Hematopathology / LOW CD27 EXPRESSION IN HIGH-RISK DISEASE
Low CD27 Expression in Plasma Cell Dyscrasias
Correlates With High-Risk Disease
An Immunohistochemical Analysis
Terry K. Morgan, MD, PhD,1 Shuchun Zhao,1 Karen L. Chang, MD,2 Terri L. Haddix, MD,1
Elisabeth Domanay,1 P. Joanne Cornbleet, MD, PhD,1 Daniel A. Arber, MD,1
and Yasodha Natkunam, MD, PhD1
Key Words: CD27; Plasma cell leukemia; Plasmacytoma; Myeloma; Monoclonal gammopathy of undetermined significance; MGUS
DOI: 10.1309/ELGMGX81C2UTP55R
Abstract
Genome-wide expression studies using
complementary DNA microarrays recently suggested a
number of intriguing candidate genes for distinguishing
plasma cell dyscrasias. Our objective was to test select
markers using immunohistochemical analysis and a
tissue microarray from paraffin-embedded bone
marrow core biopsy specimens obtained from 8 patients
with monoclonal gammopathy of undetermined
significance, 17 with plasmacytoma, 160 with multiple
myeloma, and 15 with plasma cell leukemia (PCL). We
immunostained serial sections for CD138, CD27,
CD56, p27, Ki-67, CD3, and CD20. Each core was
scored in duplicate by observers blinded to phenotype
and reported as the average percentage of CD138+
cells. The Mann-Whitney U test was used to determine
significance between groups. PCL showed significantly
less immunostaining for CD27 (P < .01) and p27
(P < .05) compared with plasmacytoma and multiple
myeloma. Low CD27 expression also was associated
with plasmacytoma progression to multiple myeloma
(P <.05). Our results support the hypothesis that low
CD27 expression correlates with high-risk disease,
including primary PCL and decreased progression-free
survival in solitary plasmacytoma.
Plasma cell dyscrasias are characterized by monoclonal
proliferations of plasma cells composed of a number of clinicopathologic entities, including monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma, multiple
myeloma, and plasma cell leukemia (PCL).1 The risk that
MGUS may evolve to myeloma is approximately 1% per year,2
whereas overt myeloma occurs in nearly 50% of solitary plasmacytoma cases within 3 years.3 PCL is a rare leukemic variant of
multiple myeloma with a dismal prognosis4,5 that is somewhat
dependent on whether it manifests as de novo (primary) or as a
secondary transformation from previous multiple myeloma.6
Syndecan-1 (CD138) is a reliable immunohistochemical
marker that labels plasma cells, including all plasma cell
dyscrasias.7-9 Markers that distinguish the type of dyscrasia by
immunophenotype, however, are not widely used. Genomewide expression analysis using complementary DNA microarrays and RNA purified from normal plasma cells, MGUS, and
multiple myeloma recently has yielded lists of intriguing candidate genes.10,11 The key genes seem to be involved in cell
signaling, adhesion, and cell cycle regulation.10,11
The low expression of one such candidate gene, CD27,
seems to be associated with clinically aggressive cases of multiple myeloma.10,12 CD27 is a member of the tumor necrosis
factor receptor family13 and normally is expressed on plasma
cells, peripheral T cells, and a subset of mature B cells.14
Stimulation of the CD27 receptor by its ligand, CD70,15 leads
to plasma cell differentiation in the presence of costimulatory
cytokines.16 Blocking CD27 inhibits terminal differentiation.17 CD27 also may affect plasma cell apoptosis, but the
data are mixed as to whether CD27 stimulates or inhibits cell
death.16,18,19 This problem is highlighted by the unexpected
finding of high CD27 expression in PCL,12 despite the very
Am J Clin Pathol 2006;126:545-551
© American Society for Clinical Pathology
545
DOI: 10.1309/ELGMGX81C2UTP55R
545
545
Morgan et al / LOW CD27 EXPRESSION IN HIGH-RISK DISEASE
aggressive nature of this phenotype. Subsequent in vitro studies suggested that CD27 stimulation may even have a modest
antiapoptotic effect in leukemic plasma cells.20
Other genes involved in cell cycle control and apoptosis
also may provide a promising avenue of distinguishing various
plasma cell dyscrasias. For example, cyclin D1 expression is
increased in a subset of multiple myeloma cases.10,21
Unexpectedly, however, the proliferation marker Ki-67 and the
cyclin-dependent kinase inhibitor p27 seem to show no difference in expression between plasmacytoma and multiple myeloma.21 Because p27 is expressed at high levels in quiescent cells
and declines with mitogen activation,22 one would expect lower
p27 and higher Ki-67 expression in high-risk disease.
Several studies have evaluated the use of the neural cell
adhesion molecule CD56 in distinguishing various plasma cell
dyscrasias. CD56 is expressed strongly in multiple myeloma,23 whereas there is variable expression in cases of
MGUS24,25 and generally low expression in cases of
extramedullary plasmacytoma and PCL.4,21 Whether CD56
correlates positivity with progression from plasmacytoma to
myeloma is not clear.26
In the present study, we evaluated CD27, p27, CD56, and
Ki-67 expression in a large number of plasma cell dyscrasias,
including MGUS (n = 8), plasmacytoma (n = 17), multiple
myeloma (n = 160), and PCL (n = 15) using immunohistochemical analysis and tissue microarrays. We hypothesized
that low CD27 and p27 expression would correlate with highrisk disease, including primary PCL.
Materials and Methods
Tissue Microarray Construction
By using an institutional review board–approved protocol
(protocol ID 79034, IRB 348, panel 1), we retrieved a total of
184 archival paraffin blocks of bone marrow core biopsies
from patients with various plasma cell dyscrasias treated at the
Stanford University Medical Center, Stanford, CA, and the
City of Hope National Medical Center, Duarte, CA, from
January 1991 to June 2003. All cores were processed similarly, including decalcification and formalin fixation. Each case
was diagnosed by expert hematopathologists (K.L.C., P.J.C.,
D.A.A., and Y.N.) using established clinical criteria.1
Duplicate 0.6-mm cores were taken from representative
areas of the bone marrow with the highest percentage of plasma
cells and inserted into a recipient paraffin block to create a tissue microarray27 containing 195 cores, including positive and
negative controls (n = 11), plasmacytoma (n = 1), MGUS (n =
8), multiple myeloma (n = 160), and PCL (n = 15). Studies have
shown that duplicate cores in tissue microarray analysis correct
for focal expression or core dropout in the majority of cases.28
Each core contained thousands of cells, which were predominantly plasma cells with the exception of the MGUS cases
❚Table 1❚ (percentage of plasma cells). The 15 cases of PCL
included 7 confirmed primary de novo cases, 4 clinical primary
cases (no history available for review), and 4 secondary cases
transformed from previous multiple myeloma. The MGUS
cases had a mean follow-up of 3.5 years. No follow-up was
available for the multiple myeloma cases. As a pilot study to test
for differences between solitary plasmacytoma and cases that
progressed to multiple myeloma, we later added whole tissue
sections from 16 extramedullary plasmacytomas seen at
Stanford from January 1993 to June 2004 that received similar
treatments and follow-up (8 solitary and 8 with later progression). Similar to the tissue array, we chose two 1.0-mm areas
with the highest percentage of CD138+ cells.
Immunohistochemical Staining
Immunostaining was performed manually using routine
microwave antigen retrieval and the EnVision+ System, horseradish peroxidase (diaminobenzidine) kit (DAKO,
Carpinteria, CA), following manufacturer’s instructions.
Commercially available monoclonal antibodies against
CD138 (1:50 dilution; DAKO), CD27 (1:40 dilution;
Novocastra Laboratories, Newcastle upon Tyne, England),
❚Table 1❚
Immunostaining of Paraffin Sections of Plasma Cell Dyscrasias*
% Plasma Cells
% Plasma Cells Positive
% Lymphocytes
Phenotype
CD138
CD27
CD56
p27
Ki-67
CD3
CD20
Plasmacytoma (n = 17)
PCL (n = 15)
Myeloma (n = 160)
MGUS (n = 8)
99 (1)
97 (2)
64 (2)
15 (3)
50 (10)†
14 (6)‡
47 (3)
90 (14)‡
23 (5)
37 (3)
77 (6)‡
99 (19)‡
61(9)
31 (6)§
73 (6)
99 (28)§
8 (2)
20 (4)§
34 (4)‡
31 (5)§
1 (1)
4 (1)
9 (1)
9 (1)
3 (3)
10 (3)
10 (1)
9 (1)
MGUS, monoclonal gammopathy of undetermined significance; PCL, plasma cell leukemia.
* Nonparametric analysis (Mann-Whitney U test) of various plasma cell dyscrasias compared with plasmacytomas.
† Data are given as mean (± SEM). Percentage of positive plasma cells was scored as percentage of cells positive for antibody (eg, CD27) divided by the percentage of CD138+
cells in the tissue core. The percentage of “contaminating” T cells and B cells was not significantly different between plasma cell dyscrasias.
‡ P < .01.
§ P < .05.
546
546
Am J Clin Pathol 2006;126:545-551
DOI: 10.1309/ELGMGX81C2UTP55R
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
p27 (KIP1; 1:1,000 dilution; Transduction Laboratories,
Lexington, KY), CD56 (1:50 dilution; Zymed Laboratories,
San Francisco, CA), Ki-67 (1:1,000 dilution; DAKO), CD20
(1:50 dilution; DAKO), and polyclonal anti-CD3 (1:100 dilution; DAKO) were used to stain 3.0-µm serial sections of the
tissue array. CD138 strongly stained the membranes of all
plasma cells; CD27 and CD56 also showed membranous
staining. Ki-67 and p27 are nuclear stains. Representative
immunohistochemical results for the various plasma cell
dyscrasias stained for CD138, CD27, p27, and CD56 are
given in ❚Image 1❚ (images acquired using Nikon Eclipse
E1000 microscope, 10× objective, and Spot digital imaging
system, Diagnostic Instruments, Sterling Heights, MI).
cell dyscrasia. Results for each subsequent antibody were
reported as the average percentage of CD138+ plasma cells.
Concordance between these 2 pathologists was excellent (correlation coefficient, R = 0.85). Analysis was performed using
Statview software 5.0 (SAS Institute, Cary, NC), and the nonparametric Mann-Whitney U test was used to determine significance between groups. Differences in progression-free survival in plasmacytoma cases as a function of CD27 staining
(eg, positive staining was defined as >10% of plasma cells29,30)
were compared by using the Mantel-Cox log-rank test. These
data also were analyzed by 2 × 2 table using the Fisher exact
test. Significance was defined as a P value of less than .05.
Analysis
The plasma cell component within each core was defined
as CD138+ cells and scored in duplicate by 2 independent
pathologists (T.K.M. and Y.N.) blinded to the subtype of plasma
Results
Plasmacytoma
Myeloma
PCL
p27
CD56
CD27
CD138
MGUS
The 17 plasmacytoma cases showed sheets of CD138+
plasma cells (mean ± SEM percentage of CD138+ cells, 99%
± 1%) (Image 1 and Table 1). Because these cases represented
❚Image 1❚ Tissue microarray analysis of plasma cell dyscrasias. Cases of paraffin-embedded bone marrow core biopsy
specimens that were assembled into a tissue microarray from patients with monoclonal gammopathy of undetermined
significance (MGUS), plasmacytoma, multiple myeloma, and plasma cell leukemia (PCL). Serial sections were immunostained
for various markers that showed markedly decreased expression of CD27 in PCL.
Am J Clin Pathol 2006;126:545-551
© American Society for Clinical Pathology
547
DOI: 10.1309/ELGMGX81C2UTP55R
547
547
Morgan et al / LOW CD27 EXPRESSION IN HIGH-RISK DISEASE
a nearly pure plasma cell population and because one of our
objectives was to distinguish immunophenotypes in plasmacytoma from multiple myeloma and PCL, we used these cases
as the reference control cases for subsequent nonparametric
statistical analysis. In contrast, the MGUS cases showed a low
percentage of plasma cells, increasing the likelihood that
results may be false-positive staining of lymphocytes or
hematopoietic elements. However, plasma cells in these cases
were identified and scored by trained pathologists (T.K.M.
and Y.N.), making false-positive staining less likely.
Moreover, immunohistochemical staining for CD3+ T cells
and CD20+ B-cells showed few contaminating lymphocytes
in the core biopsy specimens used for analysis, and there was
no significant difference in the numbers of lymphocytes by
type of plasma cell dyscrasia (Table 1). Therefore, with the
exception of the MGUS cases, which had the fewest plasma
cells for analysis (mean ± SEM, 15% ± 3%), we concluded
that the preponderance of immunostaining was a function of
plasma cell expression. This model also was supported by
carefully comparing results for each antibody tested with serial sections immunostained for CD138.
Low CD27 Immunostaining in PCL
PCL showed markedly decreased levels of CD27 and p27
immunostaining (P < .01 and P < .05, respectively) with an
increased Ki-67 proliferation fraction (P < .05) compared with
plasmacytoma (Table 1). By definition, none of our 11 cases of
primary PCL had a history of multiple myeloma, although 2
cases had a history of MGUS. We observed no significant difference in expression between primary and secondary PCL in
any of the markers tested ❚Figure 1❚. Because all of the PCL
cases showed strong immunostaining for CD138, we do not
attribute loss of CD27 to fixation artifacts or loss of antigenicity in archival material. Indeed, archival material from our plasmacytomas and multiple myelomas stained strongly for CD27.
Low CD27 Immunostaining in Plasmacytomas That
Progress to Myeloma
Our immunohistochemical analysis of 17 plasmacytoma
cases showed that low to absent staining for CD27 may be
associated with decreased progression-free survival (P < .05).
We had 9 cases of solitary plasmacytoma with no reported
progression to myeloma (mean ± SEM follow-up, 4.5 ± 0.5
years) and 8 cases that manifested as solitary plasmacytoma
but later progressed to multiple myeloma (mean ± SEM follow-up, 5.5 ± 1.6 years). The difference in follow-up time was
not statistically significant (P = .5).
Nonparametric analysis of the raw data using the MannWhitney U test to compare mean CD27 immunostaining showed
significantly fewer CD27+ plasma cells in plasmacytoma cases
that progressed to multiple myeloma (P < .05) ❚Figure 2❚. Low
p27 and CD56 staining in cases of progression showed a similar
1.2
0.8
1.0
% Plasma Cells Positive
Secondary PCL
0.6
0.5
0.4
0.3
% Plasma Cells Positive
Primary PCL
0.7
Plasmacytoma
Progressed to myeloma
*
0.8
0.6
0.4
0.2
0.2
0.1
0
0
CD27
p27
CD56
❚Figure 1❚ Low CD27 expression in cases of primary plasma
cell leukemia (PCL). Only 1 case of primary PCL (n = 11)
showed positive staining for CD27 in at least 10% of plasma
cells. Secondary PCL (n = 4) showed more variable staining
for CD27, but the mean difference was not significant by
Mann-Whitney U test in this small sample. There was no
observable difference in p27 or CD56 immunostaining
between these groups. Dots indicate outliers; bars indicate
the 10th and 90th percentiles.
548
548
Am J Clin Pathol 2006;126:545-551
DOI: 10.1309/ELGMGX81C2UTP55R
CD27
p27
CD56
❚Figure 2❚ Low CD27 expression in cases of plasmacytoma (n
= 9) that progressed to multiple myeloma (n = 8). * P < .05.
Differences in p27 and CD56 immunostaining were not
significant between the groups by the Mann-Whitney U test
(P = .10 and P = .07, respectively). Dots indicate outliers; bars
indicate the 10th and 90th percentiles.
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
trend, although they were not statistically significant (P = .10
and P = .07, respectively). The degree of Ki-67 positivity also
was not significant (P = .46). If positive immunostaining is
defined arbitrarily as the commonly used cutoff of greater than
10%29,30 of tumor cells, then 8 of 9 cases of solitary plasmacytoma were positive for CD27 ❚Table 2❚. Only 2 of 8 cases that
progressed were positive for CD27 (P < .05; Fisher exact test).
Decreased progression-free survival also was observed by
Mantel-Cox log-rank testing (P < .05). Ki-67, p27, and CD56
staining were not associated with outcome. Notably, we elected
to use the 10% cutoff because of findings in previous studies.29
If we analyzed the data using more than 0% as the cutoff, then
all 9 cases of solitary plasmacytoma were positive for CD27
and 3 of 8 cases that progressed were positive for CD27 (P <
.01; Fisher exact test). Progression-free survival was not significantly different by Mantel-Cox log-rank testing (P = .10).
❚Table 2❚
Low CD27 Expression in Solitary Plasmacytoma May Predict
Progression to Myeloma*
High CD56 in Multiple Myeloma and MGUS
We observed high CD56 expression in our cases of multiple myeloma (P < .01) and relatively low levels in plasmacytoma and PCL. Immunostaining for CD56 also was positive in
our MGUS cases (P < .01). Multiple myeloma showed less
CD27 staining than MGUS (Table 1). There also was significantly less CD27 staining compared with our subset of 9 cases
of solitary plasmacytoma (P < .05). The Ki-67 proliferation
index was higher in multiple myeloma (P < .01), whereas p27
levels were not significantly different from levels in plasmacytoma. The relatively high Ki-67 index in our cases of MGUS
is attributed to the high percentage of intermixed hematopoietic precursors, which confound analysis in these cases, and
highlights the weakness of our method in MGUS cases.
+, positive; –, negative.
* Positive is immunostaining in greater than 10% of plasma cells. Absence of CD27
staining was associated with progression to myeloma; P < .05; Fisher exact test.
Discussion
Our study shows that low CD27 expression in plasmacytomas and PCL is associated with an aggressive clinical
course. This finding is consistent with recent complementary
DNA microarray studies10 that revealed that CD27 is one of
the most significantly down-regulated genes in multiple
myeloma compared with control samples. Subsequent flow
cytometric studies also showed low CD27 immunostaining in
the most aggressive cases of myeloma.12 Surprisingly, however, Guikema et al12 also showed “homogeneous high expression of CD27” in their 3 cases of primary PCL, despite the
markedly aggressive clinical behavior of this malignancy.
They suggested that loss of CD27 in aggressive forms of multiple myeloma may have no relationship to the pathophysiology of primary PCL. For example, comparative genomic
hybridization and fluorescence in situ hybridization studies
have shown that although multiple myeloma is associated
with chromosomal gains, PCL usually shows losses.31,32
Onset
Location
CD27
p27
CD56
2000
2000
2001
2001
2001
2002
2003
2003
2003
1993
1993
1997
2003
2003
2003
2003
2004
Spine
Hard palate
Spine
Meninges
Clivus
Spine
Sinus
Vocal cord
Tonsil
Skull
Unknown
Spine
Clivus
Clivus
Sinus
Spine
Rib
+
+
+
+
+
+
+
+
–
–
–
–
–
–
+
–
+
+
+
+
+
+
+
+
+
+
+
–
+
+
+
–
+
–
+
+
–
+
+
+
–
+
+
–
–
–
–
+
+
+
–
Outcome
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Plasmacytoma
Progression
Progression
Progression
Progression
Progression
Progression
Progression
Progression
Alternatively, loss of CD27 expression may be common to
multiple myeloma and primary PCL. Our immunohistochemical results show a relative lack of CD27 staining in all 11 cases
of primary PCL. There was variable staining in our 4 cases of
secondary PCL, similar to multiple myeloma. Flow cytometry
may be more sensitive at detecting CD27 than immunohistochemical staining of paraffin-embedded sections. However,
this hypothesis would not explain why our PCL cases stained
strongly for CD138 and lacked CD27, despite strong CD27
immunostaining in most of the cores from our cases of plasmacytoma, multiple myeloma, and MGUS.
Low CD27 expression also may be associated with
decreased progression-free survival in cases of solitary plasmacytoma. Although our sample was limited (n = 17), we
observed a significant association between lack of CD27 and
overt progression to multiple myeloma. We analyzed the data
by multiple methods, including nonparametric analysis of
continuous raw data and log-rank testing of nominal data
(positive staining defined as >10% of tumor cells29,30). If we
analyzed the data using a more than 10% positivity cutoff,
only 1 of 9 cases of solitary plasmacytoma was negative for
CD27. In contrast, 6 of 8 cases that progressed to myeloma
were negative. If we analyzed the nominal data using a more
than 0% positivity cutoff, the statistical association by the
Fisher exact P value was strengthened, but progression-free
survival by Mantel-Cox log-rank test was not significant,
reflecting the limited statistical power of our relatively small
sample. These data are intriguing and warrant further study to
determine whether lack of CD27 staining in plasmacytomas is
a marker for progression to myeloma.
Am J Clin Pathol 2006;126:545-551
© American Society for Clinical Pathology
549
DOI: 10.1309/ELGMGX81C2UTP55R
549
549
Morgan et al / LOW CD27 EXPRESSION IN HIGH-RISK DISEASE
Whether CD27 has a role in the pathogenesis of plasma
cell dyscrasia is uncertain. The leading hypothesis is that
CD27 mediates an apoptotic pathway. There is some in vitro
evidence that CD27 interacts with the intracytoplasmic protein Siva, leading to apoptosis in lymphocytes and kidney
cells.18,33,34 CD27 stimulation also may lead to activation of
NF-κB and c-Jun N-terminal kinase,35 culminating in apoptosis. Inhibition of this pathway by interleukin 6 apparently
protects multiple myeloma cells from apoptosis.36 Therefore,
down-regulation of CD27 in multiple myeloma and PCL may
improve tumor cell survival. Alternatively, Guikema et al20
suggested that CD27 triggering by its ligand, CD70, may
activate mitogen-activated protein kinases and inhibit apoptosis in cases of PCL that express high levels of CD27. Further
study is needed.
Additional evidence that PCL may evade apoptosis is
seen in our immunostaining results for Ki-67 and p27. We
observed an increased Ki-67 proliferation fraction and low
p27 expression levels in PCL compared with plasmacytoma.
In comparison, our cases of multiple myeloma showed high
Ki-67 levels, but p27 expression also was high, supporting
the hypothesis that multiple myeloma may be more prone to
apoptosis than PCL.37 Similarly, we would expect more
apoptosis in the plasma cells of MGUS compared with multiple myeloma.38
The role of CD56 is less clear. Similar to previous studies, we observed strong diffuse staining for CD56 in multiple
myeloma with relatively low levels in plasmacytoma21 and
PCL.4,39 Our MGUS cases showed strong staining for CD56,
which is consistent with previous flow cytometric studies.25
Previous immunohistochemical studies of bone marrow core
biopsy specimens arbitrarily required more than 50% of plasma cells to be CD56+ to be scored24 and likely underestimated the number of CD56+ MGUS cases.
Our retrospective analysis of paraffin-embedded tissue
sections shows that lack of CD27 expression in a plasma cell
dyscrasia is associated with high-risk disease, including PCL
and cases of plasmacytoma that progress to multiple myeloma. There are only rare studies investigating immunophenotypic differences in clonal plasma cell populations.4,25,40
Previous studies have shown loss of CD27 expression in highrisk multiple myeloma. Our novel finding is the relative
absence of CD27 in cases of PCL and plasmacytoma that
progress to myeloma. Our 11 cases of primary PCL were negative for CD27, which is in direct contrast with the model suggested by Guikema et al.12,20 Whether loss of CD27 prevents
programmed cell death in these tumor cells requires further
investigation.
From the 1Departments of Pathology, Stanford University Medical
Center, Stanford; and 2City of Hope National Medical Center,
Duarte, CA.
550
550
Am J Clin Pathol 2006;126:545-551
DOI: 10.1309/ELGMGX81C2UTP55R
Address reprint requests to Dr Morgan: Dept of Pathology,
Oregon Health and Science University, 3181 SW Sam Jackson
Park Rd, Mail code L471, Portland, OR 97239.
References
1. 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;121:749-757.
2. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term
study of prognosis in monoclonal gammopathy of
undetermined significance. N Engl J Med. 2002;346:564-569.
3. Kyle RA. Monoclonal gammopathy of undetermined
significance and solitary plasmacytoma: implications for
progression to overt multiple myeloma. Hematol Oncol Clin
North Am. 1997;11:71-87.
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.
5. Noel P, Kyle RA. Plasma cell leukemia: an evaluation of
response to therapy. Am J Med. 1987;83:1062-1068.
6. Hayman SR, Fonseca R. Plasma cell leukemia. Curr Treat
Options Oncol. 2001;2:205-216.
7. Witzig TE, Kimlinger T, Stenson M, et al. Syndecan-1
expression on malignant cells from the blood and marrow of
patients with plasma cell proliferative disorders and B-cell
chronic lymphocytic leukemia. Leuk Lymphoma. 1998;31:167175.
8. Costes V, Magen V, Legouffe E, et al. The Mi15 monoclonal
antibody (anti–syndecan-1) is a reliable marker for quantifying
plasma cells in paraffin-embedded bone marrow biopsy
specimens. Hum Pathol. 1999;30:1405-1411.
9. O’Connell FP, Pinkus JL, Pinkus GS. CD138 (syndecan-1),
a plasma cell marker: immunohistochemical profile in
hematopoietic and nonhematopoietic neoplasms. Am J Clin
Pathol. 2004;121:254-263.
10. Zhan F, Hardin J, Kordsmeier B, et al. Global gene expression
profiling of multiple myeloma, monoclonal gammopathy of
undetermined significance, and normal bone marrow plasma
cells. Blood. 2002;99:1745-1757.
11. Claudio JO, Masih-Khan E, Tang H, et al. A molecular
compendium of genes expressed in multiple myeloma. Blood.
2002;100:2175-2186.
12. Guikema JE, Hovenga S, Vellenga E, et al. CD27 is
heterogeneously expressed in multiple myeloma: low CD27
expression in patients with high-risk disease. Br J Haematol.
2003;121:36-43.
13. Bigler RD, Bushkin Y, Chiorazzi N. S152 (CD27): a
modulating disulfide-linked T cell activation antigen. J
Immunol. 1988;141:21-28.
14. Jung J, Choe J, Li L, et al. Regulation of CD27 expression in
the course of germinal center B cell differentiation: the pivotal
role of IL-10. Eur J Immunol. 2000;30:2437-2443.
15. Hintzen RQ, Lens SM, Beckmann MP, et al. Characterization
of the human CD27 ligand, a novel member of the TNF gene
family. J Immunol. 1994;152:1762-1773.
16. Agematsu K, Nagumo H, Oguchi Y, et al. Generation of
plasma cells from peripheral blood memory B cells: synergistic
effect of interleukin-10 and CD27/CD70 interaction. Blood.
1998;91:173-180.
© American Society for Clinical Pathology
Hematopathology / ORIGINAL ARTICLE
17. Raman VS, Akondy RS, Rath S, et al. Ligation of CD27 on
B cells in vivo during primary immunization enhances
commitment to memory B cell responses. J Immunol.
2003;171:5876-5881.
18. Prasad KV, Ao Z, Yoon Y, et al. CD27, a member of the tumor
necrosis factor receptor family, induces apoptosis and binds to
Siva, a proapoptotic protein. Proc Natl Acad Sci U S A.
1997;94:6346-6351.
19. Katayama Y, Sakai A, Oue N, et al. A possible role for the loss
of CD27-CD70 interaction in myelomagenesis. Br J Haematol.
2003;120:223-234.
20. Guikema JE, Vellenga E, Abdulahad WH, et al. CD27triggering on primary plasma cell leukaemia cells has antiapoptotic effects involving mitogen activated protein kinases.
Br J Haematol. 2004;124:299-308.
21. Kremer M, Ott G, Nathrath M, et al. Primary extramedullary
plasmacytoma and multiple myeloma: phenotypic differences
revealed by immunohistochemical analysis. J Pathol.
2005;205:92-101.
22. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclindependent kinases. Genes Dev. 1995;9:1149-1163.
23. Van Camp B, Durie BG, Spier C, et al. Plasma cells in
multiple myeloma express a natural killer cell–associated
antigen: CD56 (NKH-1; Leu-19). Blood. 1990;76:377-382.
24. Martin P, Santon A, Bellas C. Neural cell adhesion molecule
expression in plasma cells in bone marrow biopsies and
aspirates allows discrimination between multiple myeloma,
monoclonal gammopathy of uncertain significance and
polyclonal plasmacytosis. Histopathology. 2004;44:375-380.
25. Ocqueteau M, Orfao A, Almeida J, et al. Immunophenotypic
characterization of plasma cells from monoclonal gammopathy
of undetermined significance patients: implications for the
differential diagnosis between MGUS and multiple myeloma.
Am J Pathol. 1998;152:1655-1665.
26. Schwartz TH, Rhiew R, Isaacson SR, et al. Association
between intracranial plasmacytoma and multiple myeloma:
clinicopathological outcome study. Neurosurgery.
2001;49:1039-1044.
27. Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue
microarrays for high-throughput molecular profiling of tumor
specimens. Nat Med. 1998;4:844-847.
28. Camp RL, Charette LA, Rimm DL. Validation of tissue
microarray technology in breast carcinoma. Lab Invest.
2000;80:1943-1949.
29. Masir N, Jones M, Pozzobon M, et al. Expression pattern of
FCRL (FREB, FcRX) in normal and neoplastic human B cells.
Br J Haematol. 2004;127:335-343.
30. Chen ZM, Wang HL. Alteration of cytokeratin 7 and
cytokeratin 20 expression profile is uniquely associated with
tumorigenesis of primary adenocarcinoma of the small
intestine. Am J Surg Pathol. 2004;28:1352-1359.
31. Gutierrez NC, Hernandez JM, Garcia JL, et al. Differences in
genetic changes between multiple myeloma and plasma cell
leukemia demonstrated by comparative genomic hybridization.
Leukemia. 2001;15:840-845.
32. Liebisch P, Viardot A, Bassermann N, et al. Value of
comparative genomic hybridization and fluorescence in situ
hybridization for molecular diagnostics in multiple myeloma.
Br J Haematol. 2003;122:193-201.
33. Padanilam BJ, Lewington AJ, Hammerman MR. Expression of
CD27 and ischemia/reperfusion-induced expression of its
ligand Siva in rat kidneys. Kidney Int. 1998;54:1967-1975.
34. Py B, Slomianny C, Auberger P, et al. Siva-1 and an
alternative splice form lacking the death domain, Siva-2,
similarly induce apoptosis in T lymphocytes via a caspasedependent mitochondrial pathway. J Immunol. 2004;172:40084017.
35. Akiba H, Nakano H, Nishinaka S, et al. CD27, a member of
the tumor necrosis factor receptor superfamily, activates NFkappaB and stress-activated protein kinase/c-Jun N-terminal
kinase via TRAF2, TRAF5, and NF-kappaB–inducing kinase.
J Biol Chem. 1998;273:13353-13358.
36. Xu FH, Sharma S, Gardner A, et al. Interleukin-6–induced
inhibition of multiple myeloma cell apoptosis: support for the
hypothesis that protection is mediated via inhibition of the
JNK/SAPK pathway. Blood. 1998;92:241-251.
37. Pene F, Claessens YE, Muller O, et al. Role of the
phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase
pathways in the proliferation and apoptosis in multiple
myeloma. Oncogene. 2002;21:6587-6597.
38. Witzig TE, Timm M, Larson D, et al. Measurement of
apoptosis and proliferation of bone marrow plasma cells in
patients with plasma cell proliferative disorders. Br J Haematol.
1999;104:131-137.
39. Pellat-Deceunynck C, Barille S, Jego G, et al. The absence of
CD56 (NCAM) on malignant plasma cells is a hallmark of
plasma cell leukemia and of a special subset of multiple
myeloma. Leukemia. 1998;12:1977-1982.
40. Perez-Andres M, Almeida J, Martin-Ayuso M, et al. Clonal
plasma cells from monoclonal gammopathy of undetermined
significance, multiple myeloma and plasma cell leukemia show
different expression profiles of molecules involved in the
interaction with the immunological bone marrow
microenvironment. Leukemia. 2005;19:449-455.
Am J Clin Pathol 2006;126:545-551
© American Society for Clinical Pathology
551
DOI: 10.1309/ELGMGX81C2UTP55R
551
551