 2-microglobulin of 3.9 mg/L (331 nmol/L). Serum protein electrophoresis and immunofixation were positive for a monoclonal IgG k spike (4.2 g/100 mL). A bone survey demonstrated compression fractures in the thoracic and lumbar spine and a lytic lesion in the right ninth rib. Bone marrow examination in March of 2001 revealed cellular bone marrow biopsy specimen with persistent PCL. The patient was started on thalidomide and dexamethasone and had no response. The experimental drug PS-341 (Bortezomib; Millennium Pharmaceuticals, Cambridge, MA) was initiated. The patient had no response. In December 2001, the patient underwent allogeneic peripheral blood stem cell transplant from his HLA-identical brother. The conditioning regimen consisted of fludarabine, antithymocyte globulin, and melphalan. He developed a graft-versus-host disease in his skin and gastrointestinal tract. In October 2002,

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Table 1 Summary of clinical and laboratory data in 4 patients (present study) with PCL Case

Sex

Age (y)

Ca (8.4-10.2 mg/mL)

b 2-Microglobulin (0.6-2 mg/L)

Creatinine (mg/100 mL)

Serum immunoglobulin

PCs in PB (%)

PCs in BM (%)

Type of SCT

Survival after transplant (mo)

1 2 3 4

M M F M

49 49 44 42

10 12.4 10.2 9.4

7.3 3.9 25.8 3.5

1.2 9.2 3.5 0.8

Neg IgG k IgG j Neg

49 25 29 53

50-60 85 85 60

Auto Allo Allo Allo  2

8 12 3 18 (first transplant)

Ca indicates serum calcium; PC, plasma cell; PB, peripheral blood; BM, bone marrow; Neg, negative; Auto, autologous; Allo, allogeneic.

a cervicothoracic magnetic resonance imaging demonstrated diffuse infiltration of the cervical vertebrae by PCL. The patient developed pneumonia plus renal failure and died 30 months after initial diagnosis. 3.3. Case 3 A 44-year-old woman initially presented with fatigue, easy bruising, and recurrent fevers. Physical examination revealed mild respiratory distress and abdominal ascites. A chest radiograph showed a right middle lobe infiltrate and bilateral pleural effusions. Her physician referred her to MDACC for evaluation and treatment. A complete blood count at time of referral showed a WBC count of 11.3  109/L (5-10  109/L) with 29% plasma cells (absolute plasma cell count, 3.2  109/L), hemoglobin of 8.4 g/dL (84 g/L), and platelet count of 46  109/L. Other laboratory studies included serum creatinine of 3.5 mg/100 mL (309 lmol/L); calcium, 10.2 mg/100 mL (2.55 mmol/L); LDH, 562 IU/L; and b 2-microglobulin, 25.8 mg/L (2193 nmol/L). Serum protein electrophoresis was positive for a monoclonal IgG j protein (5.4 g/100 mL). The bone marrow was diffusely infiltrated by immature plasma cells supporting the diagnosis of primary PCL. Her first chemotherapy regimen consisted of 6 cycles of hyper-CVAD plus rituximab. Bone marrow examination on day 21 after chemotherapy showed no plasma cells and a complete cytogenetic response. In December of 2000, patient developed a plasmacytoma and pathologic fracture of the left proximal humerus. Bone marrow aspiration and biopsy showed no recurrence of PCL. A month later, she developed several multiple subcutaneous nodules and received local radiotherapy. In March 2001, the patient underwent allogeneic SCT from an HLA-identical sister. The conditioning regimen consisted of busulfan and cyclophosphamide. Respiratory syncytial virus pneumonia, generalized neuromuscular weakness, gastrointestinal bleeding, acute respiratory distress syndrome, and acute renal failure complicated her posttransplant course. The patient had progressive worsening of her clinical condition despite very aggressive treatment and died 13 months after initial diagnosis.

inal computed tomography showed splenomegaly and mild compression of lumbar vertebrae. The patient was referred to MDACC for further treatment. At time of referral, a complete blood count demonstrated a WBC count of 18.0  109/L with 53% plasma cells (absolute plasma cell count, 9.5  109/L), hemoglobin of 8.8 g/dL (88 g/L), and platelet count of 20  109/L. Other laboratory results included serum creatinine of 0.8 mg/100 mL (71 lmol/L); calcium, 9.4 mg/100 mL (2.35 mmol/L); LDH, 545 IU/L; and b 2-microglobulin, 3.5 mg/L (298 nmol/L). Serum and urine electrophoresis were negative for an abnormal protein; however, serum IgG, IgA, and IgM levels were depressed. The bone marrow was extensively infiltrated by plasma cells, and the patient was diagnosed with nonsecretory primary PCL. Chemotherapy was instituted with the VAD regimen. He was considered unresponsive to treatment because of persistent thrombocytopenia. He then received 2 courses of a combination of dexamethasone, cyclophosphamide, etoposide, cisplatin, and thalidomide. A follow-up bone marrow examination 4 months after initial diagnosis showed 60% plasma cells with plasmablastic morphology. His peripheral blood smear did not reveal circulating plasma cells. The patient’s course was complicated by a deep venous thrombosis in the left lower extremity and marked weight loss. A complete bone survey 1 month later demonstrated lytic lesions of the skull, lumbar spine, and pelvis; healed pathologic fractures of multiple ribs and pubic rami; and compression fracture of T11 and entire lumbar spine. In June 2001, the patient underwent allogeneic SCT from a 5/6 HLA-matched sister. His conditioning regimen consisted of antithymocyte globulin, fludarabine, and cyclophosphamide. Bone marrow aspiration 30 days later showed 11% atypical plasma cells. The patient had primary graft Table 2 Conventional cytogenetic results of 4 cases (present study) of PCL Case

Karyotype

1

n

3.4. Case 4 A 42-year-old white man initially presented with severe low back pain in January 2001. Medical history and his initial physical examination were unremarkable. An abdom-

2 3 4

49,XY,add(2)(p23),-8,+9,der(10), t(3;10)(q13.2;p12), +11,t(11;14)(q13;q32),der(17)t(8;17)(q12;p13), der(19)idic(19)(q13.1),+21,+mar[17] n 50,idem,+3[9] 50,idem,+3,add(18)(p11.2)[3] n 46,XY,t(11;14)(q13;q32),del(12)(p13),del(13)(q14q32)[5] n 43-45,X,-X,inv(1)(p31.2p33),add(7)(q36),add(9)(p24), del(11)(q13),-14,-15,del(16)(q22),-19,-21,-22,+5 mar[cp7] n 46,XY[20]

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Table 3 Clinicopathologic features of PCL from published case reports in which the pathology of the bone marrow/peripheral smear was reported (including our 4 cases) Case no./age (y)/ sex/reference

PPCL/ SPCL

BM pattern/ percentage of PC

Morphology of neoplastic PCs

Immunophenotype of BM

Organomegaly

Bone lesions

1/39/M/10

NR

Diffuse/bextensiveQ

Immature

Splenomegaly

Yes

1/21/M/6 2/31/M/6 1/58/F/20 1-15a/9

PPCL PPCL NR 8 PPCL, 7 SPCL

Diffuse/extensive Diffuse/extensive Diffuse/65 Diffuse/50-100

No NR No 4 Splenomegaly, 7 hepatomegaly

No NR No 14 Yes, 1 no

1/49/M/ present study

PPCL

Diffuse/50-60

Mature/atypical Atypical Immature Most PC were mature with presence of immature plasmablasts Immature and mature

CD38+, CD138+, CD20 , CD56 CD38+, CD138+ CD56 NR NR

Splenomegaly

No

2/49/M/ present study 3/44/F/ present study

PPCL

Diffuse/85

Immature and mature

No

Yes

PPCL

Diffuse/85

Immature

No

Yes

4/42/M/ present study

PPCL

Diffuse/60

Immature

Splenomegaly

NR

CD19+, CD33+, CD38+, CD138+, CD20 , cytoplasmic light chains CD38+, CD138+, cytoplasmic k +, CD20 CD4+, CD38+, CD45+ (weak), cytoplasmic j +, CD20 CD38+, CD56+, cytoplasmic j +, CD20

PPCL indicates primary plasma cell leukemia; SPCL, secondary plasma cell leukemia; NR, not reported. a The pathology of all 15 cases were described as 1 group.

failure. He developed fever and cytomegalovirus-positive antigenemia treated successfully with ganciclovir. Three months later, the patient showed signs of disease progression and received cyclophosphamide and VAD and, subsequently, 2 cycles of hyper-CVAD. The patient then underwent second allogeneic stem cell transplant using the same donor in July 2002. The conditioning regimen consisted of fludarabine, melphalan, and alemtuzumab (Campath-1H; Millennium and ILEX Partners, LP, Cambridge, MA). During his posttransplant course, he developed pulmonary toxicity and cutaneous graft-versus-host disease. His last bone marrow biopsy in November 2001 showed no evidence of PCL. Patient eventually died from cytomegalovirus pneumonia and renal failure 23 months after initial diagnosis. 4. Results The clinical and laboratory information is summarized in Tables 1-3.

(Fig. 1B). Cytochemical stains for myeloperoxidase and butyrate esterase were negative in case 1. Flow cytometry immunophenotypic studies were performed on bone marrow aspirate material in all 4 cases and also on peripheral blood in case 1. Three neoplasms (cases 2-4) expressed monotypic cytoplasmic immunoglobulin light chain (2 j, 1 k), and all were negative for surface immunoglobulin. All neoplasms were positive for CD38 and negative for CD20. Two neoplasms assessed were CD138 positive. One tumor was positive for CD19 and CD33 (case 1), 1 was positive for CD4 and weak CD45 (case 3), and 1 was CD56 positive (case 4). All other antigens assessed were negative. Cytogenetic analysis was abnormal in 3 neoplasms (cases 1-3); all 3 had complex abnormalities (Table 2). Table 3 shows the clinicopathologic features of PCL from published case reports in which the pathology of the bone marrow/peripheral smear was reported (including our 4 cases).

4.1. Pathologic findings

5. Discussion

In all 4 cases, the bone marrow biopsy specimens were hypercellular, ranging from 60% to 100% (Fig. 1A-I). Neoplastic cells were numerous and present in sheets, and mitoses were identified. Bone trabeculae were normal. Intranuclear pseudoinclusions (Dutcher bodies) were identified in case 4 (Fig. 1H). In bone marrow aspirate smears, the neoplastic cells were plasmablasts in case 3 (Fig. 1E-F) or showed a range of maturation, from blastic cells to more mature plasma cells

Primary PCL is a rare neoplasm of plasma cells. Primary PCL is defined as malignant proliferation first diagnosed in the leukemic phase, whereas secondary PCL corresponds to the leukemic transformation in a patient previously diagnosed plasma cell myeloma [2-8]. The current criteria for the diagnosis of PCL is a clonal proliferation of plasma cells in the blood representing greater than 20% of the total leukocytes or an absolute plasma cell count of more than 2  109/L. Plasma cells in the bone marrow also must exceed

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Fig. 1. Trephine bone marrow biopsy sections show extensive bone marrow involvement by plasma cells. Normal bone marrow elements are decreased. Bone marrow smears show a range of maturation from blastic cells to mature plasma cells. Peripheral blood film (inset) shows immature plasma cells with irregular nuclei, fine chromatin, and high nuclear-cytoplasmic ratio. Note anemia, thrombocytopenia, and rouleaux.

10% [2-4,6-15]. In previous reports, patients with primary PCL usually have more extramedullary disease, more severe anemia, thrombocytopenia, hypercalcemia, renal failure, and higher serum LDH and b 2-microglobulin levels. Patients with PCL have elevated monoclonal immunoglobulin in the serum, usually IgG (50%) or IgA (15%), with IgD and IgE being rare. Bence Jones proteinuria occurs in approximately 80% of cases [5,16]. The clinical presentation of PCL (asthenia, severe anemia, and thrombocytopenia and, in some cases, hepatomegaly and splenomegaly) mimics the presentation of acute leukemia and differs from that classic plasma cell myeloma [5-7,16]. There are relatively few reports describing the pathologic findings of primary PCL. We have identified only a few case reports and 1 case series in the literature describing pathologic findings (Table 3). In some cases reported, most of the cells resemble normal plasma cells with basophilic cytoplasm, prominent Golgi zone, and an eccentric nucleus. Other cases have many lymphoplasmacytoid lymphocytes and only a minority of characteristic plasma cells. Yet, others have more primitive cells with a higher nuclear cytoplasmic ratio, open chromatin, a prominent nucleolus, and a less prominent Golgi zone (plasmablasts) [3,4]. These latter cases can be difficult to recognize as plasma cells by

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light microscopy alone and require immunophenotypic studies. In all 4 cases of primary PCL we report, the bone marrow was diffusely infiltrated by plasma cells disrupting normal hematopoiesis. The plasma cells displayed a spectrum of maturity, from small mature plasma cells to large, anaplastic, blastic cells that were difficult to classify. The peripheral blood smear in all cases had an increased number of plasma cells, as is part of the definition of PCL. Ancillary studies were essential in making the correct diagnosis in these cases. Immunophenotypically, PCL typically is positive for CD38 and CD138. It has been reported that the intensity of CD38 expression progressively decreases from normal plasma cell to clonal PCL [23]. The immunophenotype of primary PCL also differs from plasma cell myeloma. For example, CD56 (neuronal cell adhesion molecule) and HLADR, which can be present in plasma cell myeloma, are less frequently positive in PCL. CD20 is reported to be more common in PCL than plasma cell myeloma [2,6,10,12,16]. This was not our experience because all 4 cases of PCL we report expressed CD38 and lacked CD20. In agreement with previous reports [6,15], in this study, 3 of 4 primary PCL cases had complex cytogenetic abnormalities. Case 1 in our study had a complex hyperdiploid karyotype with t(11;14), case 2 had a complex pseudodiploid karyotype with t(11;14) del(12)(p13) and del(13)(q1432), and case 3 had a complex hypodiploid karyotype with del(11q)(13) (Table 2). Many different chromosomal translocations have been implicated in PCL. The translocations involving the immunoglobulin heavy chain locus at 14q32, specifically t(11;14) and t(14;16), are genetic markers for plasma cell myeloma and have been reported in 80% of patients with PCL [24,25]. The identification of 11q13 abnormalities in 3 cases in this study, including cases with the t(11;14) in 1 with del(11)(q13), is in accord with the literature. Also, abnormalities of chromosome 13, the global state of hypodiploidy, and abnormalities of chromosome 1, which have been associated with short survival in patients with plasma cell myeloma, were also noted in the present series [6,15,16,26]. Certain genetic abnormalities exhibit a particular immunophenotypic profile in plasma cell dyscrasias. For example, immunoglobulin heavy chain translocation to 11q13 is associated with expression of CD20, down-regulation of CD56, and lack of expression in CD117. IGH gene rearrangements and 13q deletions also show a strong association with CD117 expression [26]. However, we did not identify CD20 expression in any of the PCL cases carrying the t(11;14) in the present study. One case expressed CD19 (case 1), but the overall and immunophenotypic and cytogenetic findings, including the t(11;14), support the diagnosis of PCL. These results suggest the correlation between genetic abnormalities and immunophenotypic profile in cases of plasma cell myeloma is not absolute in primary PCL. In conclusion, PCL is the most aggressive form of plasma cell neoplasm with a poor prognosis despite aggressive

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treatment with high-dose chemotherapy, SCT, and the use of novel therapeutic agents. The 4 cases we report emphasize that the diagnosis of primary PCL is difficult based on findings alone because of diffuse bone marrow infiltration by very immature plasma cells that can have an aberrant immunophenotype. Comprehensive flow immunophenotypic studies are critical to arrive at the diagnosis of PCL. Cytogenetic analysis has shown abnormalities in approximately 75% of these cases. References [1] Dimopoulos MA, Palumbo A, Delasalle KB, et al. Primary plasma cell leukaemia. Br J Haematol 1994;88:754 - 9. [2] International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121(5):749 - 57. [3] Kyle RA, Maldonado JE, Bayrd ED. Plasma cell leukemia. Report on 17 cases. Arch Intern Med 1974;133:813 - 8. [4] Woodruff RK, Malpas JS, Paxton AM, et al. Plasma cell leukemia (PCL): a report on 15 patients. Blood 1978;52:839 - 45. [5] Kosmo MA, Gale RP. Plasma cell leukemia. Semin Hematol 1987; 24:202 - 8. [6] Saccaro S, Fonseca R, Veillon DM, et al. Primary plasma cell leukemia: report of 17 new cases treated with autologous or allogeneic stem-cell transplantation and review of the literature. Am J Hematol 2005;78:288 - 94. [7] Costello R, Sainty D, Bouabdallah R, et al. Primary plasma cell leukaemia: a report of 18 cases. Leuk Res 2001;25:103 - 7. [8] Chang H, Sloan S, Li D, et al. Genomic aberrations in plasma cell leukemia shown by interphase fluorescence in situ hybridization. Cancer Genet Cytogenet 2005;156:150 - 3. [9] Bernasconi C, Castelli G, Pagnucco G, et al. Plasma cell leukemia: a report on 15 patients. Eur J Haematol Suppl 1989;51:76 - 83. [10] Castellano-Sanchez AA, Kreisel FH. Pathologic quiz case: a 39-yearold man with severe lower back pain. Plasma cell leukemia. Arch Pathol Lab Med 2005;129:e70 - 2. [11] Hovenga S, de Wolf JT, Klip H, et al. Consolidation therapy with autologous stem cell transplantation in plasma cell leukemia after VAD, high-dose cyclophosphamide and EDAP courses: a report of three cases and a review of the literature. Bone Marrow Transplant 1997;20:901 - 4. [12] Garcia-Sanz R, Orfao A, Gonzalez M, et al. Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics. Blood 1999;93:1032 - 7. [13] Panizo C, Rifon J, Rodriguez-Wilhelmi P, et al. Long-term survival in primary plasma cell leukemia after therapy with VAD, autologous blood stem cell transplantation and interferon-alpha. Acta Haematol 1999;101:193 - 6.

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