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Blood, 1 February 2001, Vol. 97, No. 3, pp. 822-825
BRIEF REPORT
Cytogenetic, interphase, and multicolor fluorescence in situ
hybridization analyses in primary plasma cell leukemia: a study of 40 patients at diagnosis, on behalf of the Intergroupe Francophone du
Myélome and the Groupe Français de
Cytogénétique Hématologique
Hervé Avet-Loiseau,
Axelle Daviet,
Christophe Brigaudeau,
Evelyne Callet-Bauchu,
Christine Terré,
Marina Lafage-Pochitaloff,
François Désangles,
Sylvie Ramond,
Pascaline Talmant, and
Régis Bataille
From the Laboratory of Hematology, University Hospital,
Nantes, France; Laboratory of Hematology, University Hospital, Limoges,
France; Laboratory of Hematology, Hopital Lyon-Sud,
Pierre-Bénite, France; Laboratory of Cytogenetics, General
Hospital, Versailles; Laboratory of Cytogenetics, Institute
Paoli-Calmette, Marseille, France; and Laboratory of Cytogenetics,
Hospital Val-de-Grace, and Laboratory of Hematology, Hotel-Dieu, Paris,
France.
 |
Abstract |
Primary plasma cell leukemia (PCL) is a rare plasma cell
malignancy. Consequently, few large reports have been published. Presented is a cytogenetic analysis of 40 patients with primary PCL
compared with 247 newly diagnosed patients with stage III multiple
myeloma (MM). Cytogenetic abnormalities were observed in 23 of 34 patients, with usually complex hypodiploid or pseudodiploid karyotypes.
Analysis of rearrangements of the 14q32 region revealed significant
differences with high cell mass MM a higher incidence of t(11;14)
(33% vs 16%; P < .025) and of t(14;16) (13% vs 1%; P < .002) though incidences of t(4;14) were identical
and a higher incidence of monosomy 13 (68% vs 42%;
P = .005). Hypodiploid karyotypes and monosomy 13 may
explain, at least in part, the poorer prognosis of primary PCL. In
contrast, significantly longer survival was observed in patients
displaying t(11;14) in comparison with those lacking this translocation
(P = .001).
(Blood. 2001;97:822-825)
© 2001 by The American Society of Hematology.
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Introduction |
Multiple myeloma (MM) is characterized by the
accumulation of malignant plasma cells (PC) within the bone marrow. On
rare occasions, PCs are observed in the peripheral blood and mimic acute leukemia. Kyle et al1 defined strict criteria for the diagnosis of plasma cell leukemia (PCL): an absolute PC number greater
than 2 × 109/L or a relative number greater than 20% of
peripheral white blood cells. PCL is rarely encountered; it represents
less than 5% of malignant PC disorders.1-4 Consequently,
few series have been reported, and only 3 series clinically analyzing
more than 20 patients have been published.2-4 We now
report on the largest series of primary PCL (35 patients with primary
PCL and 5 patients with a primary PCL-like condition) analyzed by
cytogenetics or interphase and multicolor fluorescence in situ
hybridization (FISH). Interphase FISH results were then compared to
those obtained in a series of 247 newly diagnosed patients with a stage
III MM, as previously reported.5,6
| |
Study design |
Between 1992 and 2000, 35 patients with primary PCL and 5 patients with a PCL-like disease (less than 2 × 109
PC/L; range, 1 × 109-1.9 × 109) were
analyzed by FISH in our laboratory. Twenty of these patients were
directly analyzed in Nantes, whereas the other 20 patients were
diagnosed in other institutions, and metaphase preparations were
secondarily sent to us for FISH analysis. Most patients received melphalan-based conventional dosage chemotherapy, and 13 patients were
treated using high-dose chemotherapy followed by autologous (10 patients) or allogeneic (3 patients) stem cell rescue. These patients
have been compared with 247 patients with newly diagnosed stage III MM,
analyzed in the same conditions (most of them have been previously
reported5,6).
Bone marrow (34 patients) or peripheral blood (6 patients) cells were
cultured without mitogens for 24 to 72 hours, using standard
conditions. Cytogenetic analysis was attempted in 34 patients. Patients
with abnormal karyotype were analyzed using multicolor FISH. Briefly,
metaphase spreads were hybridized with a multicolor painting probe
panel (SpectraVysion; Vysis, Voisins-le-Bretonneux, France), and
analyzed using the software (Vysis). Each chromosome was pseudocolored
in a specific color, enabling an accurate identification of marker
chromosomes. Finally, we performed interphase FISH experiments in all
40 patients for the analysis of 14q32 and 13q14 rearrangements, as
previously reported.5,6 Other FISH analyses were
performed using specific probes to confirm some abnormalities in 11 patients.
| |
Results and discussion |
Median age was 62 years (range, 35-89 years). Five
patients did not fulfill the criteria for PCL but resembled true PCL
patients in other factors and thus were included in this series. The
median absolute number of circulating PC in PCL patients was
9.2 × 109/L (range, 2-64 × 109).
Osteolytic lesions were present in 17 of 29 patients (59%) with
available clinical data. Overall survival was brief, with a median
survival of 7 months (range, 5 days-38 months). This poor survival is
in agreement with previously reported series and confirms the poor
prognosis of primary PCL.3-5,7 However, a detailed
analysis of survival shows that 11 of 40 patients died within the first
month of diagnosis and that, in contrast, some patients are alive 2 to
3 years after diagnosis.
An abnormal karyotype was obtained in 23 of 34 patients (Table
1). Most were complex and pseudodiploid
or hypodiploid. Only 3 patients had hyperdiploidy (48, 49, and 51 chromosomes). These results are in contrast with those published in
MM,8-10 in which hyperdiploidy is observed in
approximately 60% of patients, but they confirm previously published
analyses.3,4 Multicolor FISH analysis was performed in 21 of 23 patients with an abnormal karyotype (no available metaphases for
patients 34 and 36). In several patients, it enabled the identification
of marker chromosomes. Some markers were extremely complex, containing
sequences from up to 6 chromosomes, and could not be identified by
cytogenetics (Figure 1). Among all the
abnormalities revealed by multicolor FISH analysis, t(6;8)(q12-q15;q24)
was identified in 2 patients (patients 3 and 37; Figure 1). The
involvement of c-myc was confirmed by other FISH
experiments using specific probes located on each side of the
c-myc locus (manuscript submitted), which showed a separation of both probes. This specific abnormality has been reported.11 No other translocation involving
c-myc has been identified, neither by conventional
karyotyping nor by interphase or multicolor FISH. These results
contrast with those recently reported by Shou et al12
describing c-myc rearrangements in almost 100% of myeloma
cell lines and 50% of patients with MM. No satisfactory answer can be
proposed to explain these discrepancies.
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| Figure 1.
Multicolor FISH
analysis.
(A) Partial multicolor FISH karyotype showing both derivatives of
t(6;8)(q15;q24) (patient 37). (B) Complex chromosomal marker identified
by multicolor FISH (patient 6), containing 5 different chromosomal
fragments (from chromosomes 6, 8, X, 1, and 8). (C) Complex chromosomal
marker identified by multicolor FISH (patient 16), containing 6 different chromosomal fragments (from chromosomes X, 11, 8, 12, 7, and 1).
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Interphase FISH experiments were performed in all 40 patients and
closely analyzed the 14q32 and 13q14 chromosomal bands, as previously
described.5,6 An illegitimate rearrangement of the
IGH gene was observed in 32 of 40 (80%) patients; in 3 patients, 2 different rearrangements were identified (Table 1). This
incidence of 14q32 abnormalities is significantly higher than that
observed in a control series of 247 patients newly diagnosed with stage
III MM (60%) (P = .024). Of note, 3 (7.5%) patients displayed 2 different 14q32 rearrangements, whereas only 1 of 247 stage
III patients showed this configuration. Three partners were
recurrently identified, either with metaphase or interphase FISH:
11q13, 4p16, and 16q23, in 13, 5, and 4 patients, respectively. No case
of t(8;14) was identified. Compared with the control stage III MM
population, t(11;14) and t(14;16) were significantly more frequent in
primary PCL than in stage III MM (33% and 13% vs 16% and 1%;
P = .025 and P = .002, respectively). Such a
high incidence of t(11;14) has never been reported in patients with PC
malignancies. Regarding the t(14;16), one study based on multicolor
spectral karyotyping reported a 12% (6 of 50)
incidence.11 However, clinical data were not described,
and some PCL patients may have been included. Finally, the 12% (11 of
53) incidence of t(4;14) observed in primary PCL and MM is in agreement
with that recently reported by Malgeri et al.13 Few
cytogenetic analyses of patients with primary PCL have been published.
In one study,3 9 patients were analyzed and 1 patient with
t(11;14) was described. However, a detailed analysis of karyotypes in
this study reveals 3 patients with "add (16q24)," which may
correspond to unidentified t(14;16). This abnormality is cryptic and
could be missed by conventional cytogenetics. Another study of 4 patients reported 1 with t(11;14).14 In contrast, no
differences were observed for t(4;14) between primary PCL and stage III
MM. These results clearly highlight specific associations between some
14q32 rearrangements and the type of presentation of plasma cell
dyscrasias rather than a random occurrence. Whereas t(11;14) is
observed in all types of plasma cell dyscrasia (ie, MGUS,15 MM,5 primary PCL, and myeloma cell
lines16), t(4;14) appears to be specifically associated
with MM,5,15 primary PCL, and cell lines,16
but not with MGUS, t(14;16) is mostly observed in primary PCL and
cell lines,17 and t(8;14) is specifically associated
with myeloma cell lines.12
Then we focused on chromosome 13 loss. This abnormality has been
recently identified as a poor prognostic factor.18-20
Interphase FISH analysis was performed using a probe specific for the
D13S319 locus, at 13q14. Although monosomy 13 is observed in 42% of
patients with stage III MM, 27 of 40 (68%) patients with primary PCL
displayed this abnormality (P = .005). Thus, the
cytogenetic profile presented by patients with primary
PCLhypodiploidy or pseudodiploidy and monosomy 13may explain the
poor survival observed in these patients. However, some patients
younger than 65 years without monosomy 13 may benefit from intensive
therapy and enjoy longer survival. In addition, a detailed analysis of
5 patients with a primitive PCL-like disease revealed a profile similar
to that of PCL patients (pseudodiploid or hypodiploid karyotypes, high
incidence of monosomy 13, short survival). These similarities with PCL
may suggest a reappraisal of the diagnostic criteria, empirically
defined by Kyle et al1 25 years ago.
Despite a marked heterogeneity in treatment modalities, we
performed multiple statistical analyses on overall survival using several end-points. The only significant difference was the survival at
12 months between patients with or without t(11;14)t(11;14) was
associated with significantly longer survival (P = .001;
Fisher exact test). These data contrast with previously published
reports concluding the opposite finding.21,22 Larger
prospective studies are necessary to establish definitive conclusions.
| |
Footnotes |
Submitted July 7, 2000; accepted October 2, 2000.
Supported in part by grants from the Fondation de France and from the
Association de Recherche contre le Cancer.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Hervé Avet-Loiseau and Régis Bataille,
Laboratoire d'Hématologie, Institut de Biologie, 9 quai
Moncousu, 44093 Nantes Cedex 1, France; e-mail:
havetloiseau{at}chu-nantes.fr or frb{at}sante.univ-nantes.fr.
| |
References |
1.
Kyle RA, Maldonado JE, Bayrd ED.
Plasma cell leukemia: report on 17 cases.
Arch Intern Med.
1974;133:813-818[CrossRef][Medline]
[Order article via Infotrieve].
2.
Noel P, Kyle RA.
Plasma cell leukemia: an evaluation of response to therapy.
Am J Med.
1987;83:1062-1068[CrossRef][Medline]
[Order article via Infotrieve].
3.
Dimopoulos MA, Palumbo A, Delasalle KB, Alexanian R.
Primary plasma cell leukemia.
Br J Haematol.
1994;88:754-759[Medline]
[Order article via Infotrieve].
4.
Garcia-Sanz R, Orfao A, Gonzalez M, et al.
Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics.
Blood.
1999;93:1032-1037[Abstract/Free Full Text].
5.
Avet-Loiseau H, Li JY, Facon T, et al.
High incidence of translocations t(11;14)(q13;q32) and t(4,14)(p16;q32) in patients with plasma cell malignancies.
Cancer Res.
1998;58:5640-5645[Abstract/Free Full Text].
6.
Avet-Loiseau H, Li JY, Morineau N, et al.
Monosomy 13 is associated with the transition of monoclonal gammopathy of undetermined significance to multiple myeloma.
Blood.
1999;94:2583-2589[Abstract/Free Full Text].
7.
Pruzanski W, Platts ME, Ogryzlo MA.
Leukemic form of immunocytic dyscrasia (plasma cell leukemia): a study of ten cases and a review of the literature.
Am J Med.
1969;47:60-74[CrossRef][Medline]
[Order article via Infotrieve].
8.
Laï JL, Zandecki M, Mary JY, et al.
Improved cytogenetics in multiple myeloma: a study of 151 patients including 117 patients at diagnosis.
Blood.
1995;85:2490-2497[Abstract/Free Full Text].
9.
Sawyer JR, Waldron JA, Jagannath S, Barlogie B.
Cytogenetic findings in 200 patients with multiple myeloma.
Cancer Genet Cytogenet.
1995;82:41-49[CrossRef][Medline]
[Order article via Infotrieve].
10.
Smadja NV, Fruchart C, Isnard F, et al.
Chromosomal analysis in multiple myeloma: cytogenetic evidence of two different diseases.
Leukemia.
1998;12:960-969[CrossRef][Medline]
[Order article via Infotrieve].
11.
Sawyer JR, Lukacs JL, Munshi N, et al.
Identification of new nonrandom translocations in multiple myeloma with multicolor spectral karyotyping.
Blood.
1998;92:4269-4278[Abstract/Free Full Text].
12.
Shou Y, Martelli ML, Gabrea A, et al.
Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma.
Proc Natl Acad Sci U S A.
2000;97:228-233[Abstract/Free Full Text].
13.
Malgeri U, Baldini L, Perfetti V, et al.
Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription-polymerase chain reaction analysis of IGH-MMSET fusion transcripts.
Cancer Res.
2000;60:4058-4061[Abstract/Free Full Text].
14.
Jonveaux P, Berger R.
Chromosome studies in plasma cell leukemia and multiple myeloma in transformation.
Genes Chromosomes Cancer.
1992;4:321-325[Medline]
[Order article via Infotrieve].
15.
Avet-Loiseau H, Facon T, Daviet A, et al.
14q32 Translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma.
Cancer Res.
1999;59:4546-4550[Abstract/Free Full Text].
16.
Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM.
Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma.
Proc Natl Acad Sci U S A.
1996;93:13931-13936[Abstract/Free Full Text].
17.
Chesi M, Bergsagel PL, Shonukan OO, et al.
Frequent dysregulation of the c-maf proto-oncogene at 16q23 by translocation to an Ig locus in multiple myeloma.
Blood.
1998;91:4457-4463[Abstract/Free Full Text].
18.
Tricot G, Barlogie B, Jagannath S, et al.
Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.
Blood.
1995;86:4250-4256[Abstract/Free Full Text].
19.
Zojer N, Königsberg R, Ackermann J, et al.
Deletion of 13q14 remains an independent adverse prognostic variable in multiple myeloma despite its frequent detection by interphase fluorescence in situ hybridization.
Blood.
2000;95:1925-1930[Abstract/Free Full Text].
20.
Desikan R, Barlogie B, Sawyer J, et al.
Results of high dose therapy for 1000 patients with multiple myeloma: durable complete remissions and superior survival in the absence of chromosome 13 abnormalities.
Blood.
2000;96:4008-4010.
21.
Fonseca R, Witzig TE, Gertz MA, et al.
Multiple myeloma and the translocation t(11;14)(q13;q32): a report on 13 cases.
Br J Haematol.
1998;101:296-301[CrossRef][Medline]
[Order article via Infotrieve].
22.
Laï JL, Michaux L, Dastugue N, et al.
Cytogenetics in multiple myeloma: a multicenter study of 24 patients with t(11;14)(q13;q32) or its variant.
Cancer Genet Cytogenet.
1998;104:133-138[CrossRef][Medline]
[Order article via Infotrieve].
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Abstract
Introduction