Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification

INTRODUCTION — 

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), accounting for approximately one-quarter of cases of NHL.

DLBCL is a B cell NHL that typically presents as symptomatic nodal enlargement in the neck or trunk, but it can also present with extranodal involvement, and one-third of patients have "B" symptoms (eg, unexplained fevers, night sweats, or weight loss). Morphologically, DLBCL manifests sheets of large, malignant B cells with prominent nucleoli and basophilic cytoplasm, diffuse growth pattern, high proliferative fraction, and characteristic molecular features.

The diagnosis and classification of DLBCL have evolved, and large B cell lymphomas that were previously considered subtypes of DLBCL have been reclassified as distinct (and, in some cases, provisional) entities that are distinguished from DLBCL by characteristic anatomic location, histology, cytogenetic findings, and/or other clinicopathologic features.

This topic discusses the clinical presentation, pathologic features, diagnosis, and classification of DLBCL and other large B cell lymphomas.

Related topics include:

●(See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma".)

●(See "Diffuse large B cell lymphoma: Treatment of limited-stage disease".)

●(See "Initial treatment of advanced-stage diffuse large B cell lymphoma".)

EPIDEMIOLOGY — 

DLBCL is the most common histologic category of non-Hodgkin lymphoma (NHL).

DLBCL accounts for approximately one-quarter of all NHL in the developed world [1-3]. In the United States and England, the incidence of DLBCL is approximately 7 cases per 100,000 persons per year [2-5]. The incidence in Europe is estimated to be 3 to 4 cases per 100,000 persons per year [6,7]. DLBCL is also the most common NHL in Asia, Africa, and Central and South America, but the incidence is not as well defined [8].

Approximately 55 percent of cases of DLBCL are diagnosed in males [2]. The incidence of DLBCL increases with age; in the United States, the median age at presentation is 64 years [9].

The incidence of DLBCL varies by race and ethnicity. In the United States, White Americans have the highest incidence of DLBCL, followed by (in decreasing order) Black, Asian, and American Indian or Alaska Native individuals [2,4,9,10]. In Central and South America, DLBCL accounts for approximately 40 percent of NHLs [11].

Familial aggregation of DLBCL and other NHL subtypes has been described [12,13]. A large population-based observational study of patients from Sweden and Denmark reported that relatives of probands with an aggressive NHL had a 3.5-fold increased risk for developing NHL [12].

PATHOGENESIS — 

DLBCL arises from transformation of mature B cells. DLBCL is typically composed of malignant cells that resemble centroblasts or immunoblasts.

The pathogenesis of DLBCL is complex. The molecular landscape is heterogeneous, with approximately 150 recurrently mutated genetic drivers; in one study, patients had mutations in an average of 8 percent of these genes [14]. These mutations include genetic lesions that are relatively specific for DLBCL (eg, BCL6 rearrangements) and molecular alterations that are shared with other non-Hodgkin lymphoma (NHL) variants. The pathogenesis of DLBCL is discussed in more detail separately. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma".)

In addition to occurring de novo, DLBCL can arise through the transformation of various low-grade B cell lymphomas, including chronic lymphocytic leukemia (eg, Richter's transformation), lymphoplasmacytic lymphoma, follicular lymphoma, and marginal zone lymphoma, as discussed separately. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Histologic transformation of follicular lymphoma".)

When DLBCL presents in people living with human immunodeficiency virus (HIV), it is considered an acquired immunodeficiency syndrome (AIDS)-defining malignancy. The pathogenesis of NHL in the setting of HIV infection is incompletely understood, but both chronic B cell stimulation and T cell immunodeficiency appear to contribute; the latter leads to loss of control of transforming viruses (especially Epstein-Barr virus [EBV]), as discussed separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV-related lymphomas: Clinical manifestations and diagnosis".)

CLINICAL PRESENTATION — 

Most patients with DLBCL present with a rapidly enlarging symptomatic mass. This is usually nodal enlargement in the neck or abdomen, but DLBCL can present as a mass lesion anywhere in the body.

Approximately 60 percent of patients present with advanced-stage DLBCL (usually stage III or IV disease), while others have more localized disease (table 1) [15,16]. One-third of patients have fever, weight loss, and/or drenching night sweats ("B" symptoms), and serum lactate dehydrogenase (LDH) is elevated in more than one-half [15,16]. Bone marrow is involved in up to one-third of cases, but the histology may be discordant with nodal or other extranodal disease; follicular lymphoma is found in up to one-half of those cases [17].

Nodal DLBCL can secondarily involve the liver, kidneys, lung, bone marrow, and central nervous system (CNS). DLBCL can compress blood vessels (eg, causing superior vena cava syndrome), airways (eg, tracheobronchial compression), or peripheral nerves (eg, spinal cord compression). These conditions are emergencies that require urgent attention. (See "Malignancy-related superior vena cava syndrome" and "Treatment and prognosis of neoplastic epidural spinal cord compression".)

Extranodal/extramedullary involvement is common in patients who present with early-stage disease (ie, stage I/II) [7,18]. Involvement of the stomach (picture 1) and/or other portions of the gastrointestinal (GI) tract is the most common primary extranodal presentation, but DLBCL can involve virtually any tissue, including testis, bone, thyroid, salivary glands, tonsil, skin, liver, breast, adrenals, kidneys, nasal cavity, ocular adnexa, paranasal sinuses, uterine cervix, vagina, and CNS [19-42]. Extranodal presentation of DLBCL in the GI tract is discussed separately. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

Descriptions of B symptoms and other systemic symptoms in patients with non-Hodgkin lymphoma are presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

PATHOLOGY — 

DLBCL is characterized by large transformed B cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern (picture 2), and a high (>40 percent) proliferation fraction.

Evaluation — An excisional biopsy, most often of a lymph node, is preferred for establishing the diagnosis.

It is important to obtain a biopsy specimen that enables review of the architecture of involved lymph nodes. Core needle biopsies may not provide sufficient material, and fine needle aspirates are not adequate for diagnosis. For patients without apparent lymphadenopathy, pathologic evaluation of another involved tissue (ie, pleural fluid, bone marrow, spleen) may be needed to establish a diagnosis.

A discussion of lymph node and tissue biopsy, including selection of a lymph node to biopsy, is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

Morphology — Lymph nodes usually demonstrate effacement of the normal architecture by sheets of atypical lymphoid cells.

The tumor cells of DLBCL are large (eg, nuclei at least twice the size of a small lymphocyte and larger than the nucleus of a tissue macrophage) and often resemble normal centroblasts or immunoblasts (picture 3).

Centroblasts are large, noncleaved cells with round or oval nuclei, vesicular chromatin, often multiple peripheral nucleoli, and a narrow rim of basophilic cytoplasm (picture 4). Immunoblasts are larger cells with prominent nucleoli and more abundant cytoplasm, often with plasmacytoid features (picture 5). Some tumors contain mixtures of centroblastic and immunoblastic forms.

Certain morphologic variants that were previously considered subtypes of DLBCL are now classified as distinct lymphoma categories [43,44], as described below. (See 'Other large B cell lymphoma subtypes' below.)

Immunophenotype — Immunohistochemistry and/or flow cytometry are used to determine the immunophenotype of large B cell lymphomas (figure 1). Note that immunophenotypic features that distinguish DLBCL from other large B cell lymphomas are discussed below. (See 'Other large B cell lymphoma subtypes' below.)

●B cell antigens – Tumor cells of DLBCL generally express pan-B cell antigens (CD19, CD20, CD22, CD79a) and CD45 (picture 6). Most tumors express surface or cytoplasmic monoclonal immunoglobulin (Ig; usually immunoglobulin M [IgM] isotype). Ig variable region genes have usually undergone rearrangement and somatic mutation, but clonally related subpopulations may express alternative Ig isotypes (isotype switch variants) [45].

Some subtypes of large B cell lymphomas do not typically express CD20 and/or other B cell antigens (eg, plasmablastic lymphoma, ALK-positive large B cell lymphoma).

●CD30 – CD30 is expressed in 10 to 20 percent of cases of DLBCL (particularly anaplastic variants), and this is associated with more favorable disease [46,47].

●BCL2 – BCL2 protein is expressed in 25 to 80 percent of DLBCL (picture 7) [48-53]. BCL2 expression in DLBCL is typically not associated with BCL2 gene rearrangement.

●BCL6 – Approximately 70 percent of cases express BCL6; expression of BCL6 protein is independent of BCL6 gene rearrangement (picture 8) [51,52].

●CD10 – There is variable expression of CD10 (30 to 60 percent) and MUM1/IRF4 (35 to 65 percent of cases) [54]. Although MUM1/IRF4 and BCL6 are not coexpressed in normal B cells, these markers are coexpressed in up to 50 percent of cases of DLBCL.

●Ki-67 – The proliferative fraction of cells, as determined by Ki-67 staining, is usually >40 percent, and is occasionally >90 percent (picture 9). Distinguishing DLBCL from Burkitt lymphoma can be difficult in cases with a very high proliferative index.

●MYC – MYC is usually expressed in a high fraction of cells in DLBCL with MYC translocations. However, protein staining is occasionally negative because somatic mutations altered the epitopes recognized by anti-MYC antibodies. For this reason, fluorescence in situ hybridization (FISH) should be performed to evaluate the possibility of an MYC rearrangement, even in tumors in which MYC staining is low.

Large B cell lymphoma with rearrangements of both MYC and BCL2 ("double-hit") is a distinct and aggressive lymphoma (high-grade B cell lymphoma, not otherwise specified [HGBCL, NOS]), as described below. (See 'High-grade B cell lymphomas' below.)

●CD5 – Uncommonly, DLBCL cells express CD5, a finding associated with more aggressive disease and a worse prognosis [47,55-58].

Cytogenetic features — Most cases of DLBCL have genetic abnormalities, but there is no typical or diagnostic cytogenetic finding.

BCL6 alterations — BCL6 (located on chromosome 3) is rearranged in 20 to 40 percent of cases; mutations affect the 5' noncoding region of BCL6 in 70 percent of cases of DLBCL.

The effects of 5’ noncoding mutations and translocations of BCL6 are the same: overexpression of BCL6. The 5' noncoding mutations disrupt a region of autoregulatory transcriptional repression, whereas translocations replace the BCL6 promoter with strong, constitutively active promoters from another gene; >20 different translocations involving BCL6 have been identified.

Recognition that normal germinal center cells have both BCL6 5' noncoding mutations and mutations of Ig variable regions is consistent with the derivation of DLBCL from normal germinal center B cells [59-61]. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant BCL6 expression'.)

BCL6 rearrangement with BCL2 rearrangement is found in HGBCL, NOS, as discussed below. (See 'High-grade B cell lymphomas' below.)

(14;18) translocation — The t(14;18) is present in approximately one-third of patients with DLBCL.

t(14;18) may be found in de novo DLBCL (usually cases with a germinal center B cell gene expression profile) or it may arise from histologic transformation of a prior follicular lymphoma (this translocation is seen in >85 percent of cases of follicular lymphoma) [62,63]. In cases of histologic transformation, mutations of TP53 and/or homozygous deletions at 9p21 (which involve the p15 and p16 tumor suppressors) are frequently found [64-67]. Further discussion of transformed lymphomas is presented separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Histologic transformation' and "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'TP53 mutations'.)

The t(14;18) is associated with nodal and disseminated disease, but it is not associated with a worse prognosis. BCL2 expression is observed in many tumors without BCL2 translocations [48,68].

Rearrangement of BCL2 with BCL6 is found in HGBCL, NOS, as discussed below. (See 'High-grade B cell lymphomas' below.)

Other cytogenetic findings — Other abnormalities that have been reported in DLBCL [69-71] include:

●Clonal karyotypic abnormalities were found in 87 percent of 363 cases of DLBCL [69,70]. The most common chromosomal sites involved were 14q32, 18q21, 1q21, 3q27, 1q36, 8q24, 3p21, 6q21, 1p22, and 22q11.

●Tumor-specific somatic point mutations or recurrent copy number alterations have been reported in >400 different genetic loci [72-74]. Most tumors harbor >100 mutations in coding sequences (exons) alone.

•MYC (on chromosome 8q24) is rearranged in 5 to 15 percent of cases [75-78]. (See "Prognosis of diffuse large B cell lymphoma", section on 'MYC, BCL2, and BCL6 abnormalities'.)

•Some of the most frequently mutated genes encode enzymes that modify histones, including the P300 and CREBP histone acetyltransferases and KMT2D (MLL2), a histone-lysine N-methyltransferase, suggesting that epigenetic changes in DLBCL cells have a central pathogenic role in these tumors.

●Most tumors demonstrate rearrangement of the Ig heavy and light chains and somatic mutations of the variable regions of these genes [79,80], which reflects the origin of DLBCL from transformation of maturing B lymphocytes.

DIAGNOSIS — 

DLBCL and other large B cell lymphomas should be considered in an individual with a nodal or extranodal mass.

Diagnosis is based on morphology and immunophenotyping of a lymph node or extranodal site of involvement. Typically, the biopsy reveals sheets of large, transformed B cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern, and a high proliferative fraction. Tumor cells generally express pan-B cell antigens (CD19, CD20, CD22, CD79a).

Diagnostic criteria for large B cell lymphomas are very similar in the World Health Organization 5^th edition [43] and the International Consensus Classification [44].

CLASSIFICATION — 

Both the World Health Organization 5^th edition (WHO5) and the International Consensus Classification (ICC) recognize two subdivisions of large B cell lymphomas [43,44]:

●DLBCL, not otherwise specified (DLBCL, NOS) – No clinical or pathologic features are present that distinguish DLBCL, NOS from the other large B cell variants.

●DLBCL with sufficiently distinct clinicopathologic features to be designated (at least provisionally) as a specific subtype.

DLBCL, NOS — Both WHO5 and ICC define DLBCL, NOS as having a mature B cell phenotype and large cell morphology, but having none of the criteria that define specific large B cell lymphoma subtypes [43,44]. (See 'Other large B cell lymphoma subtypes' below.)

Both classification systems encourage the use of either gene expression studies or immunohistochemistry to determine cell-of-origin (COO) status in cases of DLBCL, NOS [14,81,82]. ICC distinguishes germinal center B cell (GCB) versus activated B cell (ABC) subtypes of DLBCL, NOS; WHO5 does not make this distinction. The impact of these genetic clusters on stratifying treatment and defining outcomes is uncertain [83,84].

COO status can be defined by gene expression profiling (GEP) or immunohistochemistry:

●GEP

•GCB-like subtype – The GEP of GCB DLBCL is like that of germinal center (GC) cells. GCB DLBCL expresses CD10, and these lymphomas are enriched for t(14;18)/IGH::BCL2 fusion and mutations of EZH2, GNA13, MEF2B, KMT2D, TNFRSF14, B2M, and CREBBP.

•ABC-like subtype – ABC-type DLBCL expresses IRF4/MUM1; is enriched for BCR pathway mutations (eg, MYD88, CD79B, PIM1), BCL6 rearrangements, and PRDM1/BLIMP1 mutation/deletion; depends on BCR signaling and NFkB activation; and is negative for most GC markers.

●Immunohistochemistry – Most hematopathology laboratories assign COO status based on immunohistochemistry using a limited set of markers. The most widely used panel is the Hans algorithm, which distinguishes GCB from ABC subtypes and assigns COO status based on BCL6, CD10, and MUM1 staining [82]. For each marker, positivity is defined as staining in 30 percent of the tumor cells.

•GCB – The GCB subtype includes:

-CD10-positive

-CD10-negative, BCL6-positive, MUM1-negative

•Non-GCB – CD10-negative, MUM1-positive

Different combinations of driver mutations also correlate with the assigned COO [85]. There are ongoing efforts using large-scale genomic studies to create an entirely new classification system for DLBCL, but the impact of these genetic subtypes on stratifying treatment and defining outcomes is uncertain [83,84,86].

Other large B cell lymphoma subtypes — Various subtypes of large B cell lymphoma (table 2) are distinguished from DLBCL, NOS according to anatomic location, histology, cytogenetic findings, and/or other characteristic clinicopathologic features.

WHO5 and ICC generally apply similar diagnostic criteria to these lymphomas, but some differences are noted below.

Primary mediastinal B cell lymphoma — Primary mediastinal B cell lymphoma (PMBCL) is an uncommon large B cell lymphoma that arises in the mediastinum.

The growth pattern of PMBCL is diffuse, and the medium- to large-size malignant cells express B lineage antigens (eg, CD19, CD20, CD79), but not immunoglobulin (Ig). The tumor cells often express CD30 and PDL-1 due to amplification of the PDL-1 gene. Rearrangements of BCL2, BCL6, and MYC are absent.

PMBCL is considered a distinct lymphoma subtype by both WHO5 and ICC. Further details are presented separately. (See "Primary mediastinal large B cell lymphoma".)

T cell/histiocyte-rich large B cell lymphoma — T cell/histiocyte-rich large B cell lymphoma manifests a dominant population of nonmalignant cells and a minor population of CD20-positive tumor cells.

The malignant cells are uniformly positive for CD20 and negative for CD5, CD10, CD15, and CD138. Both T cell/histiocyte-rich large B cell lymphoma and DLBCL, NOS contain variable numbers of infiltrating reactive T cells and macrophages (histiocytes), but the difference is one of degree. T cell/histiocyte-rich large B cell lymphoma (picture 10) demonstrates a dominant population of nonmalignant cells, with <10 percent tumor cells; by contrast, DLBCL, NOS usually has a much smaller number of infiltrating T cells and histiocytes.

The median age at presentation was 49 years, with a male to female ratio of 2.6:1 in a study of 40 patients with T cell/histiocyte-rich large B cell lymphoma [87]. Splenomegaly, bone marrow involvement, and hepatomegaly were common. In another study, the PDL1 gene was amplified in two-thirds of cases of T cell/histiocyte-rich large B cell lymphoma, and was associated with high levels of PD-L1 expression [88].

Plasmablastic lymphoma — Plasmablastic lymphoma shares certain pathologic features with DLBCL, but it can be distinguished by the morphology and immunophenotype of the malignant cells.

The plasmablast-like tumor cells typically exhibit large, eccentrically placed nuclei (often with a prominent single nucleolus), abundant basophilic cytoplasm, and express plasma cell markers (eg, CD138) instead of the pan-B cell markers (eg, CD20, CD79a) that are typically expressed by DLBCL. The malignant cells of plasmablastic lymphoma can be mistaken for anaplastic myeloma when they involve the bone marrow. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and 'Other cytogenetic findings' above.)

Oropharyngeal plasmablastic lymphomas occur most often in people living with HIV, and the tumors are often positive for Epstein-Barr virus (EBV). (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

Primary cutaneous DLBCL, leg type — This cutaneous large B cell lymphoma is distinguished from DLBCL by the absence of findings of extracutaneous involvement after staging studies are completed.

Primary cutaneous DLBCL, leg type typically presents as red or bluish nodules or tumors on one or both legs (typically below the knee); 10 to 15 percent present outside of the lower extremities. Unlike other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites and manifest an aggressive course.

Primary cutaneous DLBCL, leg type is discussed in more detail separately. (See "Primary cutaneous diffuse large B cell lymphoma, leg type".)

Large B cell lymphomas of immune-privileged sites — This category has been eliminated by ICC but is retained by WHO5. These large B cell lymphomas, which involve the central nervous system (CNS) or testis, share certain biologic similarities [89-91]. This category in WHO5 does not include large B cell lymphomas that involve the ovary, skin, or other extranodal sites.

WHO5 and ICC classify lymphomas involving the CNS or testis differently:

●WHO5 groups large B cell lymphomas of the CNS, the vitreoretina, and the testis as variants of large B cell lymphomas of immune-privileged sites [43].

●ICC considers large B cell lymphoma of the testis as a distinct subtype, and groups tumors of the vitreoretinal or other CNS locations as large B cell lymphoma of the CNS [44].

Intravascular large B cell lymphoma — This rare lymphoma, which can present with protean clinical findings, is considered a distinct category of lymphoma in both WHO5 and ICC. (See "Intravascular large B cell lymphoma".)

This lymphoma usually presents with disseminated intravascular proliferation of large lymphoid cells involving small blood vessels without an obvious extravascular tumor mass or leukemia (picture 11). The CNS, kidneys, lungs, and skin are most often affected, but virtually any site can be involved. Nearly all cases are B cell-derived. Intravascular large B cell lymphoma is discussed in more detail separately. (See "Intravascular large B cell lymphoma".)

DLBCL associated with chronic inflammation — Both WHO5 and ICC include DLBCL with chronic inflammation as a category of large B cell lymphoma. WHO5 also created a distinct category called fibrin-associated large B cell lymphoma, while the ICC considers this a variant of DLBCL with chronic inflammation.

DLBCL associated with chronic inflammation most often develops in older patients with a lengthy history (often decades-long) of pyothorax; similar tumors may arise at other sites of chronic inflammation [92]. These tumors are uniformly EBV-positive and are believed to arise from post-GCB cells that are latently infected with EBV.

DLBCL with chronic inflammation often expresses LMP1 (latent membrane protein 1) and EBNA2 (EBV nuclear protein 2); this pattern of gene expression implies that the tumors arise in the context of local immunosuppression within the sites of chronic inflammation. DLBCL associated with chronic inflammation occurs worldwide, but it appears to be more common in Japan and China. In some large series, it is clinically aggressive, with a five-year survival of 20 to 35 percent in the prerituximab era of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy [92].

Fibrin-associated DLBCL is a rare entity in which the tumor is found as single cells or loose aggregates within a fibrinous matrix; they usually do not produce a mass. Fibrin-associated DLBCL may occur as pseudocysts, cardiac myxomas, and cavities around prosthetic devices. It is usually EBV-positive and typically occurs in immunocompetent patients. Unlike other forms of DLBCL with chronic inflammation, fibrin-associated DLBCL tends to have an indolent course and is often an incidental finding [93].

DLBCL with rearrangement of IRF4 — This rare subtype of DLBCL is characterized by IRF4 gene rearrangement, usually in the form of an IRF::IgH (immunoglobulin heavy chain gene) fusion, which leads to strong overexpression of IRF4 (also called MUM1; a transcription factor that regulates aspects of B cell development).

Microscopically, DLBCL with rearrangement of IRF4 may have a follicular, diffuse, or mixed pattern of growth, but it is included here as a category of DLBCL because it is always composed of large cells (usually with centroblast-like morphology). These lymphomas typically express CD20, BCL6, and MUM1, and lack MYC rearrangements. In tumors with a follicular growth pattern, strong expression of MUM1 is a feature that distinguishes it from follicular large B cell lymphoma (also called follicular lymphoma, grade 3B, in the ICC [44]). In addition to IRF4 rearrangements, other characteristic molecular features include mutations involving genes in the NF-kB pathway and losses of chromosome 17p13.2 [94].

DLBCL with rearrangement of IRF4 is relatively common in pediatric and young adult populations and tends to present limited-stage disease in the head and neck region, including Waldeyer's ring. It can be strongly suspected based on clinical, morphologic, and immunophenotypic features, but definitive diagnosis requires demonstration of an IRF4 rearrangement (typically by fluorescence in situ hybridization [FISH]). DLBCL with rearrangement of IRF4 has a relatively favorable prognosis, but older age, high genetic complexity, an ABC gene expression profile, and TP53 mutations have been associated with a poor prognosis.

ALK-positive large B cell lymphoma — This very rare subtype of large B cell lymphoma is strongly positive for ALK expression caused by CLTC::ALK rearrangement. Both WHO5 and ICC consider it a distinct category of large B cell lymphoma characterized by ALK expression.

ALK-positive large B cell lymphoma cells are typically very large, with abundant cytoplasm, and may have a plasmablastic appearance. Diagnosis is based on its characteristic morphology and the presence of ALK protein (usually in a granular cytoplasmic distribution) along with staining for plasma cell markers. The tumors are usually positive for plasma cell markers (eg, CD138) and negative for B cell markers (eg, CD20). It is also characteristically positive for CD30 but easily distinguished from anaplastic large cell lymphoma (a T cell tumor) by the lack of T cell markers. Some experts consider this a variant of plasmablastic lymphoma.

ALK-positive large B cell lymphoma is an aggressive neoplasm that most often presents with lymphadenopathy, fever, night sweats, and weight loss. It may affect people of any age but is more common in young adults and males. The disease typically progresses rapidly, with a median survival time <2 years. The prognosis is poor, with 20 to 30 percent five-year overall survival, but durable responses have been seen in some patients with primary refractory disease who were treated with ALK inhibitors [95].

Large B cell lymphoma with 11q aberration — Tumors that were previously called Burkitt-like lymphoma with 11q aberration, based on their resemblance to Burkitt lymphoma but lacking MYC rearrangement, are now recognized as a distinct variant with a mutational landscape that more closely resembles DLBCL of the GCB subtype.

The ICC renamed this provisional entity large B cell lymphoma with 11q aberration [44]; by contrast, WHO5 renamed it high-grade B cell lymphoma with 11q abnormality, based on the inconsistency of typical DLBCL morphology [43]. Chromosome 11q gains and losses typical of tumors with this abnormality can be identified using FISH or deoxyribonucleic acid (DNA) microarrays.

EBV-positive DLBCL — The ICC recognizes this tumor as EBV-positive DLBCL, while WHO5 labels it EBV-positive DLBCL, NOS.

This large B cell lymphoma can occur in patients without known immunodeficiency or prior lymphoma. It is most common in middle-aged adults, but it is increasingly recognized in younger patients without evidence of immunodeficiency [96-98]. It is most common in Asian countries, where it accounts for 8 to 10 percent of DLBCL among patients without a known immunodeficiency [96,99-101]. Most patients present with extranodal disease, with or without nodal involvement.

This entity can occur at any age, displays a morphologic spectrum that ranges from monomorphic to polymorphic, and can have an aggressive clinical course [97,102]. The EBV-positive tumor cells express the immune checkpoint marker PDL-1 and indoleamine 2,3-dioxygenase, an enzyme that participates in metabolic pathways implicated in the induction of immune tolerance, both of which may contribute to the "escape" of EBV-positive tumor cells from immune surveillance.

Primary effusion lymphoma/fluid overload-associated large B cell lymphoma — This rare subtype of large B cell lymphoma typically develops within serous cavities (ie, pleura, pericardium, and/or abdomen). The ICC describes this as a provisional entity called human herpesvirus-8 (HHV-8) and EBV-negative primary effusion-based lymphoma [44], while WHO5 labels it fluid overload-associated large B-cell lymphoma [43].

Primary effusion lymphoma (PEL) is uniformly associated with latent HHV-8 infection of the tumor cells; the tumor cells are also infected with EBV in some instances. It is most common in HIV-positive individuals, but it can also occur with other causes of T cell immunodeficiency and occasionally in older adults. A small minority of tumors occur as masses rather than in effusions.

PEL cells usually have a plasmablastic appearance and express plasma cell markers (eg, CD138, MUM1, CD38) and CD30. B and T cell markers are typically negative. Detection of HHV-8 LANA protein by immunohistochemistry is a key part of establishing the diagnosis.

The prognosis of PEL is generally poor, with a median survival time often <6 months.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of DLBCL and other large B cell lymphomas includes reactive causes of lymphadenopathy; various other B cell, T cell, and Hodgkin lymphomas; and other cancers (table 2).

Infectious mononucleosis — Epstein-Barr virus (EBV)-associated infectious mononucleosis can present with fever, malaise, lymphadenopathy, splenomegaly, and/or other symptoms that resemble DLBCL.

The diagnosis of infectious mononucleosis is based on clinical evaluation and antibody testing for EBV; a lymph node biopsy is not needed to diagnose infectious mononucleosis. Clinical presentation and diagnosis of infectious mononucleosis are discussed separately. (See "Infectious mononucleosis", section on 'Diagnosis'.)

If a lymph node biopsy is performed, the prominent immunoblasts and Hodgkin-like cells can resemble the immunoblastic variant of DLBCL. However, T immunoblasts predominate in infectious mononucleosis, whereas large B cells predominate in DLBCL.

Histologic transformation — A subset of patients with pathologic findings of DLBCL have a previously undiagnosed indolent lymphoma (eg, follicular lymphoma) that underwent histologic transformation.

Such patients may have a history of waxing and waning lymphadenopathy, with a more recent rapid progression of lymphadenopathy, infiltration of extranodal sites, development of systemic symptoms, and/or elevated serum lactate dehydrogenase.

The histology of a transformed lymphoma can vary in different sections of the same lymph node, and careful examination is key to determining whether a component of another lymphoma is present. A lymphoma of small B cells may also be found in the bone marrow in a patient with nodal DLBCL; discordant histologic features suggest transformation of a previously undiagnosed indolent lymphoma. Histologic transformation is discussed separately. (See "Histologic transformation of follicular lymphoma".)

High-grade B cell lymphomas — These lymphomas share clinicopathologic features with DLBCL but are distinguished by specific cytogenetic findings. The labels that are applied to some categories of high-grade B cell lymphomas differ between the World Health Organization 5th edition (WHO5) and the International Consensus Classification (ICC).

●WHO5 separates DLBCL/high-grade B cell lymphoma with MYC and BCL2 rearrangements from high-grade B cell lymphoma with MYC and BCL6 rearrangements (which are classified as either a subtype of DLBCL, not otherwise specified [NOS], or a subtype of high-grade B cell lymphoma, NOS based on morphology) [43].

●ICC defines three separate categories of high-grade B cell lymphoma: high-grade B cell lymphoma with MYC and BCL2 rearrangements (previously labeled as double-hit lymphoma); a provisional entity called high-grade B cell lymphoma with MYC and BCL6 rearrangements (also previously labeled as double-hit lymphoma); and a third extremely rare category, high-grade B cell lymphoma NOS, which lacks double-hit genetics [44].

Lymphomatoid granulomatosis — Lymphomatoid granulomatosis is an EBV-positive large B cell lymphoma with a T cell-rich background that is clinically and pathologically distinct from DLBCL [5,103].

Patients with lymphomatoid granulomatosis typically present with cough or dyspnea, fever, malaise, neurologic findings, chest pain, and/or rash/skin nodules [104]. Extranodal disease is common. At some point during their clinical course, most patients have lung involvement. Other commonly involved sites include the kidney, liver, brain, and skin, but lymph nodes and spleen are only rarely involved. Evidence of past or present immunodeficiency may be found.

Histologically, the infiltrates show extensive necrosis, often with only a few atypical large B cells in a pleomorphic background of lymphocytes, plasma cells, and histiocytes; the infiltrate may be both angiocentric and angioinvasive. The large, atypical B cells that are the neoplastic component are latently infected with EBV. Pulmonary nodules may exhibit central necrosis and cavitation. (See "Pulmonary lymphomatoid granulomatosis".)

Nodular lymphocyte-predominant B cell/Hodgkin lymphoma — WHO5 labels this entity nodular lymphocyte-predominant Hodgkin lymphoma and considers it to be a subtype of Hodgkin lymphoma [43]. By contrast, ICC calls it nodular lymphocyte-predominant B cell lymphoma and classifies it as a subtype of B cell non-Hodgkin lymphoma [44].

Lymph nodes are effaced by a nodular, nodular and diffuse, or predominantly diffuse infiltrate of small lymphocytes, histiocytes, and malignant cells that resemble those of Hodgkin lymphoma but express B cell markers CD20, OCT2, CD75, CD79a, OCT2, BOB1, and PAX5, as well as CD45 [5]. Details of presentation and diagnosis are presented separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

Some cases of nodular lymphocyte-predominant Hodgkin lymphoma with a diffuse growth pattern closely resemble T cell/histiocyte-rich large B cell lymphoma morphologically and immunophenotypically [105,106]. A helpful clue for distinguishing between the two entities is the number of background reactive B cells, which are sparse to absent in T cell/histiocyte-rich large B cell lymphoma and typically plentiful in nodular lymphocyte-predominant Hodgkin lymphoma.

Burkitt lymphoma — Burkitt lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma characterized by translocation and deregulation of MYC and a very high proliferation fraction.

There are three distinct clinical forms of BL: endemic (African), sporadic (nonendemic), and immunodeficiency-associated. These forms of BL are histologically identical and have similar clinical behavior, but they differ in epidemiology, clinical presentation, and genetic features. WHO5 distinguishes between EBV-positive BL and EBV-negative BL.

BL is composed of monomorphic medium-sized B cells with basophilic cytoplasm and numerous mitotic figures. In some cases, DLBCL can be difficult to distinguish from BL and from high-grade B cell lymphoma with MYC and BCL2 or BCL6 rearrangements. Cases that have morphologic features intermediate between DLBCL and BL and lack rearrangements in MYC, BCL2, and BCL6 should be categorized as high-grade B cell lymphoma, NOS. (See 'Other large B cell lymphoma subtypes' above.)

Details of clinical manifestations, pathologic features, and diagnosis of BL are presented separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Diffuse large B cell lymphoma'.)

Classic Hodgkin lymphoma — Classic Hodgkin lymphoma (cHL) has malignant Hodgkin/Reed-Sternberg (HRS) cells admixed with a polymorphous inflammatory and fibrotic infiltrate. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults", section on 'Diagnosis'.)

DLBCL and cHL share certain aspects of clinical presentation and pathology. However, cHL is distinguished by the distinctive immunophenotype of the tumor cells in most cases and the presence of bilobed, double, or multiple nucleated HRS cells in an inflammatory and/or fibrotic milieu. There are four histologic subtypes of cHL: nodular sclerosis (NS), mixed cellularity, lymphocyte-rich, and lymphocyte-depleted. (See "Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults".)

In addition to these four cHL subtypes, WHO5 considers nodular lymphocyte-predominant Hodgkin lymphoma to be another subtype of Hodgkin lymphoma; by contrast, ICC has renamed this entity nodular lymphocyte-predominant B cell lymphoma and classifies it among B cell lymphomas, as discussed above. (See 'Other large B cell lymphoma subtypes' above.)

Mediastinal gray zone lymphoma — Both ICC and WHO5 include mediastinal gray zone lymphoma (MGZL) as a distinct category of lymphoma.

MGZL has features that overlap with primary mediastinal B cell lymphoma and cHL (especially NS cHL). This category replaces what was previously called B cell lymphoma, unclassifiable with features intermediate between DLBCL and cHL.

Some cases have composite tumors that contain areas of cHL and areas of DLBCL. Similarly, there may be sequential occurrence of both tumor types at different times in a patient's course; this situation arises most often in patients with primary mediastinal large B cell lymphoma, which shares genetic and immunophenotypic features with cHL. (See "Primary mediastinal large B cell lymphoma".)

Systemic anaplastic large cell lymphoma — Systemic anaplastic large cell lymphoma (sALCL) is a T cell malignancy that can present as a nodal lymphoma or as extranodal disease.

The malignant cells of sALCL are CD30-positive with generally large eccentric, horseshoe-shaped, or kidney-shaped nuclei. The tumors are distinguished from DLBCL by their T cell immunophenotype and by expression of CD30. Both WHO5 and ICC distinguish between ALK-positive and ALK-negative subtypes of sALCL.

Details of the clinical presentation and diagnosis of sALCL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Other cancers — When metastatic solid tumors present as isolated lymphadenopathy, they can clinically resemble DLBCL.

●Carcinoma – Metastatic carcinomas can occasionally present as isolated lymphadenopathy. Biopsy of a lymph node reveals large, atypical cells that are positive for cytokeratins but lack B cell markers by immunohistochemistry.

●Melanoma – Melanoma can present as large, atypical cells involving lymph nodes. Unlike DLBCL, melanoma stains positively for S100, HMB-45, and/or Melan A and is negative for B cell markers. (See "Pathologic characteristics of melanoma".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Management of diffuse large B cell lymphoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Diffuse large B cell lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Diffuse large B cell lymphoma in adults (Beyond the Basics)")

SUMMARY

●Description – Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately one-quarter of NHL cases. Other types of large B cell lymphoma are distinguished from DLBCL based on characteristic anatomic location, histology, cytogenetic findings, and/or other clinicopathologic features.

●Presentation – Patients usually present with enlarging lymph nodes in the neck or abdomen. One-third of patients have systemic "B" symptoms (ie, fever, weight loss, sweats), and 40 percent have extranodal disease. (See 'Clinical presentation' above.)

●Pathology

•Morphology – Lymph node architecture is typically effaced by sheets of large, atypical lymphocytes with prominent nucleoli and basophilic cytoplasm, diffuse growth pattern, and a high proliferation fraction (picture 2). The malignant cells resemble normal centroblasts (picture 4) or immunoblasts (picture 5). (See 'Morphology' above.)

•Immunophenotype – Tumor cells generally express pan-B cell antigens (CD19, CD20, CD22, CD79a). (See 'Immunophenotype' above.)

•Cytogenetic/molecular – Most cases of DLBCL have cytogenetic (eg, t(14;18)) or molecular findings (eg, abnormal BCL6), but no single finding is typical or diagnostic. (See 'Cytogenetic features' above.)

●Diagnosis – DLBCL should be considered in any patient with a nodal or extranodal mass. (See 'Diagnosis' above.)

Diagnosis is based on characteristic morphology and immunophenotyping of an excisional or incisional lymph node biopsy or extranodal tissue (when a nodal mass is not seen). (See 'Diagnosis' above.)

●Classification – DLBCL and other large B cell lymphomas are classified as follows (see 'Classification' above):

•DLBCL, not otherwise specified – Meets diagnostic criteria for DLBCL but lacks features that define specific large B cell lymphoma entities. Cases should be classified by immunohistochemistry and/or gene expression studies according to cell-of-origin (COO) status as germinal center B cell (GCB)-like subtype or activated B cell (ABC)-like subtype. (See 'DLBCL, NOS' above.)

•Other large B cell lymphomas – Distinct large B cell lymphoma subtypes that are distinguished by anatomic location, histology, cytogenetic findings, and/or other clinicopathologic features are:

-(See 'Primary mediastinal B cell lymphoma' above.)

-(See 'T cell/histiocyte-rich large B cell lymphoma' above.)

-(See 'Plasmablastic lymphoma' above.)

-(See 'Primary cutaneous DLBCL, leg type' above.)

-(See 'Large B cell lymphomas of immune-privileged sites' above.)

-(See 'Intravascular large B cell lymphoma' above.)

-(See 'DLBCL associated with chronic inflammation' above.)

-(See 'DLBCL with rearrangement of IRF4' above.)

-(See 'ALK-positive large B cell lymphoma' above.)

-(See 'EBV-positive DLBCL' above.)

-(See 'Primary effusion lymphoma/fluid overload-associated large B cell lymphoma' above.)

●Differential diagnosis – DLBCL must be distinguished from various reactive causes of lymphadenopathy, other lymphomas, and other cancers (table 2):

•(See 'Infectious mononucleosis' above.)

•(See 'Histologic transformation' above.)

•(See 'High-grade B cell lymphomas' above.)

•(See 'Lymphomatoid granulomatosis' above.)

•(See 'Nodular lymphocyte-predominant B cell/Hodgkin lymphoma' above.)

•(See 'Burkitt lymphoma' above.)

•(See 'Classic Hodgkin lymphoma' above.)

•(See 'Mediastinal gray zone lymphoma' above.)

•(See 'Systemic anaplastic large cell lymphoma' above.)

•(See 'Other cancers' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Arnold S Freedman, MD, who contributed to earlier versions of this topic review.