Review Article

Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

Gisele Rodrigues Gouveia

Sheila Aparecida Coelho Siqueira
Juliana Pereira
Hospital das Clnicas da Faculdade de
Medicina, Universidade de So Paulo - USP,
So Paulo, SP, Brazil

Diffuse large B-Cell lymphoma is the most common subtype of non-Hodgkin lymphoma in the West. In
Brazil, it is the fifth cause of cancer, with more than 55,000 cases and 26,000 deaths per year. At Hospital
das Clnicas da Faculdade de Medicina da Universidade de So Paulo - HCFMUSP, diffuse large B-Cell
lymphoma represents 49.7% of all non-Hodgkin lymphoma cases. Initially, the classification of non-Hodgkin
lymphoma was based on morphology, but advances in immunology and molecular medicine allowed the
introduction of a biological classification for these diseases. As for other cancers, non-Hodgkin lymphoma
involves patterns of multifactorial pathogenesis with environmental factors, as well as genetic, occupational
and dietary factors, contributing to its development. Multiple lesions involving molecular pathways of
B-cell proliferation and differentiation may result in the activation of oncogenes such as the BCL2, BCL6,
and MYC genes and the inactivation of tumor suppressor genes such as p53 and INK4, as well as other
important transcription factors such as OCT-1 and OCT-2. A dramatic improvement in survival was seen
after the recent introduction of the anti-CD20 monoclonal antibody. The association of this antibody to the
cyclophosphamide, hydroxydaunorubicin, oncovin and prednisolone (CHOP) regimen has increased overall
survival of diffuse large B-Cell lymphoma and follicular lymphoma patients by 20%. However, 50% of all
diffuse large B-Cell lymphoma patients remain incurable, creating a demand for more research with new
advances in treatment. Thus, it is important to know and understand the key factors and molecular pathways
involved in the pathogenesis of diffuse large B-Cell lymphoma.
Keywords: Lymphoma; Lymphoma, B-cell/physiopathology; Prognosis; Oncogenes; Genes, tumor suppressor

Introduction

Conflict-of-interest disclosure:
The authors declare no competing financial
interest
Submitted: 4/13/2012
Accepted: 9/28/2012
Corresponding author:
Gisele Rodrigues Gouveia
Immunopathology Laboratory - Hospital
das Clnicas da Faculdade de Medicina da
Universidade de So Paulo - HCFMUSP
Av. Dr. Enas Carvalho de Aguiar, 155,
1 Andar - Cerqueira Csar
05403-000 - So Paulo, SP, Brazil
Phone: 55 11 3061-5544
[email protected]

www.rbhh.org or www.scielo.br/rbhh
DOI: 10.5581/1516-8484.20120111
Rev Bras Hematol Hemoter. 2012;34(6):447-51

Non-Hodgkin lymphomas (NHLs) occur as a result of an expansion and progressive

accumulation of a mature single clone of lymphocytes(1). The most common subtype, diffuse
large B-Cell lymphoma (DLBCL), is characterized by a diffuse proliferation of large and
mature B-cells. These cells usually are larger than, or equal to, twice the normal size of
macrophages or lymphocytes(2).
DLBCL is clinically and biologically heterogeneous, aggressive, and includes several
subtypes(2). It may arise as primary or de novo, or may result from a transformation of an
indolent lymphoma(3). The majority of cases occur in lymph nodes with 40% in extranodal
sites(4). These cases occur most frequently in the gastrointestinal tract, but may appear in any
organ, including the skin, central nervous system (CNS), bone marrow (BM), salivary gland,
lung, kidney, and liver(5,6). Bone marrow involvement is found in 11% to 27% of all cases but
rarely infiltrates the peripheral blood(7).
Initially, the classification of NHL was based on morphological features of the malignant
cell, but today it is also based on immunological and molecular data. Thus, complementary
techniques of immunohistochemistry, flow cytometry, cytogenetic, polymerase chain reaction,
and gene signature by microarray are used.
According to the World Health Organization (WHO)(7), DLBCLs may be subdivided into
morphological variants.
The centroblastic variant presents medium to large lymphoid cells, vesicular nuclei, fine
chromatin and scant cytoplasm. In some cases, it may feature cells with multiple lobules and
more than 90% of immunoblasts with a marked polymorphism. Shahi & Manga(3) observed
one to three prominent basophilic nucleoli in some cases. Indeed, they suggest that this variant
may present two morphological subtypes. The first is called the monomorphic subtype, with
almost 100% of centroblasts, and the second, comprising of 10% of centroblasts and less than
90% of immunoblasts, the polymorphic subtype(7).
In the immunoblast subtype, the cell population comprises more than 90% of
immunoblasts. It is characterized by cells with a single central nucleus and a basophilic
and variable cytoplasm, but less than 10% of centroblasts. Immunophenotyping and clinical
characteristics are essential to differentiate it from the plasmablastic variant of DLBCL.
According to Shahi & Manga(3), the plasmablastic variant represents 10% of all DLBCL and
is more common in immunosuppressed patients, especially those with HIV(7).
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Gouveia GR, Siqueira SA, Pereira J

DLBCL rich in T-cells and histiocytes is formed by a high

quantity of reactive T-cells with or without histiocytes, and less
than 10% of large neoplastic B-cells. The growth pattern of this
subtype of DLBCL is predominantly diffuse, with fine reticular
fibers in the tumor microenvironment. Immunophenotyping
is essential to differentiate it from classic Hodgkin lymphoma
(cHL). This variant is rare and presents a worse prognosis(6).
The anaplastic subtype is characterized by oval or
polygonal cells with pleomorphic nuclei. Cells may take on a
cohesive growth pattern, such as that found in carcinoma, or
a sinusoidal growth pattern. The malignant cells express the CD30
(ki-1) antigen and the main differential diagnoses are Hodgkins
lymphoma (HL) and T-cell NHL that express CD30(6).
Primary Central Nervous System (CNS) DLBCL represents
all cases of intra-cerebral or intraocular lymphomas and
corresponds to less than 1% of NHL cases and 2-3% of all brain
tumors. The average age at incidence is 60 years. The clinical
characteristics are neurological disorders as observed in 80% of
patients. Neuropsychiatric symptoms are observed in 20 to 30%
and high intracranial pressure may also be observed(7).
Primary cutaneous DLBCL (leg type) represents 4% of all
primary cutaneous DLBCL, and 20% of all primary cutaneous
B-cell lymphomas. It occurs in elderly women in the seventh
decade of life. It usually affects the legs but in 10 to 15% may
occur in other sites(7).
Epstein-Barr Virus (EBV)-positive DLBCL of the elderly
is a clonal proliferation of large B-cells. Its incidence is more
common after the fifth decade of life and in patients with no
previous immunodeficiency. Other rare subtypes of DLBCL are
lymphomatoid granulomatosis and primary effusion lymphoma.
DLBCL associated with chronic inflammation is a lymphoid
neoplasm associated with EBV. The mean time elapsed between
chronic inflammation and lymphoma is 10 years. Diagnosis
occurs between the fifth and eighth decades of life with a median
age of 65 years. The most common sites of involvement are the
pleural cavity, femur and periarticular tissue. The tumor mass is
greater than 10 cm in more than half of all cases. There is direct
invasion of adjacent structures, but the tumor is often limited to
the thoracic cavity until diagnosis. About 70% of patients present
clinical stage I or II(7).
Unclassifiable B-cell lymphomas with features
intermediate between DLBCL and Burkitt Lymphoma (BL)
are aggressive lymphomas that, owing to their clinical and
biological characteristics, may not be included in one of these
two categories. In most cases, morphological characteristics
are intermediate, with cells smaller than in typical DLBCL and
larger than in typical BL but the phenotype of cells is compatible
with BL. This lymphoma is rare in adults and more than half
the patients show extranodal disease, such as bone marrow and
peripheral blood involvement(7).
B-cell lymphomas with features intermediate between
DLBCL and cHL are common in young males (20 to 40
years). Etiology is unknown and the most common site
of involvement is the mediastinum, with or without the
involvement of lymph nodes(7).
Studies of gene expression patterns divided DLBCL into
three subtypes that are morphologically indistinguishable:
448

activated B-cell DLBCL, germinal center DLBCL, and primary

mediastinal B-cell lymphoma. They express distinct genes that
have been found at different stages of B-cell differentiation(8).

Epidemiology
DLBCL represents 80% of all aggressive lymphomas(3) and
30 to 40% of all NHL cases in the West and are one of the most
frequent in developing countries(2). At the Hospital das Clnicas
da Faculdade de Medicina da Universidade de So Paulo HCFMUSP, DLBCL represents 49.57% of all NHL cases(9).
NHL is the fifth most common type of cancer in Brazil, with an
incidence of 55,000 cases and over 26,000 deaths per year(10). In
So Paulo, in 1998, the incidence of NHL cases was 12.2/100
thousand inhabitants(11). Likewise, DLBCL is the most common
lymphoma in adults (31%), followed by follicular lymphoma (FL)
(12-14)
. The median age at incidence is 70 years and it predominates
in males (55%)(12).
According to Friedberg (12), the incidence of DLBCL has
been increasing by 3 to 4% per year in both genders, in white
and non-white populations, and in all age groups, except
for adolescents. Factors such as more sensitive diagnostic
techniques, changes in the classification of lymphoproliferative
disorders and, particularly, the increase of NHL in HIV patients
have contributed to the escalation in the incidence of this disease.
Environmental factors, as well as genetic, occupational
and dietary factors, may have contributed to the development
of NHL(15). NHLs are associated with chronic inflammatory
diseases such as Sjgren syndrome, celiac disease and
rheumatoid arthritis. Indeed, infectious agents are also related to
the pathogenesis, but no greater incidence of NHL has been found
in individuals who handle organic solvents, organophosphates,
benzene or carbon tetrachloride(16).
In DLBCL, factors such as ultraviolet radiation, pesticides,
and hair dye are potentially associated with higher risk. In
addition, immunosuppression, especially related to HIV, is a risk
factor and it may be associated with Epstein-Barr virus(13).

Pathophysiology
DLBCL arises from mature B-cells at different stages of
differentiation. Several gene mutations promote changes in
B-cells, changing the gene expression and promoting a neoplastic
transformation (Figure 1)(17).
During B lymphocyte ontogeny, after leaving the bone
marrow, those cells travel to secondary lymphoid tissues
where they will find their respective antigens promoting the
development of secondary follicles. An antigen-dependent phase
of B-cell development occurs at this site. In the germinal center
of the secondary follicle, these lymphocytes are transformed
into centroblasts that have a high rate of proliferation, while
frequent and continuous somatic mutations of genes of the
immunoglobulin variable chain occur, promoting maturation
and differentiation into centrocytes and subsequently into
plasma cells or in memory B-cells(17). In the germinal center,
the BCL2 gene expression is usually down regulated and BCL6
is hyperexpressed(8,17).
Rev Bras Hematol Hemoter. 2012;34(6):447-51

Pathophysiology and molecular aspects of diffuse large B-cell lymphoma

Antibodies:
IgG, IgA
Memory cells

Imunoblast

Ag
Stem Cell

B Lymphoblast

Mutations

Plasma cell

Non-receptor
expression antigens

Mutations

Pre-B Cell

Apoptosis

Centroblasts
(BCL2- / BCL6+)

Centrocytes

Lower
affinity
for Ag

Apoptosis
BCL2 + = Proliferation

GERMINAL CENTER
Greater
affinity for
Ag

Figure 1 - Diagram of the differentiation and maturation of normal B lymphocytes and possible
molecular alterations that can lead to the pathogenesis of diffuse large B-Cell lymphoma
Guilherme et al.(17) - adapted by the authors.

DLBCL

BCL6 - : memory cells

plasma cells

TRANSLOCATION

t(14;18): BCL2 x IgH (15-30%)

t(8,14): MYC x IgH (6%)

Molecular Events Involved in DLBCL Pathogenesis

Proto-oncogenes are important to control cell proliferation.
However, when inappropriately activated by genetic
abnormalities such as chromosomal translocations, gene
mutations or amplification, the cells may acquire a malignant
transformation. In contrast, tumor suppressor genes promote cell
differentiation and decreased cell proliferation. In the malignant
transformation process, oncogene activation and inhibition of the
tumor suppressor genes usually occur. Similar to other cancers,
the pathogenesis of DLBCL occurs in multiple steps that results
in the development of the disease (Figure 2)(1,14,18).
As previously described, the B lymphocyte ontogeny
occurs in the bone marrow and in peripheral lymphoid tissues
and depends on various genetic recombinations that function
as points of vulnerability, subject to deleterious events that
affect the immune system and the individual. However, in most
cases, protective mechanisms surmount these disorders and the
physiological homeostasis is preserved resulting in the formation
of immunologically perfect B-cells. Examples of important
genetic events that are essential in the development of B-cells are
the recombination of genes encoding the heavy Ig chains driven
by the RAG1 and RAG2 genes, and the hypermutation of variable
regions of the genes responsible for encoding the light Ig chains
and the switch of the Ig class(1,8).
The BCL6 gene is one of the most frequently affected in
DLBCL. On the other hand, the t(14;18), which juxtaposes the
BCL2 oncogene located on chromosome 18 to the promoter
region of the gene encoding the heavy Ig chain on chromosome
14, results in an overexpression of the BCL2 protein, a condition
found in 15% to 30%of all DLBCL cases(14,19-22).
Rev Bras Hematol Hemoter. 2012;34(6):447-51

MUTATION

AMPLIFICATION

(20%)
p53

(20%)
MYC, BCL2

DLBCL
REPLACING
THE
PROMOTER
(30-40%)
BCL6

SOMATIC
HYPERMUTATION
(50%)
BCL6, MYC, PAX5,
PIM1

Figure 2 - Main genetic lesions that occur in the pathogenesis of diffuse

large B-Cell lymphoma (DLBCL) and their respective frequencies.
Lossos(14) - adapted by the authors.

Main oncogenes involved in the pathogenesis of

DLBCL
BCL2
The BCL2 gene, which encodes an anti-apoptotic protein
located in the outer membrane of the mitochondria and
cytoplasm, plays an important role in the pathogenesis of NHL.
This protein is involved in mechanisms related to resistance to
chemotherapy(23-25). Amen et al.(26) demonstrated higher overall
survival and disease-free survival in DLBCL with no BCL2 and
Cyclin D2 expression. However, other authors have demonstrated
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Gouveia GR, Siqueira SA, Pereira J

a negative effect of the expression of BCL2 only in the subgroup

of activated B-cell DLBCL(22-25,27).

BCL6 Gene
The BCL6 gene is a proto-oncogene located on chromosome
3q27 expressed on normal B-cells in the germinal center(28-30). The
BCL6 protein blocks genes involved in cell cycle progression
and response to DNA damage(8). Chromosomal translocations
involving the BCL6 gene occur in 30% to 40% of tumors and arise
from disorders in the sequence in the promoter region of DNA. The
role of the BCL6 gene in the pathogenesis of DLBCL was recently
elucidated. Alterations in BCL6 protein expression may cause
failure in cell differentiation and continuous activation and cell
proliferation. Consequently, it promotes a higher cell survival and
genetic instability that contributes to malignant transformations(14).

Main tumor suppressor genes related to the

pathogenesis and prognosis of DLBCL
p53 Gene
The p53 gene is located on chromosome 17, encoding a
nuclear phosphoprotein p53. This protein acts by regulating
the DNA transcription, cell proliferation and apoptosis(28).
Sixty percent of malignant human tumors and 30% of B-cell
lymphomas present the p53 mutation. Most of them occur in
exons 5 and 9 and affect their function in the control of the
DNA repair. Patients with absent or mutated p53 present more
aggressive disease and worse prognosis(31). Some studies have
suggested that p53 may be inactivated by the BCL6 gene during
the genesis of lymphoma(14).

the promoter of the BCL2 gene and is involved in the malignant

transformation in B lymphomas. The low expressions of OCT-1,
OCT-2 and BOB1 are inversely proportional to apoptosis(34).

Conclusions
DLBCL is the most common subtype of NHL and only 40 to
50% of all adult patients are cured. Knowledge of the malignant
cell biology has promoted an increase in the overall survival rate.
However, this knowledge is incipient and many other studies of the
gene expression of malignant cells and the tumor microenvironment
are necessary. The advance in molecular biology techniques has
been essential and its continuous improvement is fundamental to
achieve maximum understanding of the biology. The final goal is to
translate the knowledge of the biology of DLBCL into new options
of therapy to try to improve patient survival.

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