Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL) accounting for approximately 25 percent of NHL cases [1-3]. (See "Classification of hematopoietic neoplasms".)

The diagnostic category of DLBCL is heterogeneous in terms of morphology, genetics, and biologic behavior. A number of clinicopathologic entities are now recognized in the 2017 World Health Organization (WHO) classification that are sufficiently distinct to be considered separate diagnostic categories:

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

●Primary DLBCL of the mediastinum, also called primary mediastinal (thymic) large B cell lymphoma. (See "Primary mediastinal large B cell lymphoma".)

●Intravascular large B cell lymphoma. (See "Intravascular large B cell lymphoma".)

●Lymphomatoid granulomatosis, an Epstein-Barr virus positive large B cell lymphoma. (See "Pulmonary lymphomatoid granulomatosis" and 'Lymphomatoid granulomatosis' below.)

●Primary DLBCL of the central nervous system. (See "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors".)

●Primary cutaneous DLBCL, leg type. (See "Primary cutaneous large B cell lymphoma, leg type".)

●DLBCL associated with chronic inflammation. (See 'Diffuse large B cell lymphoma associated with chronic inflammation' below.)

Each of these is discussed separately in the sections that follow the general discussion of DLBCL or in their own topics. In addition, the WHO classification includes several disease categories that have features that overlap with DLBCL and other entities [2,3]:

●"High grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements" and "high grade B cell lymphoma, not otherwise specified." Some tumors in this group were previously classified as "Burkitt-like" lymphoma. (See 'Burkitt lymphoma' below.)

●"B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma," sometimes referred to colloquially as "gray zone lymphoma." (See 'Hodgkin lymphoma' below.)

The epidemiology, clinical presentation, pathologic features, and diagnosis of DLBCL are reviewed in this topic.

The pathobiology and treatment of DLBCL and approach to the diagnosis, staging, and prognosis of the lymphomas are discussed separately. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas" and "Initial treatment of limited stage diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma".)

EPIDEMIOLOGY — DLBCL is the most common lymphoma and accounts for approximately 25 percent of all NHLs in the developed world [1,4,5]. In the United States and England, the incidence of DLBCL is approximately 7 cases per 100,000 persons per year [1,6]. In Europe as a whole, the incidence is approximately 4.92 cases per 100,000 persons per year [7]. Incidence varies by ethnicity, with White Americans having higher rates than Black, Asian, and American Indian or Alaska Native individuals, in order of decreasing incidence [1,6,8]. By comparison, the incidence in Denmark is approximately 3 cases per 100,000 adults per year [9]. DLBCL appears to be a more frequent subtype of NHL in Central and South America, where it accounts for approximately 40 percent of NHLs [10].

Like most other NHLs, there is a male predominance with approximately 55 percent of cases occurring in men [1]. Incidence increases with age; the median age at presentation is 64 years for patients as a whole, but appears to be younger for Black compared with White Americans [11]. Familial aggregation of patients with DLBCL and other NHL subtypes has been noted [12,13]. As an example, a large population-based observational study of patients from Sweden and Denmark reported that relatives of probands with aggressive NHL had an approximately 3.5-fold increased risk of developing NHL [12].

PATHOGENESIS — DLBCL arises from a mature B cell and is usually comprised of cells resembling centroblasts or immunoblasts, two distinct types of activated B cells. The molecular pathogenesis of DLBCL is complex and includes both genetic lesions that are relatively specific for this disease (ie, rearrangements of BCL6) and molecular alterations that are shared with other 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 many different types of low grade B cell lymphomas, including B cell chronic lymphocytic leukemia (eg, Richter's transformation), lymphoplasmacytic lymphoma, follicular lymphoma, marginal zone (MALT) lymphoma, and splenic marginal zone lymphoma. This is discussed in more detail separately. (See "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Histologic transformation of follicular lymphoma".)

DLBCL is an AIDS-defining malignancy. The pathogenesis of NHL in the setting of HIV infection is incompletely understood, but chronic B cell stimulation and T cell immunodeficiency leading to loss of control of transforming viruses, particularly Epstein-Barr virus (EBV), are thought to play important roles. This is discussed in more detail separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV-related lymphomas: Clinical manifestations and diagnosis".)

CLINICAL PRESENTATION — Patients with DLBCL typically present with a rapidly enlarging symptomatic mass, most usually nodal enlargement in the neck or abdomen, or, in the case of primary mediastinal large B cell lymphoma, the mediastinum, but may present as a mass lesion anywhere in the body. Extranodal involvement is common among those presenting with stage I/II disease [14]. Systemic "B" symptoms (ie, fever, weight loss, drenching night sweats) are observed in approximately 30 percent of patients, and the serum lactate dehydrogenase (LDH) is elevated in over one-half [15,16]. A more detailed discussion of systemic symptoms seen in patients with NHL is presented separately, along with the specific definitions of B symptoms. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Systemic "B" symptoms'.)

Approximately 60 percent of patients will present with advanced stage DLBCL (usually stage III or IV disease) while 40 percent have more localized disease, usually defined as that which can be contained within one irradiation field (table 1) [15,16]. The bone marrow is involved in up to 30 percent of cases, but may be of a discordant histologic type, such as follicular lymphoma [17], in as many as half of those cases. The staging of DLBCL is discussed in more detail separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Staging'.)

In up to 40 percent of cases, the disease arises in extranodal extramedullary tissues [9]. The most common site of primary extranodal disease is the stomach/gastrointestinal tract (picture 1), but the disease can arise in virtually any tissue, including the testis, bone, thyroid, salivary glands, tonsil, skin, liver, breast, adrenals, kidneys, nasal cavity, ocular adnexa, paranasal sinuses, uterine cervix, vagina, and central nervous system [18-41]. Many of these presentations are discussed separately:

●Skin (see "Primary cutaneous large B cell lymphoma, leg type")

●Lung (see 'Lymphomatoid granulomatosis' below and "Pulmonary lymphomatoid granulomatosis")

●Bone

●Gastrointestinal tract (see "Clinical presentation and diagnosis of primary gastrointestinal lymphomas")

●Mediastinum (see "Primary mediastinal large B cell lymphoma")

●Central nervous system (see "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation")

●Testis (see "Anatomy and pathology of testicular tumors", section on 'Testicular lymphoma')

●Heart (see "Cardiac tumors")

Conversely, primary nodal disease may secondarily involve the liver, kidneys, lung, bone marrow, and central nervous system. DLBCL also can be locally highly invasive, leading to compression of vessels (eg, superior vena cava syndrome) or airways (eg, tracheo-bronchial compression), involvement of peripheral nerves, and destruction of bone (eg, cord compression), requiring urgent attention. (See "Malignancy-related superior vena cava syndrome" and "Treatment and prognosis of neoplastic epidural spinal cord compression".)

DLBCL is an AIDS-defining malignancy. When compared with lymphoma in the HIV-negative population, systemic lymphoma in the HIV-positive population is characterized by more frequent B symptoms (ie, fever, weight loss, night sweats), extranodal disease, involvement of unusual locations (eg, body cavity, rectum, soft tissue), and advanced stage at diagnosis. This is discussed in more detail separately. (See "HIV-related lymphomas: Clinical manifestations and diagnosis".)

PATHOLOGY — DLBCL is a heterogeneous group of tumors consisting of large, transformed B cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high (>40 percent) proliferation fraction (picture 2).

Morphology

Typical morphology — Lymph nodes usually demonstrate complete effacement of the normal architecture by sheets of atypical lymphoid cells. The tumor cells are of large size (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 very prominent nucleoli and abundant cytoplasm, often with plasmacytoid features (picture 5). Some tumors contain mixtures of centroblastic and immunoblastic forms.

In addition to the common centroblastic and immunoblastic morphologies, several other cytologic variants are recognized (eg, multilobated and anaplastic), but their clinical significance is debated [42]. In addition, there is poor intra- and inter-observer reproducibility among hematopathologists attempting to subtype DLBCL based on the appearance of the tumor cells, and as a result the morphologic subtypes of DLBCL are lumped together in a single diagnostic category in the current World Health Organization (WHO) classification of lymphoid neoplasms [3]. In contrast, plasmablastic lymphoma is a morphologic variant that displays immunophenotypic characteristics that allow for its distinction from other DLBCLs.

Plasmablastic lymphoma — The tumor cells of plasmablastic lymphoma typically have large, eccentrically placed nuclei, often with prominent single nucleoli, and abundant basophilic cytoplasm, which together constitute a "plasmablast-like" appearance. Unlike the other morphologic variants described above, plasmablastic tumors are immunophenotypically distinct. Specifically, these tumors are comprised of late B cells that express plasma cell markers (eg, CD138) instead of the pan-B cell markers found in typical DLBCL (eg, CD20 and CD79a). Some tumors belonging to this group have distinctive genetic or clinicopathologic features. For example, oropharyngeal plasmablastic lymphomas occur most frequently in HIV-positive individuals and are often positive for Epstein-Barr virus. Another rare genetic subtype of plasmablastic lymphoma has rearrangements of the ALK tyrosine kinase gene, discussed in more detail below. Because of the plasmacellular differentiation of these tumors, they can be easily mistaken for anaplastic myeloma when they involve the bone marrow. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and 'Other mutations' below.)

Immunophenotype — The immunophenotype of DLBCL can be confirmed by histochemistry or flow cytometry (figure 1). Tumor cells in DLBCL generally express pan B cell antigens (CD19, CD20, CD22, CD79a), as well as CD45 (picture 6). Fifty to 75 percent of tumors express surface or cytoplasmic monoclonal immunoglobulin (Ig), most often of the IgM isotype. The immunoglobulin variable region genes have undergone rearrangement and are commonly somatically mutated; clonally related subpopulations may express alternative isotypes (isotype switch variants) [43]. Expression of CD30 is present in approximately 25 percent of cases (particularly the anaplastic variant) and is associated with more favorable disease [44,45]. Uncommonly, DLBCLs express CD5, a finding associated with more aggressive disease and worse prognosis [45-49].

BCL2 protein is expressed in 25 to 80 percent of DLBCL (picture 7) [50-55]. Approximately 70 percent express B cell lymphoma 6 (BCL6) protein; this expression is independent of BCL6 gene rearrangement (picture 8) [53,54]. Other markers that are commonly expressed include CD10 (30 to 60 percent of cases) and MUM1/IRF4 (35 to 65 percent of cases). Although MUM1/IRF4 and BCL6 are not coexpressed in normal B cells, coexpression of both markers is found in up to 50 percent of DLBCLs. The proliferative fraction of cells, as determined by Ki-67 staining, is usually higher than 40 percent, and may occasionally be >90 percent, which may make distinguishing DLBCL from Burkitt lymphoma difficult in some cases (picture 9). (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma" and "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant BCL6 expression'.)

Genetic features — Most cases of DLBCL have genetic abnormalities, but there is no typical or diagnostic cytogenetic change. Most tumors demonstrate rearrangement of the immunoglobulin heavy and light chain genes and somatic mutations of the variable regions of these genes [56,57].

Alterations in BCL6 — The BCL6 gene, located on chromosome 3, is rearranged in 20 to 40 percent of cases and shows mutations in the 5' noncoding region in 70 percent [58-62]. Over 20 different translocations involving BCL6 have been identified. Both 5' noncoding mutations of the BCL6 proto-oncogene and mutations of the immunoglobulin gene variable regions are found in normal germinal center cells [63-65]; their presence in DLBCL is consistent with a germinal center or post-germinal center stage of differentiation. The 5' noncoding mutations abolish negative autoregulation of expression by BCL6, which is a transcriptional repressor, whereas the translocations replace the BCL6 promoter with strong, constitutively active promoters derived from many different genes. The net effect of both the mutations and translocations is the same: overexpression of BCL6, which is a common oncogenic mechanism in DLBCL. (See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma", section on 'Aberrant BCL6 expression'.)

(14;18) translocation — The t(14;18) seen in >90 percent of cases of follicular lymphomas is also present in approximately 30 percent of patients with DLBCL. Such cases may represent histologic transformation of a prior follicular lymphoma or may be a de novo DLBCL subset demonstrating a germinal center B cell gene expression profile [66,67]. In cases of histologic transformation, mutations of TP53 are observed at a high frequency as well as homozygous deletions at 9p21, which involve the p15 and p16 tumor suppressors [68-71]. (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 is not associated with a worse prognosis. Furthermore, as with BCL6, expression of BCL2 is observed in many tumors without BCL2 translocations [50,72].

Other mutations — Other abnormalities have been reported in DLBCL [73-75]:

●A comprehensive analysis of 363 cases of DLBCL found clonal karyotypic abnormalities in 87 percent [73,74]. The most common sites involved were 14q32, 18q21, 1q21, 3q27, 1q36, 8q24, 3p21, 6q21, 1p22, and 22q11.

●The MYC gene (ie, 8q24) is rearranged in 5 to 15 percent [59,76-78]. (See "Prognosis of diffuse large B cell lymphoma", section on 'MYC, BCL2, BCL6 abnormalities'.)

●Rare plasmablastic forms of DLBCL have a (2;17)(p23;q23) translocation involving ALK and the clathrin gene (CLTC) [79,80]. These are late B cell tumors that are usually negative for CD20, CD79a, and CD30, positive for plasma cell markers such as CD138, and show granular cytoplasmic staining for ALK. Some series indicate a male predominance and a poor prognosis [81,82]. (See 'Plasmablastic lymphoma' above.)

●Deep sequencing of DLBCL genomes has identified over 400 different loci involved by tumor-specific somatic point mutations or recurrent copy number alterations [83-85], with most tumors harboring >100 mutations in coding sequences (exons) alone. Of note, a number of the most frequently mutated genes encode enzymes that modify histones, including the histone acetyltransferases P300 and CREBP and the histone-lysine N-methyltransferase KMT2D (MLL2), suggesting that epigenetic changes in DLBCL cells are likely to have a central pathogenic role in these tumors.

DIAGNOSIS

Evaluation — The diagnosis of DLBCL is best made based by excisional tissue biopsy, most commonly a lymph node. While an excisional lymph node biopsy is the preferred diagnostic test for most patients, some patients do not present with overt lymphadenopathy and require the pathologic evaluation of another tissue (ie, pleural fluid, spleen) for diagnosis. A discussion of lymph node and tissue biopsy including the 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'.)

Diagnosis — The pathologic diagnosis of DLBCL is based on morphology and immunophenotyping, which is essential to make the diagnosis. Staining for pan-B cell markers, such as CD20 and CD79a, is sufficient to establish the diagnosis in many cases, but a much broader set of stains may be needed in cases with atypical morphologic features. In rare cases with plasmablastic features, correlation with other clinical and laboratory features may be necessary to distinguish the tumor from multiple myeloma.

As described in more detail above, DLBCL is a heterogeneous group of tumors consisting of large, transformed B cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high proliferation fraction. Tumor cells in DLBCL generally express pan B cell antigens (CD19, CD20, CD22, CD79a). The majority has genetic abnormalities, but there is no single cytogenetic change that is typical or diagnostic.

Molecular subtype — The initial pathologic evaluation of DLBCL should include an assessment of molecular risk to further classify cases into germinal center B cell DLBCL and nongerminal center B cell lymphoma (including activated B cell lymphoma) and to identify double hit DLBCL [2]. This is discussed in more detail separately. (See "Prognosis of diffuse large B cell lymphoma", section on 'Molecular genetics' and "Initial treatment of advanced stage diffuse large B cell lymphoma", section on 'Clinical and laboratory'.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of DLBCL includes other entities that can result in lymphadenopathy and similar pathologic features. These include infectious mononucleosis and malignancies such as carcinoma, melanoma, and other types of lymphoma (table 2). These are described in more detail below.

The differential diagnosis of patients presenting with primary extranodal involvement depends upon the presenting symptoms. Many of these extranodal presentations are described in more detail separately:

●Skin (see "Primary cutaneous large B cell lymphoma, leg type")

●Lung (see "Pulmonary lymphomatoid granulomatosis")

●Bone

●Gastrointestinal tract (see "Clinical presentation and diagnosis of primary gastrointestinal lymphomas")

●Mediastinum (see "Primary mediastinal large B cell lymphoma")

●Central nervous system (see "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation")

●Testis (see "Anatomy and pathology of testicular tumors", section on 'Testicular lymphoma')

●Intravascular lymphoma (see "Intravascular large B cell lymphoma")

Infectious mononucleosis — Both infectious mononucleosis and the immunoblastic variant of DLBCL have prominent immunoblasts and Hodgkin-like cells on lymph node biopsy. However, T immunoblasts predominate in infectious mononucleosis, while large B cells predominate in DLBCL. (See "Infectious mononucleosis".)

"Gray zone lymphoma" — The colloquial term "gray zone lymphoma" has been used by some to describe lymphomas with morphologic, immunophenotypic, and/or genotypic features that are either intermediate between DLBCL and Burkitt lymphoma (BL) or between DLBCL and Hodgkin lymphoma but do not clearly fit into any of these individual categories. These terms lack precision and are not used in the current World Health Organization (WHO) classification; as such, these entities should be categorized according to the descriptions below.

Burkitt lymphoma — The differentiation between DLBCL and Burkitt lymphoma (BL) can be difficult since DLBCL can have a high proliferation fraction and cytogenetic abnormalities, such as t(8;14), that are typically seen in BL, and BL can have atypical morphologic features, including some variation in cell size.

In the 2017 revision of the WHO classification system, a category previously described as "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" was eliminated due to concerns regarding imprecision in the definition and inconsistency in its application [2,3]. Instead, the following was proposed:

●Tumors that show some atypical morphologic features but that have the immunophenotypic and genotypic features of BL should be categorized as BL.

●Most tumors that have rearrangements of MYC and BCL2 and/or BCL6 (so-called "double hit" or "triple hit" lymphomas) have been placed in a new category, "high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements," except for rare tumors that have these rearrangements but otherwise resemble lymphoblastic lymphoma or follicular lymphoma.

●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, not otherwise specified."

This remains a difficult and somewhat controversial diagnostic area and additional refinements are likely to be forthcoming.

Features that favor the diagnosis of DLBCL over BL or "high grade B cell lymphoma" include the presence of isolated cytogenetic abnormalities involving BCL6 or BCL2 and Ki-67 staining in less than 95 percent of the tumor cells. Expression of BCL2 (which is present in most DLBCLs and usually absent from BL) is helpful in distinguishing DLBCL from BL, but cannot distinguish between DLBCL and "high grade B cell lymphoma" with or without MYC, BCL2, and BCL6 rearrangements, as these tumors frequently overexpress BCL2. Gene expression profiling also shows promise in distinguishing DLBCL from BL [86,87]. In contrast, "high grade B cell lymphoma" with or without MYC, BCL2, and BCL6 rearrangements tend to have gene expression profiles intermediate between DLBCL and BL and are best recognized by other criteria (morphology, immunophenotype, and genotype). (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma", section on 'Diffuse large B cell lymphoma'.)

Hodgkin lymphoma — The 2017 WHO classification system provides an overlap category termed "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma" [2,3]. This category includes tumors that morphologically resemble classical Hodgkin lymphoma, but have immunophenotypes that are more typical of DLBCL.

Some cases of the T cell histiocyte rich large B cell variant bear some resemblance to Hodgkin lymphoma of either the lymphocyte predominant or lymphocyte rich classic types [88-91]. Lymphocyte predominant Hodgkin lymphoma (LPHL) usually has a nodular growth pattern and presents with low-stage disease, in contrast to T cell/histiocyte-rich large B cell lymphoma, which grows in a diffuse pattern and typically presents with disseminated disease involving the liver and spleen. However, the distinction between unusual cases of advanced stage LPHL and T cell histiocyte rich large B cell lymphoma can be difficult, as the tumor cells in these two disorders have similar immunophenotypes. The lymphocyte rich subtype of classic Hodgkin lymphoma is usually more easily distinguished by expression of markers that are specific for classic forms of Hodgkin lymphoma, such as CD15 and CD30, and the presence of Epstein-Barr virus, which can be detected in 40 percent of lymphocyte rich classic Hodgkin lymphoma, but is not associated with T cell histiocyte rich large B cell lymphoma. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

A potentially related issue is the occurrence of composite tumors containing areas of classic Hodgkin lymphoma and areas of DLBCL. Similarly, there may be sequential occurrence of both of these 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 certain genetic and immunophenotypic features with classical Hodgkin lymphoma. (See "Primary mediastinal large B cell lymphoma".)

Anaplastic large cell lymphoma — Cases of the anaplastic variant of DLBCL are morphologically identical to those of anaplastic large cell lymphoma (ALCL) T/null-cell type and strongly express CD30 (Ki-1). The key diagnostic criterion for such cases is the expression of B cell antigens, which are absent in ALCL. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Histologic transformation — A subset of patients with pathologic findings consistent with DLBCL will have had a previously undiagnosed indolent lymphoma (eg, follicular lymphoma) that has undergone 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 (LDH).

Histology can vary greatly in different sections of the same lymph node. As such, careful examination of the sampled lymph node is key to determining whether a component of DLBCL is present. Discordant histologic features suggest transformation of a previously undiagnosed indolent lymphoma. As an example, a small B cell proliferation may be identified in the bone marrow in a patient with DLBCL in a lymph node. The detection of areas of DLBCL within the lymph node denotes transformation to an aggressive phase of disease. This subject is discussed in detail separately. (See "Histologic transformation of follicular lymphoma".)

Carcinoma — Morphologically, lymph node involvement with carcinoma may resemble DLBCL in that both tumors are comprised of large atypical cells. Carcinoma can be readily distinguished from DLBCL by the presence of cytokeratins and the absence of B cell markers by immunohistochemistry.

Melanoma — Both melanoma and DLBCL are comprised of large atypical cells and can involve lymph nodes. However, 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".)

DISTINCTIVE DLBCL SUBTYPES AND RELATED ENTITIES

T cell histiocyte-rich large B cell lymphoma — All cases of DLBCL have some infiltrating reactive T cells and macrophages (histiocytes), but in some tumors these cells predominate. This is the so-called T cell histiocyte-rich large B cell lymphoma (picture 10). Some experts have suggested that less than 10 percent of the cellularity should be comprised of tumor cells for this diagnosis to be made.

In one study of 40 patients with this variant, the median age was 49 years (range: 21 to 87), with a male to female ratio of 2.6:1 [92]. Splenomegaly, bone marrow involvement, and hepatomegaly were present in 60, 43, and 40 percent, respectively. The International Prognostic Index (IPI) (table 3) was ≥2 in 77 percent of the patients. Neoplastic cells were uniformly positive for CD20 and negative for CD5, CD10, CD15, and CD138. Despite their relatively young age and the use of combination chemotherapy, complete remissions were attained in only 40 percent, with an overall survival of 50 percent at three years. On multivariate analysis, only the IPI and loss-of-function mutations (eg, deletions or point mutations) in p53 were predictive of failure-free survival. In another report, like primary mediastinal large B cell lymphoma, T cell histiocyte-rich large B cell lymphoma had amplification of PDL1 gene in 64 percent of cases, a finding associated with high levels of PD-L1 expression [93].

In a separate study, there was no difference in five-year overall survival or event-free survival between this variant and DLBCL when subjects were matched for the prognostic features comprising the IPI [94].

Primary mediastinal large B cell lymphoma — Primary large B cell lymphoma of the mediastinum is a distinct clinicopathologic entity that arises from the thymic (medullary) B cell. It has clinical and pathologic features that differ from DLBCL. (See "Primary mediastinal large B cell lymphoma".)

Intravascular large B cell lymphoma — Intravascular large B cell lymphoma, which is almost always of B-cell type (but occasionally of T cell origin [95] and rarely of NK-cell origin), usually presents with disseminated intravascular proliferation of large lymphoid cells involving small blood vessels without an obvious extravascular tumor mass or leukemia (picture 11). This tumor has been variously known as intravascular lymphomatosis, angiotropic large cell lymphoma, and malignant angioendotheliomatosis. The organs most commonly affected are the central nervous system, kidneys, lungs, and skin, but virtually any site may be involved. This disorder is discussed in more detail separately. (See "Intravascular large B cell lymphoma".)

Diffuse large B cell lymphoma, leg type — Diffuse large B cell lymphoma, leg type typically presents as red or bluish (violaceous) nodules or tumors on one or both legs, typically below the knee; 10 to 15 percent will develop outside of the lower extremities. Unlike other cutaneous B cell lymphomas, these tumors frequently disseminate to extracutaneous sites and pursue an aggressive course. DLBCL, leg type is discussed in more detail separately. (See "Primary cutaneous large B cell lymphoma, leg type".)

Diffuse large B cell lymphoma associated with chronic inflammation — DLBCL associated with chronic inflammation, which is also known as pyothorax-associated DLBCL, typically develops in patients with a lengthy (eg, several decades) history of pyothorax; similar tumors may arise at other sites of chronic inflammation [96]. These tumors are uniformly Epstein-Barr virus (EBV)-positive and are believed to arise from post-germinal center B cells that are latently infected with EBV.

The tumors often exhibit EBV latency III patterns of gene expression (LMP1 and EBNA2 are expressed), which has been taken to mean 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 five-year survival of 20 to 35 percent in the pre-rituximab era of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) therapy [96].

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 [3,97].

Patients with lymphomatoid granulomatosis typically present with cough (60 percent), fever (60 percent), rash/nodules (40 percent), malaise (35 percent), weight loss (35 percent), neurological abnormalities (30 percent), dyspnea (30 percent), or chest pain (15 percent) [98]. Extranodal disease is common. Most patients have lung involvement at some point during their clinical course. Other commonly involved sites include the kidney, liver, brain, and skin. Lymph nodes and spleen are very 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 are the neoplastic component and are latently infected with EBV. Pulmonary nodules may exhibit central necrosis and cavitation. (See "Pulmonary lymphomatoid granulomatosis".)

Although the infiltrates may resemble those of nasal/angiocentric lymphoma, there is no biological and little clinical overlap, since the latter is an NK cell or T cell neoplasm that involves the upper airway and midfacial region, skin, and sometimes the gastrointestinal tract, and rarely the lung or central nervous system. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal NK/T cell lymphoma, nasal type".)

EBV-positive DLBCL, NOS — EBV-positive DLBCL, not otherwise specified (NOS), is a variant of DLBCL that replaced EBV-positive DLBCL of the elderly in the 2017 World Health Organization (WHO) classification, based on the recognition that it may occur in people of any age [2,3]. This is a clonal B cell lymphoproliferative disorder seen in patients without known immunodeficiency or prior lymphoma. It is differentiated from EBV-positive lymphomatoid granulomatosis (described above) based on morphology, as the EBV-positive neoplastic cells make up a major fraction of the tumor cellularity in EBV-positive DLBCL and are uncommon in EBV-positive lymphomatoid granulomatosis.

This entity is most common in Asian countries, where it accounts for 8 to 10 percent of DLBCL among patients without a known immunodeficiency [99-102]. Most patients present with extranodal disease, with or without nodal involvement.

While the initial reports were in adults >50 years old, this entity has been increasingly recognized in younger patients [100,103,104]. One report described the occurrence of EBV-positive DLBCL in young patients (median age 23 years) without evidence of immunodeficiency [103]. EBV-positive tumor cells in these cases expressed the immune checkpoint marker PDL-1 and indoleamine 2,3-dioxygenase (IDO), an enzyme that participates in metabolic pathways implicated in induction of immune tolerance, both of which may contribute to "escape" of EBV-positive tumor cells from immune surveillance. (See 'Lymphomatoid granulomatosis' above.)

EBV-positive mucocutaneous ulcer — EBV-positive mucocutaneous ulcer is considered a provisional entity in the 2017 revision of the WHO classification [2,3]. It is defined by the presence of isolated, circumscribed, ulcerative lesions, typically occurring in elderly individuals, sometimes in the setting of immunosuppression [105,106]. The lesions are most common in the oropharynx but may also occur in the skin or in the gastrointestinal tract. The lesions contain a polymorphous inflammatory infiltrate mixed with scattered EBV-infected B cells, which frequently include cells resembling Hodgkin/Reed-Sternberg cells morphologically and immunophenotypically. The entity is distinguished from Hodgkin lymphoma by its extranodal presentation and retention of B cell markers on the tumor cells in most cases. Although the degree of cytologic atypia in the EBV-positive lesional cells is often striking, raising the possibility of EBV-positive DLBCL, this entity follows a benign course, with frequent spontaneous regressions and excellent responses to conservative treatment.

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

●Diffuse large B cell lymphoma (DLBCL) – DLBCL is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25 percent of NHL cases. (See 'Epidemiology' above.)

●Presentation – Patients usually present with an enlarging mass of lymph nodes in the neck or abdomen. One-third have systemic "B" symptoms (ie, fever, weight loss, sweats), while 30 percent have bone marrow involvement 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) (picture 6). (See 'Immunophenotype' above.)

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

●Diagnosis – The diagnosis of DLBCL is based on characteristic morphology and immunophenotyping (described above) and is best determined with an excisional or incisional biopsy. If no nodal involvement is identified, the diagnosis can be made using extranodal tissue (eg, pleural fluid, spleen) (See 'Diagnosis' above.)

Distinguishing between germinal center B cell DLBCL and nongerminal center B cell DLBCL (including activated B cell lymphoma) provides useful prognostic information. (See "Prognosis of diffuse large B cell lymphoma", section on 'Molecular genetics'.)

●Differential diagnosis – Other large cell malignancies, such as carcinoma, melanoma, and other types of lymphoma (table 2), may present with a similar clinical presentation. (See 'Differential diagnosis' above.)

●DLBCL subtypes – DLBCL is a heterogeneous category of NHL that includes distinct clinicopathologic entities, including:

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

•Primary mediastinal large B cell lymphoma. (See 'Primary mediastinal large B cell lymphoma' above.)

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

•Lymphomatoid granulomatosis, Epstein-Barr virus (EBV)-positive large B cell lymphoma. (See 'Lymphomatoid granulomatosis' above.)

•EBV-positive DLBCL, not otherwise specified (NOS). (See 'EBV-positive DLBCL, NOS' above.)

•Primary DLBCL of the central nervous system (CNS). (See "Overview of the clinical features and diagnosis of brain tumors in adults".)

•Primary cutaneous DLBCL, leg type. (See "Primary cutaneous large B cell lymphoma, leg type".)

•DLBCL associated with chronic inflammation. (See 'Diffuse large B cell lymphoma associated with chronic inflammation' above.)