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The Histological Classification of Diffuse Large B-cell

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Cite this article as: Yi Xie MD, PhD, Stefania Pittaluga MD, PhD, Elaine S. Jaffe MD, The
Histological Classification of Diffuse Large B-cell Lymphomas,
Semin Hematol , http://dx.doi.org/10.1053/j.seminhematol.2015.01.006

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 The Histological Classification of Diffuse Large B-cell Lymphomas

Yi Xie, MD PhD, Stefania Pittaluga, MD PhD, Elaine S. Jaffe, MD

From Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National

Cancer Institute, Bethesda, Maryland

Address correspondence to:

Dr. Elaine S. Jaffe

Building 10/ Room 2B42

10 Center Drive MSC-1500

National Institutes of Health

Bethesda, MD 20892-1500

Phone: 301/496-0184 FAX: 301-402-2415

Email: elainejaffe@nih.gov

The authors declare that they have no conflicts of interest or competing financial or personal

relationships that could inappropriately influence the content of this article.

1
Abstract

Diffuse large B cell lymphomas (DLBCLs) are aggressive B-cell neoplasms with considerable

clinical, biologic and pathologic diversity, in part reflecting the functional diversity of the B-cell

system and multiple pathways of transformation. In recent years, the advent of new high-

throughput genomic technologies has provided new insights into the biology of DLBCL, leading

to the identification of distinct molecular identities and novel pathogenetic pathways. This

increasing complexity had led to an expanding number of entities in the WHO classification.

Using a multi-modality approach, the updated 2008 classification delineated some new

subgroups, including DLBCLs associated with particular age groups or specific anatomic sites,

as well as two borderline categories: tumors at the interface between classical Hodgkin

lymphoma (cHL) and DLBCL as well as between Burkitt Lymphoma (BL) and DLBCL. This

article reviews the histopathologic features of the various aggressive B-cell lymphoma subtypes

included in the 2008 classification, with emphasis on some of the new entities as well as areas of

diagnostic challenge.

2
Introduction

Diffuse large B cell lymphoma (DLBCL) is an aggressive B-cell lymphoma, histologically

characterized by diffuse proliferation of large neoplastic B lymphoid cells with a nuclear size

equal to or exceeding normal histiocyte nuclei.1 It is the most common form of lymphoma,

accounting for 30-40% of adult non-Hodgkin lymphoma worldwide. DLBCLs are clinically and

pathologically diverse, partially reflecting the diversity of the B-cell system. As the response to

treatment is different, there has been vast clinical and basic research devoted to identifying

prognostically or biologically distinct subgroups. Over the past few years, significant efforts

focused on the identification of molecular signatures and pathogenetic pathways that might be

the subject of molecularly targeted therapy. The 2008 WHO classification lists a large number

of entities that fall under the broad heading of DLBCL based on distinct clinical, pathologic or

biologic features. This review summarizes current knowledge, with emphasis on some of the

new entities as well as areas of diagnostic challenge.

DIFFUSE LARGE B-CELL LYMPHOMA, NOT OTHERWISE SPECIFIED (DLBCL, NOS)

DLBCL, NOS is the most common category of DLBCL. As the name implies, it is a diagnosis of

exclusion, applying to DLBCL cases that do not fit into any specific disease subgroups. DLBCL

is more common in the elderly but may be seen in any age group. It can arise de novo or as a

progression or transformation from low grade B-cell malignancy, such as follicular lymphoma or

chronic lymphocytic leukemia (CLL), so-called Richter’s transformation. Patients may present

with nodal or extranodal diseases. Frequent extranodal sites of involvement include

gastrointestinal tract, bone, testis, spleen, thyroid, and lung.

3
DLBCL, NOS demonstrates a broad cytologic spectrum. Three common morphologic variants

have been described, referred to as centroblastic, immunoblastic and anaplastic variants (Figure 1

A and B).2 The designation of immunoblastic was reserved for tumors with greater than 90% of

immunoblasts and was associated with a worse prognosis.3, 4 However, the results have not been

reproducible in other studies, probably reflecting variation in criteria for the immunoblastic

designation and poor inter-observer reproducibility. All variants may be admixed with a variable

number of T cells and/or histiocytes. In contrast to T-cell/histiocytes rich large B-cell lymphoma

(THRLBCL) described below, the neoplastic B cells in DLBCL, NOS are more numerous and

tend to form clusters or sheet out.

In recent years, the development of high-throughput technologies has greatly accelerated our

understanding of the molecular complexity of DLBCL. Using gene expression profiling (GEP),

Staudt and colleagues identified two molecularly distinct forms of DLBCL which were

morphologically overlapping but had gene expression patterns indicative of different stages of B-

cell differentiation, resembling either germinal center B-cells (GCB) or activated B-cells

(ABC).5 Consistent with their putative “cell-of-origin” (COO), GCB DLBCLs display high-level

expression of the master regulator BCL6 and harbor hypermutated immunoglobulin genes with

ongoing somatic hypermutation, whereas ABC DLBCLs show activation of NF-κB and BCR

signaling pathways, and upregulation of genes required for plasmacytic differentiation.6 The

COO classification has been shown to identify distinct DLBCL prognostic subgroups, with GCB

DLBCLs being associated with a significantly better outcome as compared with the ABC

subgroup.7, 8 While the introduction of Rituximab to traditional CHOP therapy has decreased the

4
impact of the COO distinction, the ABC subtype remains less responsive to therapy than the

GCB subtype.9 Importantly, more recent studies have shown that DLBCL subgroups harbor

different genetic lesions and/or disrupted signaling pathways, providing a genetic rationale for

the development of potential therapeutic targets,10-13 as discussed in other articles in this issue.

Because of the technical difficulties in applying GEP in daily clinical practice, various

immunohistochemical (IHC) algorithms have been developed as surrogates of the GEP. The

classic Hans algorithm utilized antibodies against CD10, BCL6 and MUM-1/IRF4.14 With the

development of new IHC antibodies, the panel has been expanded in newer iterations known as

“Choi”, “Tally” and “Visco-Young” algorithms.15-17 The degree to which the IHC

categorizations, ABC vs. GCB, correlate with COO as defined by GEP is variable, and whether

they have prognostic value in the rituximab era is controversial.18 As highlighted by several

studies examining reproducibility among different laboratories, this lack of concordance may be

in part due to sampling and technical issues as well as interpretation variations.19-21

In addition to COO classification, DLBCL prognostic models based on limited sets of genes or

immunohistochemical markers have been proposed. More recently, DLBCLs with translocations

of MYC, or MYC and BCL2 (“double-hit” lymphomas) have been shown by many studies, to

have an extremely poor outcome with standard R-CHOP therapy.22-24 It is less clear if high

protein expression of MYC and/or BCL2 in the absence of translocations carries the same

adverse prognosis.22, 25 While the optimal treatment has not yet been determined, in preliminary

data from NCI, MYC+ and MYC- DLBCLs treated with DA-EPOCH-R had a similar event-free

survival at 5 years.26

5
DLBCL SUBTYPES IN SPECIFIC ANATOMIC SITES

The 2008 WHO classification recognizes several subtypes of DLBCL with distinctive sites of

presentation. These include primary DLBCL of the central nervous system (CNS), primary

cutaneous DLBCL, leg type, and intravascular large B-cell lymphoma.

Primary CNS DLBCL refers to DLBCL arising in and confined to the CNS. It also includes

cases presenting with intraocular disease, and patients with intraocular disease often have

simultaneous or sequential CNS involvement. Histologically, the lymphomas mostly show a

diffuse growth pattern and characteristically involve the perivascular spaces. Very rarely, the

tumor cells are widely scattered in the white matter without mass formation or perivascular

accumulation, so called “lymphomatosis cerebri”. GEP studies have demonstrated some unique

molecular characteristics that distinguish CNS lymphomas from nodal and/or extranodal

DLBCL.27-29 However, a consistent pattern as ABC or GCB has not emerged. Interestingly,

primary CNS DLBCL shares many pathological and biological features with DLBCL presenting

in the testis, perhaps because both arise in immune privileged sites.30, 31

Primary cutaneous DLBCL, leg-type often presents as rapidly growing tumors on the leg, but

it may arise at other sites. Most patients are elderly women, with a M:F ratio of 1: 3–4.

Morphologically, the lymphoma is characterized by a generally monotonous proliferation of

immunoblasts or centroblast-like cells with few admixed reactive cells. By GEP and

immunophenotype, it resembles the activated B-cell type of nodal DLBCL.32 Unlike primary

cutaneous follicle center lymphoma (PCFCL), which may be composed predominantly of large

B-cells in some cases, primary cutaneous DLBCL, leg type nearly always express strong BCL2,

6
IRF4/MUM1and FOX-P1.33 They are more aggressive than PCFCLs and usually require

chemotherapy for clinical management.34

Intravascular large B-cell lymphoma is a rare type of extranodal DLBCL characterized by the

selective growth of lymphoma cells within the lumina of small or intermediate vessels.35 Many

organs can be affected, but lymph nodes are usually spared. There are two distinct patterns of

clinical presentation, a Western form with neurological and cutaneous manifestations and an

Asian form with pancytopenia, hepatosplenomegaly, multiorgan failure and hemophagocytic

syndrome.35 Cases with cutaneous involvement appear to have a better prognosis, perhaps

because of earlier diagnosis. The disease is often not diagnosed until autopsy because of the lack

of definitive radiological or clinical evidence of disease, and diverse symptomatology. Using

immunophenotyping as a surrogate for the GEP, the majority of intravascular DLBCL has an

ABC phenotype.36 Coexpression of CD5 has been seen in most intravascular large B-cell

lymphomas. 37

T-CELL/HISTIOCYTE RICH LARGE B-CELL LYMPHOMA (T/HRLBCL)

T-cell/histiocyte-rich large B-cell lymphoma is a morphological variant of DLBCL in which

there is a limited number of scattered large atypical B cells embedded in a T-cell/histiocytes rich

background. T/HRLBCL accounts for approximately 10% of DLBCL.38, 39 It occurs more

commonly in middle-aged males, and the patients often present with advanced stage disease with

liver, spleen and bone marrow involvement.39 Recent studies have focused on the mechanisms of

recruitment of inflammatory cells and the relationship to the microenvironment.40

7
T/HRLBCL shares several morphologic and immunophenotypic similarities with nodular

lymphocyte-predominant Hodgkin’s lymphoma (NLPHL), posing a great diagnostic challenge in

some cases. The neoplastic cells in T/HRLBCL have a wide cytologic spectrum. They may

mimic the LP cells of NLPHL, centroblasts or Hodgkin/ Reed-Sternberg (HRS) cells. Their

immunophenotype is similar to the LP cells, with the exception of more frequent lack of BCL6

and expression of IRF4/MUM1. The histologic distinction between T/HRLBCL and NLPHL

largely relies on immunohistochemical analysis of the background population. Features that

favor T/HRLBCL include the absence of background small B-cells and lack of remnants of

follicles such as follicular dendritic cell meshworks. Despite a rich T-cell background, well-

formed T-cell rosettes are usually absent. The distinction between these two entities can be

problematic in needle core biopsy specimens, and is best rendered on excision biopsies.

Although the clinical presentation and behavior of these two diseases are generally quite

different, some cases of T/HRLBCL appear related to NLPHL.41 In addition, NLPHL may

progress to a process indistinguishable from de novo T/HRLBCL. The relationship of primary

and “secondary T/HRLBCL” is not fully resolved.

Other cases with an overlapping morphological appearance may be composed of EBV-positive

cells resembling HRS-like cells in a background rich in T-cells.42 Once considered a subtype of

T/HRLBCL, EBV-positive cases are now included within EBV-positive large B-cell

lymphoma.42 T/HRLBCL patients are generally treated similarly to their DLBCL, NOS

counterparts with anthracycline containing chemotherapy, prednisone and Rituximab.43

8
EBV-POSITIVE DIFFUSE LARGE B-CELL LYMPHOMA

First described by Oyama et al. in elderly Japanese patients, this entity is now included as a

provisional category in the WHO classification as EBV positive diffuse large B-cell lymphoma

of the elderly.44 It is defined as an EBV+ clonal B-cell lymphoproliferation that occurs in

patients who are generally over the age of 50 without any known immunodeficiency or history of

lymphoma. The lesion is thought to be related to immunosenescence, the natural decay of the

immune system as a consequence of aging.44 However, similar lesions can also be seen more

rarely in younger patients.45 The clinical course is usually aggressive, with frequent extranodal

involvement, B symptoms and overall poor prognosis.44

Two morphologic variants have been described, the polymorphic and monomorphic variants.

The more common polymorphous lesion has variable amounts of reactive cells such as small

lymphocytes, histiocytes and plasma cells, whereas the monomorphic variant has sheets of tumor

cells with minimal reactive component. However, both variants may contain large transformed

cells, immunoblasts or HRS-like cells. The tumor cells often have an ABC immunophenotype.

They may be weak or negative for CD20. CD30 is frequently expressed whereas CD15 is

negative. The differential diagnoses of EBV+ DLBCL include various EBV related benign

lymphoproliferations as well as other lymphomas like lymphomatoid granulomatosis,

plasmablastic lymphoma and Hodgkin lymphoma. Historically, cells resembling HRS cells have

been described in many EBV-associated conditions.46-48 In some cases, distinction from Hodgkin

lymphoma may be particularly problematic. The correct diagnosis requires integration of clinical

and pathological features, with the immunophenotype interpreted in context.

9
Adding to the spectrum of EBV+ B-cell lymphoproliferative disorders, Dojcinov et al. described

EBV-driven proliferations presenting in cutaneous or mucosal sites, termed mucocutaneous

ulcer.49 The cells in mucocutaneous ulcer often have an HRS -like morphology and an

immunophenotype resembling cHL, with expression of CD30, CD15 and variable CD20. Despite

the alarming histology, this lesion has a much more indolent and often self-limited clinical

course.48, 49

Another distinctive form of EBV-positive DLBCL is DLBCL associated with chronic

inflammation. This lesion was initially described in patients with chronic pyothorax, hence the

name “Pyothorax-associated lymphoma (PAL)”.50 However, lymphomas with similar features

are also recognized in other chronic inflammatory conditions. Most cases involve body cavities

or narrow spaces, such as pleural cavity, bone (especially femur) and joints.51 In most cases, the

tumor cells exhibit a type III EBV latency (EBER+, LMP1+, EBNA-2+). Occasional cases may

lose CD20 and/or CD79a, or exhibit aberrant expression of one or more T-cell markers, causing

problems in lineage assignment.52, 53

PRIMARY MEDIASTINAL (THYMIC) LARGE B-CELL LYMPHOMA (PMBL)

PMBL is a distinct clinicopathologic entity thought to be derived from thymic B cells.54-56 It mainly

affects adolescents and young adults (median age in the fourth decade), and there is a female

predominance.57 Clinically, patients usually present as early stage, bulky mediastinal mass. At

progression, dissemination to distant extranodal sites including kidney, adrenal, liver and central

nervous system may occur, but bone marrow involvement is rare. PMBL shows a wide cytological

10
spectrum, like many other DLBCLs (Figure 1C). The cells express CD20 and CD79a, but often do not

express surface immunoglobulin. CD30 is positive in most of the cases but its expression is usually

weak and heterogeneous. At the genetic level, PMBL demonstrates a GEP differing from other DLBCL

and resembling cHL, with activation of the NF-κB pathway.56, 58-60 In some cases the distinction from

nodular sclerosis cHL can be difficult, so-called “grey zone lymphomas”.61 PMBL is reviewed in depth

in other articles within this issue.

DIFFUSE LARGE B-CELL LYMPHOMAS WITH PLASMA CELL IMMUNOPHENOTYPE

ALK-positive large B-cell lymphoma is a rare subtype of DLBCL that expresses the ALK

protein.62 This disease mainly affects adults, but can be seen in children. There is a marked male

predominance. The cells have plasmablastic morphology and phenotype. They express CD138,

EMA and most commonly, cytoplasmic IgA lambda immunoglobulin, and often lack mature B-

cell associated antigens such as CD20 and PAX-5. The overexpression of ALK protein is

associated with abnormal fusion between ALK and other partner genes. The t(2;17) involving

ALK and clathrin is the most common of these, but the classical t(2;5) of anaplastic large cell

lymphoma (ALCL) has also been reported.63 Unlike ALK+ ALCL, CD30 is negative and the

prognosis is poor.64, 65

Plasmablastic lymphoma (PBL) is an aggressive neoplasm that predominantly occurs in the

setting of immunodeficiency, most commonly HIV infection, but can also occur in other settings

such as advanced age and congenital or acquired iatrogenic immunosuppression.66, 67 PBL

typically presents in extranodal sites, often with a mucosal or cutaneous localization. The median

age of presentation is 50 years with a striking male predominance. Histologically, the lymphoma

11
cells usually demonstrate immunoblastic or plasmablastic morphology, with expression of

plasma cell markers (CD138 and/or CD38) and frequent loss of B-cell markers (CD20 and

CD79a). Nearly all cases of PBL are EBV-positive, and they are negative for HHV8 (Figure 2 A

and B). In addition to overlapping morphological and immunophenotypic features, recent studies

have shown similar cytogenetic changes with a high incidence of MYC translocations in PBL and

plasmablastic variant plasma cell myeloma, indicating a close relationship between these two

neoplasms.68-70

Primary effusion lymphoma (PEL) is a human herpesvirus 8 (HHV-8)-associated, unique form

of large B cell lymphoma that typically manifests as malignant effusion in the body cavities.71 It

occurs most frequently in young or middle-aged males with HIV infection. Usually, there is co-

infection with EBV. The disease also occurs in iatrogenically immunosuppressed transplant

patients and elderly individuals.72 Some affected patients also have a history of Kaposi sarcoma,

and less frequently multicentric Castleman’s disease.73 The most common sites of involvement

are the pleural, pericardial and peritoneal cavities. Rare cases may present as solid tumor masses

involving the gastrointestinal tract, soft tissue and other extranodal sites, termed extracavitary

PEL.74

The neoplastic cells exhibit a range of appearances, from immunoblastic, plasmablastic to

frankly anaplastic. Immunophenotypically, the cells typically display activation and plasma cell

markers, such as CD30, CD38, CD138 and EMA, but routine B-cell markers (CD20, CD19,

CD79a and surface immunoglobulin) are absent. T-cell antigens may be aberrantly expressed.75

Immunohistochemistry for the HHV8/KSHV-associated latent protein (LANA) is most useful in

12
making the diagnosis (Figure 2 C and D). The lesion may simulate pyothorax-associated

DLBCL, which is usually EBV-positive, but HHV-8 negative.76 Interestingly, stabilization of

MYC also has been implicated in pathogenesis of PEL through unknown mechanisms.77, 78 PEL

has an extremely poor prognosis with a median survival reported to be less than 6 months.

Large B-cell lymphoma arising in HHV-8 associated multicentric Castleman disease

(MCD) is a controversial lesion, and may represent a variant of MCD rich in HHV-8 infected

cells, and not true transformation to large cell lymphoma.

B-CELL LYMPHOMA, UNCLASSIFIABLE, WITH FEATURES INTERMEDIATE

BETWEEN DIFFUSE LARGE B-CELL LYMPHOMA AND BURKITT LYMPHOMA (B-

UNC/BL/DLBCL)

B-UNC/BL/DLBCL was introduced in the 2008 WHO classification to address aggressive B-cell

lymphomas that have morphologic, immunophenotypic or cytogenetic features intermediate

between DLBCL and BL.79 DLBCL and BL can have overlapping morphologic and

immunophenotypic features. For years, a variety of terms, such as “small non-cleaved”, “non-

Burkitt”, “atypical BL”, and “Burkitt-like lymphoma”, have been used to describe these

borderline cases. Recently, GEP studies have provided some insights into the aggressive B-cell

lymphomas bordering on BL.80, 81 In one study, a group of cases diagnosed as DLBCL or high

grade B-cell lymphomas were identified to have the GEP similar to BL.80 While some of these

cases may represent true BL that have atypical features precluding their diagnosis, some cases

have a complex karyotype and MYC translocations with non-IG gene partners, differing from

BL. Similarly, another GEP study identified a group of tumors with an intermediate expression

13
profile between BL and DLBCL and frequently, a MYC complex karyotype.81 Many of these

cases have dual translocations involving MYC and BCL2 (or BCL6), so called “double-hit

lymphomas”. Less frequently, translocations involving MYC, BCL2 and BCL6 are seen together,

hence the term “triple-hit lymphomas”.

Double hit and triple hit lymphomas comprise the largest cohort within the category of B-

UNC/BL/DLBCL. Many cases in this category morphologically resemble BL, but exhibit

atypical features such as a greater cytologic pleomorphism or an aberrant immunophenotype

(strong to moderate BCL2 expression, or Ki-67 proliferative index <95%) (Figure 1D).

Clinically, these tumors most often present in middle aged to elderly adults. Advanced stage is

common with generalized adenopathy or extranodal disease.82 Double-hit lymphomas are

generally refractory to standard chemotherapy regimen and have a poor prognosis.24, 25, 83

Currently, specific histological or immunophenotypic criteria to recognize double-hit lymphomas

have not been defined. However, most cases with MYC translocations have high levels of nuclear

staining for MYC, whereas cases negative for the BCL-2 protein are unlikely to carry a BCL2

translocation. Therefore immunohistochemistry for MYC and BCL2 may be a useful screening

tool to determine which cases require further genetic testing.

The term B-UNC/BL/DLBCL should be used with discretion. The mere presence of MYC

translocation or high proliferation index (100%) by itself in an otherwise typical DLBCL would

not qualify for an entry into this category. There is also a subset of cases that otherwise would be

classified as BL, but exhibit minor morphologic variability or weak BCL-2 expression. In the

presence of a classical cytogenetic profile (i.e. isolated MYC translocation), such cases can be

14
retained as BL.84 However, FISH studies for BCL2 and BCL6 should be performed to rule out

more aggressive double-hit and triple-hit lymphomas.

B-CELL LYMPHOMA, UNCLASSIFIABLE, WITH FEATURES INTERMEDIATE

BETWEEN DIFFUSE LARGE B-CELL LYMPHOMA AND HODGKIN LYMPHOMA (B-

UNC/cHL/DLBCL)

B-UNC/cHL/DLBCL, also referred to as grey zone lymphoma (GZL), is defined as a large B-

cell lymphoma that demonstrates overlapping clinical, morphologic and immunophenotypic

features between cHL and DLBCL, especially the PMBL type. While these lymphomas are most

commonly associated with mediastinal disease, involvement of peripheral lymph nodes has been

reported. Unlike cHL and PMBL which occur more commonly in young women, GZL patients

are more likely to be young man of 20-40 years of age.85 Non-mediastinal GZLs tend to affect an

older patient population.85 This category was originally termed “Hodgkin-like anaplastic large

cell lymphoma” and was believed to be a disease with poor prognosis with standard treatment.86

The morphologic pattern of GZL is transitional with features of both cHL and PMBL. Sheets or

clusters of tumor cells reminiscent of HRS-cells or PMBL may be seen in a diffusely fibrotic

stroma. The inflammatory infiltrate is usually scant, but scattered eosinophils, lymphocytes, and

histiocytes may be present. The immunophenotype of GZL is also intermediate, with frequent

asynchrony between the morphology and immunophenotype.61 Many of these cases

morphologically resemble cHL but have unusual features, including a large number of

mononuclear variants, diminished inflammatory background, or aberrant phenotype with

retention of B-cell program in concert with Hodgkin markers. Alternatively, cases may resemble

15
PMBL but contain HRS-like cells and demonstrate CD15 positivity or loss of CD20. While a

close relationship between cHL and PMBL has been demonstrated via GEP, gene profiling

studies of grey zone lymphomas have not yet been undertaken. In a recent large-scale

methylation profiling, principle component analysis indicated that GZL did not cluster with

either cHL or PMBL, but demonstrated a unique epigenetic profile distinct from both parent

entities.87

GZLs are extremely rare and the optimal treatment of GZL is not yet established. Historical data

indicate that they have done poorly with traditional approaches developed for the treatment of

either cHL or NHL.86, 88 Prospective studies from NCI have shown that DA-EPOCH-R is an

effective treatment for GZL. However, compared with PMBL patients who received the same

chemotherapy regimen, GZL patients have an inferior survival.89 These patients are more likely

to require radiation than patients with PMBL.90

16
Conclusion

Diffuse large B-cell lymphomas are heterogeneous neoplasms including a group of common and

rare entities with distinct clinical and histopathologic characteristics. Over the past few years, the

use of new technologies, such as GEP, miRNA profiling, and DNA sequencing, has yielded

novel insights into its biology and allowed the recognition of at least three molecularly distinct

subtypes, GCB, ABC and PMBL. These subtypes arise from different stages of B-cell

differentiation and are associated with distinct genetic abnormalities and diverse clinical

outcomes. GEP has led to the development of immunohistochemistry algorithms that are more

readily available in routine practice. Identification of double-hit lymphomas also has important

implications due to its extremely dismal outcome. To date, most patients with newly diagnosed

DLBCL are treated with R-CHOP. However, there are a significant percentage of patients who

fail the conventional therapy. Further studies are needed to determine the optimal treatment

approach for the high risk categories, such as double-hit lymphomas. With improved

understanding of tumor biology and transformation pathways, it is anticipated that the future

management of DLCBL will increasingly employ therapies tailored for individual subtypes and

targeted towards specific molecules or deregulated genetic pathways.

17
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Figure Legends

Figure 1. DLBCL subtypes. (A) DLBCL, centroblastic variant. The cells have vesicular

chromatin and often membrane-bound nucleoli. Polylobated centroblasts may be common, as in

this case. (B) DLBCL, immunoblastic variant. The cells are round with prominent central

nucleoli. (C) PMBL. The cells have clear cytoplasm and fine compartmentalizing fibrosis. (D)

B-UNC/BL/DLBCL is composed of monomorphic medium-sized cells without a starry sky

pattern. This case had translocations involving both MYC and BCL2, so-called double hit.

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Figure 2. DLBCLs associated with virus infection. (A) Plasmablastic lymphoma involving the

oral cavity. There is sheet-like growth of tumor beneath the mucosa. The tumor cells are

positive for EBV by EBER in situ hybridization (B). (C) PEL, pleural fluid containing large,

atypical cells with a plasmacytoid appearance. The nuclei are strongly positive for the HHV8-

associated latent protein, LANA (D).

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Table 1. Histological Subtypes of Diffuse Large B-cell Lymphomas according to the WHO
Classification.
Diffuse large B-cell lymphoma, not otherwise specified*
Primary DLBCL of the central nervous system##
Primary cutaneous DLBCL, leg type
Intravascular large B-cell lymphoma
T cell/histiocyte rich large B-cell lymphoma
EBV-positive DLBCL#
DLBCL associated with chronic inflammation
Primary mediastinal (thymic) large B-cell lymphoma
ALK positive large B-cell lymphoma
Plasmablastic lymphoma#
Primary effusion lymphoma#
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman Disease
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell
lymphoma and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell
lymphoma and classical Hodgkin lymphoma##

Abbreviations: DLBCL, diffuse large B-cell lymphoma. * Term used when no specific subtype
is designated. # Subtypes associated with EBV infection of tumor cells. ## Subtypes less
often associated with EBV.

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