Berkala Ilmu Kedokteran

Kedokteran, Volume 39, No. 3, September 2007: 122-128

Vol. 39, No. 3, September 2007: 122-128

Expression of CD5, CD10, Bcl-2 and Bcl-6

in diffuse large B cell lymphoma based on
International Prognostic Index
Indrawati1, Tody Guntersah1, Rizki Zuchri2, Gogor Meisadona2,
M. Adrian Hasdianda2, Windhi Dwijanarko2
1
Departement of Anatomic Pathology, Faculty of Medicine
Gadjah Mada University, Yogjakarta
2
Student of Faculty of Medicine Gadjah Mada University, Jogjakarta

ABSTRACT
Indrawati1, Tody Guntersah1, Rizki Zuchri2, Gogor Meisadona2, M. Adrian Hasdianda2, Windhi Dwijanarko2
– Expression of CD5, CD10, Bcl-2 and Bcl-6 in diffuse large B cell lymphoma based on International
Prognostic Index

Background : Diffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma. This
tumor has heterogeneous clinical feature, morphology, genetic and molecular alterations. Diffuse large B
cell lymphoma with a germinal centre ( GC ) pattern of gene expression including CD10 and Bcl-6 has a
more favorable outcome. CD5 and Bcl-2 expression has been shown to have an adverse effect on the
outcome in diffuse large B cell lymphoma
Objective: To investigate the difference of CD5, CD10, Bcl-2 and Bcl-6 expression based on International
Prognostic Index (IPI) in diffuse large B cell lymphoma
Methods: Fourty five cases of B cell diffuse large B cell lymphoma from embedding parafin tissue were
constituted the basis of the study. Immunohistochemical examination using CD20, CD5, CD10, Bcl-2 and
Bcl-6 monoclonal antibody was done. The difference of CD5, CD10, Bcl-2 and Bcl-6 expression between
high and low IPI of diffuse large B cell lymphoma were analized by chi square test
Result: There was significant difference between the number of cases with positivity of CD5 and CD10
expression in high and low IPI of diffuse large B cell lymphoma. The result supported that immunophenotyping
related B cell differentiation can help to predict clinical behavior and prognosis in diffuse large B cell
lymphoma.
Conclusion: Conclusion: There was significant difference between the number of cases with positivity of
CD5 and CD10 expression in high and low IPI of diffuse large B cell lymphoma. The result supported that
immunophenotyping related B cell differentiation can help to predict clinical behavior and prognosis in
diffuse large B cell lymphoma.

Key words : diffuse large B cell lymphoma, CD5, CD10, IPI

ABSTRAK
Indrawati1, Tody Guntersah1, Rizki Zuchri2, Gogor Meisadona2, M. Adrian Hasdianda2, Windhi Dwijanarko2
– Ekspresi CD5, CD10, Bcl-2 and Bcl-6 berdasarkan International Prognostic Index pada diffuse large B
cell lymphoma

Latar belakang :Diffuse large B cell lymphoma merupakan jenis limfoma non-Hodgkin yang paling sering
dijumpai. Penyakit ini memiliki gambaran klinis, morfologi serta perubahan genetik, dan molekular yang
heterogen. Diffuse large B cell lymphoma yang memiliki fenotip serupa dengan sel sentrum germinativum
normal atau ditandai dengan ekspresi CD5 dan CD10 berhubungan dengan perilaku klinis dan prognosis

Indrawati, Tody Guntersah, Departement of Anatomic Pathology,

Faculty of Medicine Gadjah Mada University, Yogjakarta
Rizki Zuchri, Gogor Meisadona, M. Adrian Hasdianda, Windhi
Dwijanarko, Student of Faculty of Medicine Gadjah Mada University,
Yogyakarta

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 Indrawati et al, Expression of CD5, CD10, Bcl-2 and Bcl-6 in diffuse large B cell lymphoma

baik. Diffuse large B cell lymphoma dengan ekspresi CD5 dan Bcl-2 positif berhubungan dengan perilaku
klinis dan prognosis buruk.
Tujuan Penelitian: Mengetahui perbedaan ekspresi CD5, CD10, Bcl-6 dan Bcl-2 berdasarkan International
Prognostic Index pada diffuse large B cell lymphoma
Metoda: Penelitian dilakukan secara retrospektif dengan menggunakan 45 sediaan kasus diffuse large B
cell lymphoma .Digunakan analisis statistik chi square untuk mengetahui perbedaan jumlah kasus diffuse
large B cell lymphoma dengan ekspresi CD5, CD10, Bcl-2 dan Bcl-6 positif pada IPI tinggi dibandingkan
jumlah kasus diffuse large B cell lymphoma dengan ekspresi CD5, CD10, Bcl-2, dan Bcl-6 positif pada IPI
rendah
Hasil: Pada penelitian ini didapatkan perbedaan bermakna antara jumlah kasus dengan ekspresi CD5 dan
CD10 positif pada IPI tinggi dibandingkan jumlah kasus dengan ekspresi CD5 dan CD10 positif pada IPI
rendah.Hasil tersebut menunjukkan bahwa gambaran imunofenotip sesuai diferensiasi sel limfosit B dapat
digunakan untuk membantu memperkirakan perilaku klinis dan prognosis diffuse large B cell lymphoma.
Simpulan: Pada penelitian ini didapatkan perbedaan bermakna antara jumlah kasus dengan ekspresi CD5
dan CD10 positif pad a IPI tinggi dibandingkan jumlah kasus dengan ekspresi CD5 dan CD10 positif pad a
IPI rendah.Hasil tersebut menunjukkan bahwa gambaran imunofenotipe sesuai diferensiasi sel limfosit B
dapat digunakan untuk membantu memperkirakan perilaku klinis dan prognosis diffuse large B eel/lymphoma.

INTRODUCTION During the last decade, most studies dealing

Diffuse large B-cell lymphoma (DLBL) is the
most common type of non-Hodgkin lymphoma and
accounts for 30% to 40% of new diagnosis.1.
Although diffuse large B-cell lymphoma is usually
considered as aspecific category, the diversity in
the clinical presentation, morphology, genetic and
molecular alterations strongly suggest that this tumor
represents a heterogeneous group of neoplasms
rather than a single clinicopathologic entity.2
Approximately half of all patients with diffuse large
B-cell lymphoma can be cured by conventional
chemotherapy. The remainder have tumors that are
either refractory to currently available treatment
or have relapse after a period of remission, and
most of these patients will die of the disease.3
Therefore, it is important to identify at diagnosis
those who may benefit from more aggressive or
experimental therapies.
The most effective tool for predicting the
outcome of patients with diffuse large B-cell
lymphoma is the International Prognostic Index
(IPI), which has been validated in many clinical
trials. The IPI is a clinical index, based on the extent
of the disease, as determined by the stage and
lactate dehydrogenase (LDH), and on the patient’s
age and Eastern Cooperative Oncology Group
performance status (ECOG score).4 Although these
clinical parameters still reflect a mixture of
underlying biologic or genetic differences, the IPI
successfully identifies subgroups of patients with
very poor or good outcome.5
with the heterogeneity of diffuse large B-cell
lyphoma have focused on morphologic features,
individual protein expression or molecular
alterations. The expression of individual antigens
related to different stages of B-cell differentiation
including CD5, CD10, Bcl-6 and oncogen such as
Bcl-2 may help define group of tumors with
different clinical and pathological characteristics.6
Two main gene patterns have been characterized
according to the germinal center (GC) or post-GC
(activated B-cell) origin.7 Although there were some
controversions, those with a GC pattern of gene
expression which is characterized by CD10 and
Bcl-6 expression had a more favorable outcome.8
On the other hand, the expression of CD5 and Bcl-
2 protein has been shown an adverse effect on
outcome.9
MATERIAL AND METHODS
The study design for this research is a cross-
sectional study. The patients were selected only on
the basis of availability of clinical information and
histologic material. The research subjects were 50
paraffin embedded tissue patients of diagnosed for
diffuse large cell lymphoma by routine haemato-
xylin-eosin staining in Anatomic Pathology
Laboratory, Sardjito Hospital. The samples were
examined by immunohistochemistry staining using
CD20 monoclonal antibody as B cell marker. Fourty
five cases of diffuse large B cell lymphoma
confirmed by the positivity of CD20 (positive
membrane staining) constituted the basis of the

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study. The paraffin blocks of the cases were stained

for CD5, CD10, Bcl-2 and Bcl-6 monoclonal antibody
using the Dako kit in standard immunohistochemistry.
CD5 positivity was considered when more than 20%
tumor cells presented membrane staining and CD10
positivity was considered when more than 25% tumor
cells presented membrane staining. Bcl-2 expression
was scored as positive if more than 50% of the tumor
cells had membrane and cytoplasmic staining. In
addition, tumor will be scored as Bcl-6 positive if more
than 25% of the tumor displayed nuclear staining. FIGURE 2. Positive expression of CD5 showed brown
IPI (International Prognostic Index) data was membrane staining
obtained from the medical record of the patients.
The components of IPI were staging, lactate
dehydrogenase (LDH) level, the patient’s age,
performance status and the number of extranodal
locations. Each IPI components were categorized
as score 0 and 1. Score 1 was given if the patient
was more than 60 years old, the staging was more
than stage II, had high level of LDH, bad
performance status and more than two extranodal
locations. If the score was more than 2, the case
was considered to have high IPI.
FIGURE 3. Positive expression of CD10 showed brown
The difference of CD5, CD10, Bcl-2 and Bcl-
membrane staining
6 expression between high and low IPI of these
patients were analized by chi square test.

RESULT
Out of 45 diffuse large B cell lymphoma with
CD20 expression (FIGURE 1), 8 (17.8%) cases
had high IPI. Seventeen of 45 (37.8 %) of the cases
expressed CD5 (FIGURE 2) and 20 of 45 (44.4%)
cases expressed CD10 (FIGURE 3). The positivity
of Bcl-2 (FIGURE 4) and Bcl-6 (Figure 5 expression
was found in 28 ( 62.2% ) cases and 24 (53.3%)
cases (TABLE 1). FIGURE 4. Positive expression of Bcl-2 showed brown
membrane and cytoplasmic staining

There was significant difference between the

frequency of high and low IPI score in diffuse large
B cell lymphoma cases with positive CDS (p < 0.05)
as well as in cases with positive CDIO (p = 0.05).
There was no significant difference between the
frequency of high and low IPI score in diffuse large
B cell lymphoma cases with positive Bc1-2 (p <
0.05) as well in as cases with positive Bc1-6 (p >
FIGURE 1. Positive expression of CD20 showed brown
0.05).
membrane staining

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 Indrawati et al, Expression of CD5, CD10, Bcl-2 and Bcl-6 in diffuse large B cell lymphoma

FIGURE 5. The nuclear brown staining showed the expression of Bcl-6

TABLE 1. The number of cases with CD5, CD 10, Bcl 2 and Bcl 6 expression based on IPI score

DISCUSSION malignancies, including CLL and MCL, represent

a high incidence of bone marrow involvement and
Of the factors examined in this study, it was
advanced disease, though the clinical behaviour of
observed that CD5+ expression was associated with
the CLL patients is generally indolent. This finding
high IPI in diffuse large B cell lymphoma.
suggests that CD5+ B cells have a tendency to
Statistically significant association between CD5+
spread widely within the tissues. Some authors have
expression and high IPI was also reported in a
recently reported that CD5 molecule on B cells
previous study.10 The CD5 molecule is a 67-kd
interacts as a ligand with heavy-chain variable
glycoprotein that is expressed by most T cells and
framework regions of surface immunoglobulins,
subset of B cells. CD5 B cells are the predominant
which implies a possible role in the maintenance,
B cell population in human fetal spleen and cord
selection or expansion of normal, autoimmune or
blood, but they represent only 10% to 20% of adult
transformed B cells. The molecular bases for these
peripheral B cells. They are distinct from CD5
phenomena mediated by CD5 on B cells deserved
conventional B cells with respect to anatomic
to be clarified in the future.10,12
localization, gene usage and function.11 In the mature
The previous array Comparative Genomic
B-cell neoplasms, CD5 is expressed in most
Hibridization analysis study identified largely
patients with chronic lymphocytic leukemia (CLL)
identical genomic aberration patterns in the CD5+
and mantle cell lymphoma (MCL). CD5+ B-cell

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and in CD5- groups. However, gains of 10p14-p15.3
and 19q 13.32-13.43 and losses of 1 q43-q44 and
8p23.1-p23.2 are found to be characteristic of CD+
diffuse large B cell lymphoma. Genomic loss of
8p23 has frequently been found in leukemic mantle
cell lymphoma and this deletion may be linked with
leukemic dissemination and poor prognosis for
patients with this tumor.13
This study also showed that CD10 expression
associated with low IPI in diffuse large cell
lymphoma. The previous study also indicated that
CD10 expression in diffuse large B cell lymphoma
may predict favorable outcome. 14,15 CD10 is a
membrane-associated, neutral endopeptidase that
is expressed in a variety of human tissues. 16
Although initially considered a tumor specific
antigen, CD10 was subsequently detected on a
variety of normal cells of haemopoietic and non
haemopoietic origin. CD10, also called neutral
peptidase, possesses a well-defined enzymatic
activity, but its function in the physiology of lymphoid
cells is largely unknown.17
In addition to Bcl-6, CD10 expression is
normally expressed in follicular germinal centre cells
(GCs) and preferentially expressed in GC-derived
diffuse large B cell lymphoma. CD10 expression
in diffuse large B cell lymphoma has also been
associated with the presence of t(14;18)
translocation, indicating a possible origin of these
tumor in germinal centre-derived cells. 18 The
presence of a GC phenotype should have a favorable
effect on outcome of the diffuse large B cell
lymphoma. Normal GC cells are highly susceptible
to apoptosis and it is posible that susceptibility to
apoptosis is retained by neoplastic GC cells, making
them more sensitive to chemotherapy. 19 The
previous study also found that in diffuse large B
cell lymphomas, the germinal centre B-cell-like
differentiation immunophenotypic profile was
significantly correlated with high apoptotic index,
high expression of the proapoptotic proteins bax,
bak and bid and low expression of the antiapoptotic
protein bcl-xl.20 With respect to the relation between
CD10 and apoptosis, it was suggested that CD10
might degrade cytokines that reach the cell when
apoptosis has already started. Because a variety
of cytokines may play a protective role in B and T-
cell apoptosis, CD10 expression may potentiate the
126
apoptotic ability of B and T cells by inhibiting the
protective signals. As suggested by Cutrone et al21,
this could be consistent with the capacity of CD10
to hydrolyze a variety of active peptides, including
growth and chemotactic factors.22
This study failed to find significant association
between Bcl-6 expression and low IPI, which has
been presented in the previous study. The bcl-6
gene is normally expressed in B and CD4+ T cells
of the follicular GCs and it is necessary for GC
formation.23 Rearrangements and point mutations
of this gene have been detected in a number of
diffuse large B cell lymphoma, but their potential
significance still have conflicting result.3,24 The
reason for these discordant results in different series
are not clear but they may be related in part to the
heterogeneity of the selected patients. Some
previous studies was restricted to primary nodal
diffuse large B cell lymphoma and the specific
histologic appearance of centroblastic large-cell
lymphomas. Primary extranodal lymphoma,
particularly gastrointestinal, showed Bcl-6
expression more frequently than nodal cases.25 On
the contrary, only one third of primary breast diffuse
large B cell lymphoma showed Bcl-6 expression.26
In addition, other previous study indicated that
diffuse large B cell lymphoma cases could be
classified into three expression patterns : GC
(germinal centre) B-cell pattern (pattern A)
expressing CD10 and/or Bcl-6 but not activation
markers ; activated GC B-cell pattern (pattern B)
expressing at least one of GC B-cell markers and
one of activation markers ; and activated non-GC
B cell pattern (pattern C) expressing MUM1/IRF4
and / or CD138 but not GC B-cell markers. Patients
with pattern A had much better overall survival than
those with the other two patterns. Moreover,
comparing with CD10 expression, Bcl-6 less
consistently related with germinal centre type of
diffuse large B cell lymphoma. All patients
expressing CD10 were also positive for Bcl-6,
whereas a group of patients with Bcl-positive
tumors did not express CD10.24,27
In this study, there was no association between
Bcl-2 expression and IPI. Although some studies
had found that Bcl-2 expression was associated
with a significantly worse prognosis, the other
previous studies had found no significant
 Indrawati et al, Expression of CD5, CD10, Bcl-2 and Bcl-6 in diffuse large B cell lymphoma
difference.3,28 The reason for these discordant results
may be due to the mechanism of Bcl-2 expression.
The function of Bcl-2 as an inhibitor of
apoptosis is well known and it is reasonable to assume
that the adverse effect on prognosis may be due to a
reduction in the level of apoptosis induced by
chemotherapy. However, the mechanism of expession
of Bcl-2 in diffuse large B cell lymphoma is less clear.29
It is likely that in some of the tumors, Bcl-2 expression
was a consequence of a t(14;18) and in these cases
expression of GC phenotype would also be
expected. A weak association between Bcl-2
expression and a GC phenotype was demonstrated
in the previous study. On the other hand, no
association was demonstrated between Bcl-2
expression and GC features by Alizadeh et al.30 It
has been shown that the Bcl-2 expression in some
diffuse large B cell lymphoma may be due to the
amplification of the bcl-2 locus.31
CONCLUSION
There was significant difference between the
number of cases with positivity of CD5 and CD10
expression in high and low IPI of diffuse large B
cell lymphoma. There was no significant difference
between the number of cases with positivity of Bcl-
2 and Bcl-6 expression in high and low IPI. The
result supported that immunophenotyping related
B cell differentiation can help to predict clinical
behavior and prognosis of diffuse large B cell
lymphoma.
ACKNOWLEDGEMENTS
We are thankful to the Dean of Medicine School
Gadjah Mada University for giving of research fund of
Public Fund allocated for Medicine School Gadjah Mada
University.
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