Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3607-3609
CORRESPONDENCE
Primary Plasma Cell Leukemia and Multiple Myeloma: One or Two
Diseases According to the Methodology
 |
LETTER |
To the Editor:
Recently, García-Sanz et al1 reported a series of
26 patients with plasma cell leukemia (PCL) in whom a number of
biological parameters were studied, with particular emphasis about
measure of DNA cell content by flow cytometry and detection of numeric chromosomal aberrations by interphase fluorescent in situ hybridization (FISH). For the purposes of comparison, the same parameters were tested
in a series of 56 multiple myeloma (MM) patients. Their data, as
presented, showed clear differences between the PCL and MM patients studied.
Firstly, all except 1 PCL patient studied showed a normal DNA content,
whereas most MM patients (57%) showed a hyperdiploid DNA content.
Secondly, FISH studies using 15 chromosome-specific probes performed in
13 PCL and 56 MM cases showed statistically significant differences
between PCL and MM for the following chromosomes: 
13 (84% in PCL
and 26% in MM), +9 (0% in PCL and 52% in MM), and +6 (0% in PCL and
32% in MM). Although chromosome 3, 7, 11, and 15 were found trisomic
in MM cases only, the results of the statistical analysis regarding
these defects are not mentioned. On the other hand, no difference was
found for chromosome 1 involvement (43% in PCL and 37% in MM). The
used chromosome 1 probe hybridized to the 1q12 heterochromatic region,
making trisomy of chromosome 1 indistinguishable from the presence of a
1q chromosome derivative, a frequent finding in these
pathologies.2
The investigators concluded that, in PCL and MM, the DNA cell content
and cytogenetic characteristics are different, leading to a different
disease evolution.
We do not agree with these results, because we think that the
techniques used, ie, flow cytometry and FISH with centromeric probes,
are not appropriate to compare genetic aberrations in PCL and MM
patients because they missed a number of aberrations detected by other techniques.
Whereas flow cytometry is a good technique to detect hyperdiploidy, it
is not able to detect a minor error in DNA content such as a small
hypodiploid clone or, moreover, pseudodiploid aberrations. Zandecki et
al,3 using a different technique to appreciate the plasma
cell DNA content (histochemical staining with computed analysis), found
that 58.7% of patients were hyperdiploid, as reported by
García-Sanz et al,1 but they also detected 24%
patients with hypodiploidy and 4.3% with biclonality among a series of
46 MM patients. Elsewhere, conventional cytogenetics (CC) in stage III
MM and in PCL cases lead to informations in more than 70%
of cases studied.4-7 Using CC, we studied a series of 81 MM
patients with an abnormal karyotype and found 2 different cytogenetic
patterns based on chromosome number: a hyperdiploid pattern (54%) with
recurrent trisomies 3, 5, 7, 9, 11, 15, and 19 and a second pattern
(46%) showing either pseudoploid, hypoploid, or near tetraploid
karyotypes. In this study, a prognostic correlation was found between
the cytogenetic pattern and overall survival: hyperdiploid patients had
a longer survival than patients belonging to the
pseudo/hypo/near-tetraploid group.8
In the same way, a recent conventional cytogenetic study of 13 primary
PCL patients showed that 12 of 13 had an abnormal clone. A hypodiploid
karyotype was found in 9 cases and a pseudodiploid was found in 2 cases. It was concluded that PCL patients share a poor prognosis with
MM patients with a hypodoploid karyotype.7
From a cytogeneticist point of view, we do not find any difference
between plasma cell leukemia and hypo/pseudo/near-tetraploid multiple
myeloma associated with poor prognosis. We think that PCL and these MM
are, in fact, the same disease. PCL could be is a fulminant form of MM
and could be compared with those rare cases of chronic myeloid leukemia
showing an acute phase at presentation.
Nicole
Véronique Smadja
Laboratoire de Recherche en
Cytogénétique Hématologique
Hôpital Saint
Antoine
Paris, France
Christian Bastard
Laboratoire de
Génétique Oncologique
Centre Henri Becquerel
Rouen,
France
Christophe Brigaudeau
Laboratoire
d'Hématologie
Hôpital de Limoges
Limoges,
France
| |
REFERENCES |
1.
García-Sanz R, Orfão A, González M, Tabernero MD, Bladé J, Moro MJ, Fernández-Calvo J, Sanz MA, Pérez-Simón JA, Rasillo A, San Miguel JF:
Primary plasma cell leukemia: Clinical, immunophenotypic, DNA ploidy and cytogenetic characteristics.
Blood
93:1032, 1999[Abstract/Free Full Text]
2.
Sawyer JR, Tricot G, Mattox S, Jagannath S, Barlogie B:
Jumping translocations of chromosome 1q in multiple myeloma: Evidence for a mechanism involving decondensation of pericentromeric heterochromatin.
Blood
91:1732, 1998[Abstract/Free Full Text]
3.
Zandecki M, Bernardi F, Laï JL, Facon T, Izydorczyk, Bauters F, Cosson A:
Image analysis in multiple myeloma at diagnostic. Correlation with cytogenetic study.
Cancer Genet Cytogenet
74:115, 1994[Medline]
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4.
Smadja NV, Louvet C, Isnard F, Dutel JL, Grange MJ, Varette C, Krulik M:
Cytogenetic study in multiple myeloma at diagnosis: Comparison of two techniques.
Br J Haematol
90:619, 1995[Medline]
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5.
Brigaudeau C, Trimoreau F, Gachard N, Rouzier E, Jaccard A, Bordessoule D, Praloran V:
Cytogenetic study of 30 patients with multiple myeloma: Comparison of 3 and 6 day bone marrow cultures stimulated or not with cytokines by using a miniaturized karyotypic method.
Br J Haematol
96:594, 1997[Medline]
[Order article via Infotrieve]
6.
Smadja NV, for the GFCH (Groupe Français de cytogenetique Hématologique):
Conventional cytogenetic in multiple myeloma: Detection of karyotype abnormalities depends on technical and clinical factors.
Br J Haematol
102:P-1385, 1998 (abstr)
7. Brigaudeau C, Desangles F, Trimoreau F, Avet-Loiseau H, Terre C,
Talmant P, Ramond S, Praloran V: Karyotypic abnormalities in primary
plasma cell leukaemia and closely related plasma cell dyscrasias. Br J
Haematol (submitted)
8.
Smadja NV, Fruchart C, Isnard F, Louvet C, Dutel JL, Cheron N, Grange MJ, Monconduit M, Bastard C:
Chromosomal analysis in multiple myeloma: Cytogenetic evidence of two different diseases.
Leukemia
12:960, 1998[Medline]
[Order article via Infotrieve]
Response
We are pleased for the interest that Smadja et al have demonstrated on
our report,1 in which we report on the clinical and
biological characteristics of a series of primary PCL. In their letter,
they add cytogenetic information on 81 multiple myelomas and give a
reference submitted for publication concerning 13 primary PCL,
concluding that MM with pseudoploid, hypoploid, or near tetraploid
karyotypes show similar genetic characteristics as compared with PCL.
According to this information, they conclude that both diseases are the
same, which would be in contrast to the conclusion that presumably we
support in our report. Actually, in our previous publication, we just
concluded that, because PCL and MM show overall distinct clinical,
immunophenotypic, DNA ploidy, and cytogenetic characteristics, the link
between both diseases remains unclear. In this sense, the apparent
discrepancies between these investigators and us would be merely based
on data interpretation.
Actually, a careful analysis of the information reported by Smadja et
al would support our own data, even considering that different
technical approaches were used for the analysis of chromosomal aberrations. They report on 81 MM, in which 54% are hyperdiploid (this
prevalence is almost exactly the same as the 56% of MM with a DNA
index >1 identified in our series). In contrast, no hyperdiploid PCL
were found by Brigadeau et al2 among 13 cases tested, which is also coincidental with our experience (series 0/22 PCL had a DNA
index >1). It is obvious that these differences favor the notion
that, overall, PCL and MM are different diseases.
The most relevant cytogenetic molecular marker of PCL is the deletion
of the Rb gene, located at chromosome 13, because it was present in the
great majority of our PCL cases (86%). Nevertheless, this is not a
specific marker of PCL, because a subset of myeloma patients also share
this chromosomal change. This subset of patients display an unfavorable
prognosis.3-5 Therefore, it could be argued that these MM
patients are tightly related to PCL. However, upon analyzing other
chromosomal changes, we observed that a high proportion of MM cases
with monosomy 13 concomitantly show trisomy 9 (67% of cases) and
trisomy 6 (33%), whereas none of these changes was observed in our PCL
patients. Moreover, as shown in Fig
1, the survival of MM patients
with monosomy 13 was significantly better than in those PCL patients
with the same chromosome abnormality (median survival, 16 and 7 months,
respectively; P = .011). Based on these results, it could be
speculated that the occurrence of a deletion in the closer area of the
Rb gene would be a critical alteration that changes the clinical
behavior of the disease. However, this alteration would appear in MM in
a different moment of the clonal evolution as compared with de novo
PCL. In addition, from the biological point of view, we described in
our report several other parameters, including the proliferative
activity, extramedulary involvement, LDH serum level, immunophenotype,
response to therapy, etc, that were also different between MM and PCL, suggesting that MM and PCL are different.
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| Fig 1.
Overall survival curves of patients with monosomy 13 according to the presence of plasma cell leukemia or multiple myeloma
criteria.
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|
Despite these data, we think that the answer to the question on whether
PCL and MM are the same disease remains open. In this sense, we still
can recognize overlapping cases that accomplish MM or PCL criteria but
display clinical or biological characteristics of the other form. This
was already reported in our publication. This fact could lead to the
hypothesis that MM and PCL belong to the same group of diseases (here
we should use the unspecific term monoclonal gammopathies), but there
is a different pattern in the accumulation of genetic alterations
leading to a different clinical behavior in the 2 forms of the disease.
Because the clonal evolution and the genetic way to acquire aberrations
depend on many circumstances,6 this could explain why there
exist some overlapping cases.
R. García-Sanz
A. Orfão
J.F. San Miguel
Department of Hematology
University Hospital of Salamanca
Salamanca, Spain
| |
REFERENCES |
1.
García-Sanz R, Orfão A, González M, Tabernero MD, Bladé J, Moro MJ, Fernández-Calvo J, Sanz MA, Pérez-Simón JA, Rasillo A, San Miguel JF:
Primary plasma cell leukemia: Clinical, immunophenotypic, DNA ploidy and cytogenetic characteristics.
Blood
93:1032, 1999
2. Brigadieu C, Desangles F, Trimoureau F, Avet-Loiseau H, Terre C,
Talmant P, Ramond S, Praloran V: Karyotypic abnormalities in plasma
cell leukemia and closely related plasma cell discrasias. Br J Haematol
(submitted)
3.
Pérez-Simón JA, García-Sanz R, Tabernero MD, Almeida J, González M, Fernández-Calvo J, Moro MJ, Hernández JM, San Miguel JF, Orfão A:
Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes.
Blood
91:3366, 1998[Abstract/Free Full Text]
4.
Tricot G, Barlogie B, Jagannath S, Bracy D, Mattox S, Vesole DH, Naucke S, Sawyer J:
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
86:4250, 1995[Abstract/Free Full Text]
5.
Seong C, Delasalle K, Hayes K, Weber D, Dimopoulos MA, Swantkowski J, Huh Y, Glassman A, Champlin R, Alexaniana R:
Prognostic value of cytogenetics in multiple myeloma.
Br J Haematol
101:189, 1998[Medline]
[Order article via Infotrieve]
6.
Hallek M, Bergsagel PL, Anderson KC:
Multiple myeloma: Increasing evidence for a multistep transformation process.
Blood
91:3, 1998[Free Full Text]
