Diffuse large B cell lymphoma classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2] Anila Hussain, MD [3]

Overview

Diffuse large B cell lymphoma may be classified based on location into nodal and extranodal disease and based on pathological and clinical features.

Classification

Classification Based on Location

Diffuse large B cell lymphoma may be classified based on location:

• Nodal disease
• Extranodal disease

Classification Based on Pathological and Clinical Features

According to the updated WHO classification, diffuse large B cell lymphoma may be classified based on pathological and clinical features into the following:

Diffuse large B cell lymphoma, not otherwise specified

• Diffuse large B-cell lymphoma, NOS (represents more than 80% of cases of large B-cell lymphomas)

• Molecular subtypes: GCB subtype, about 60%; ABC subtype, about 25–30%; unclassifiable, about 10–15%; new molecular entities recently characterized

Diagnostic features

Diffuse proliferation of medium or large lymphoid B cells typically expressing CD19, CD20, CD22, CD79a, PAX5, and surface or cytoplasmic immunoglobulin; molecular techniques (e.g., GEP) or IHC-based algorithms recommended to classify subtypes

Clinical Features and Outcome

• The median age is 65–70 yr

• Nodal presentation is the most common and 30–40% of cases are primary extranodal

• prognosis is variable

Other Large B Cell Lymphoma (DLBCL) type

T-cell/histiocyte-rich large B cell lymphoma (rare)

• Few large B cells embedded in a background of T cells and histiocytes; distinguish from nodular lymphocyte-predominant Hodgkin lymphoma
• Commonly found in middle-aged men, advanced stage with extranodal involvement (liver, spleen, bone marrow); poor prognosis

Primary diffuse large B cell lymphoma of the central nervous system (rare)

• Typically ABC subtype; frequent loss of HLA class I/II; frequent mutation of MYD88
• Exclusively in CNS or intraocular region, rare systemic involvement; poor prognosis; specialized treatment with CNS-penetrating agents, with or without radiation therapy, required; targeted therapies under investigation

Primary Cutaneous DLBCL, Leg type (rare)

• Typically ABC subtype; frequent mutation of MYD88; distinguish from other cutaneous B-cell lymphoma
• Typically in elderly patients and women; presents with skin nodules in lower legs; 10–15% of cases arise in other sites; poor prognosis

EBV-positive diffuse large B-cell lymphoma, NOS (rare)

• Variable histologic features, including Hodgkin-like lesions, monomorphic to polymorphic patterns; EBV detectable in tumor and frequently in serum
• Typically in patients older than 50 yr; more frequent in Asia and Latin America than elsewhere; extranodal involvement common; prognosis varies

EBV-positive mucocutaneous ulcer (rare)

• Polymorphic infiltrate with frequent Hodgkin-like cells; EBV is detectable in tumor
• Presents as localized, ulcerated lesions in oral mucosa, intestine, or skin; dissemination is rare; commonly occurs as iatrogenic or age-related disease in immunocompromised patients; favorable prognosis; consider reduction of immunosuppressive therapy

Diffuse large B-cell lymphoma associated with chronic inflammation (rare)

• Morphologically similar to DLBCL, NOS but strongly associated with EBV; also called pyothorax-associated lymphoma, when associated with chronic pyothorax
• Occurs in context of chronic inflammation, involving pleural cavity or other sites such as bone and joints; male predominance; poor prognosis

Lymphomatoid granulomatosis (rare)

• EBV-driven angiocentric and angiodestructive lymphoproliferation with reactive T cells; grade based on proportion of EBV positive B cells and cytologic features
• Commonly involves extranodal sites (lung >90%); often in context of immunodeficiency; prognosis varies; no standard therapy

Large B-cell lymphoma with IRF4 rearrangement (rare)

• Strong expression of IRF4/MUM1, usually with IRF4 rearrangement; diffuse-to-follicular morphologic features; distinguish from pediatric-type follicular lymphoma
• Commonly in children and young adults; typically involves Waldeyer’s ring or cervical lymph nodes; favorable prognosis

Primary mediastinal (thymic) large B-cell lymphoma (around 6% of large B-cell cases)

• Putative thymic B-cell origin; medium-to-large B cells, frequently with sclerosis; distinctive phenotype (CD30, CD23, PDL1, PDL2) and unique GEP signature; frequent 9p21 amplification, genomic alterations of CIITA
• Typically in young adults, female predominance; mediastinal prominence with local invasion; can involve other nodal or extranodal sites (kidney and liver); prognosis varies; DA-EPOCH-R an option

Intravascular large B-cell lymphoma (rare)

• Lymphoma cells exclusively within lumina of small or intermediate vessels; bone marrow and skin biopsy may be useful to establish diagnosis
• Wide intravascular dissemination (lung, bone marrow, skin, CNS, kidney), often associated with fever of unknown origin or neurologic or cutaneous symptoms; poor prognosis

ALK-positive large B-cell lymphoma (rare)

• ALK-positive large B cells, immunoblastic features and plasma cell phenotype, typically CD20-negative
• Typically in young men with generalized lymphadenopathy; prognosis varies

Plasmablastic lymphoma (rare)

• Immunoblastic or plasmablastic B cells, plasma-cell phenotype (CD138-positive, CD20-negative), often EBV-positive; distinguish from multiple myeloma
• Often associated with HIV infection or immunosuppression; frequently extranodal; poor prognosis; consider more intensive regimens

HHV8-positive diffuse large B-cell lymphoma (rare)

• HHV8-positive IgM lambda plasmablasts; often associated with HHV8-positive multicentric Castleman disease
• Often associated with HIV infection; lymphadenopathy and splenomegaly are common; poor prognosis; no standard therapy

Primary effusion lymphoma (rare)

• Immunoblastic or plasmablastic B cells, HHV8-positive and usually EBV-positive; plasma-cell phenotype lacking usual B-cell markers; CD20-negative
• Often associated with HIV infection or immunosuppression; presents as pleural, pericardial, or peritoneal serous effusions, often without detectable tumor mass; poor prognosis; DA-EPOCH an option

High-grade B-cell lymphoma

• High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or both (doublehit or triple-hit lymphoma) (4–8% of large B-cell cases)
• Variable morphology, including DLBCL, B-cell lymphoma unclassifiable (with features intermediate between DLBCL and Burkitt lymphoma), and blastoid features; MYC and BCL2 and/or BCL6 rearrangements, detected by FISH
• Frequently aggressive clinical presentation; higher risk of CNS involvement; poor prognosis; consider more intensive immunochemotherapy regimens, such as DA-EPOCH-R

High-grade B-cell lymphoma, NOS (rare)

• Heterogeneous category; often has morphologic features intermediate between DLBCL and Burkitt lymphoma; lacks MYC and BCL2 and/or BCL6 rearrangements
• Frequently aggressive clinical presentation; increased risk of CNS involvement; poor prognosis; consider more intensive immunochemotherapy regimens

B-cell lymphoma, unclassifiable

• B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma (grey-zone lymphoma) (rare)
• Overlapping morphologic or immunophenotypic features, or both, between DLBCL and classic Hodgkin lymphoma
• Male predominance, younger age (20–40 yr); mediastinal presentation most common (80% of cases) but can occur in other sites; prognosis varies; no standard therapy, consider therapy suitable for DLBCL or Hodgkin lymphoma