lymphoma
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lymphoma classification WHO 2022
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I now have enough material from the textbooks to provide a comprehensive overview and classification of lymphoma. Let me compile the answer.
Lymphoma: Overview & Classification
Lymphoma is the fifth most common malignancy in developed countries. It is a clonal proliferation of lymphoid cells - broadly split into Hodgkin lymphoma (HL) and the non-Hodgkin lymphomas (NHL). They differ in biology, spread pattern, and prognosis.
Key Differences: HL vs. NHL
| Feature | Hodgkin Lymphoma | Non-Hodgkin Lymphoma |
|---|---|---|
| Nodal spread | Orderly, contiguous | Noncontiguous, unpredictable |
| Sites | Axial nodes (cervical, mediastinal, para-aortic) | Multiple peripheral nodes |
| Extranodal | Rare | Common |
| Waldeyer ring / mesenteric | Rarely involved | Commonly involved |
| Defining cell | Reed-Sternberg cell | Depends on subtype |
- Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 13.7
1. Hodgkin Lymphoma (HL)
- Accounts for ~0.7% of all new cancers in the US (~9,000 cases/year)
- Bimodal age distribution: one peak in young adults, a second in adults >55 years
- First human cancer successfully cured with radiation + chemotherapy
Defining Pathology: Reed-Sternberg (RS) Cells
- Large cells (~45 µm), multinucleated or multi-lobed, with prominent inclusion-like "owl-eye" nucleoli (~5-7 µm)
- RS cells derive from germinal center or post-germinal center B cells (clonal IGH rearrangements confirmed)
- Despite B-cell origin, they fail to express B-cell genes including immunoglobulin - due to epigenetic reprogramming
- Key signaling: NF-κB activation (via EBV LMP-1, IκB mutations, or TNF pathway) rescues "crippled" GC B cells from apoptosis
- RS cells secrete cytokines (IL-5, IL-10, M-CSF, eotaxin) that recruit reactive T cells, eosinophils, histiocytes, and plasma cells - which comprise >90% of tumor bulk
- RS cells express PD-L1/PD-L2 (chromosome 9p gains), enabling immune evasion
WHO Classification of HL (5 subtypes)
Classical HL (cHL) - 95% of all HL - all share the same immunophenotype (CD15+, CD30+, CD45-):
| Subtype | Frequency | Notes |
|---|---|---|
| Nodular sclerosis (NS) | ~75% | Most common; bulky anterior mediastinal mass; only subtype without male preponderance |
| Mixed cellularity (MC) | 15-20% | More common in HIV, developing countries; aggressive |
| Lymphocyte-rich | ~5% | Favorable prognosis |
| Lymphocyte-depleted (LD) | <5% | Rarest; aggressive, advanced-stage |
Nodular Lymphocyte-Predominant HL (NLPHL) - 5%:
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Different immunophenotype: L&H ("popcorn") cells, CD20+, CD45+, CD15-, CD30-
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Origin: germinal center B cell
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Indolent course; middle-aged men; peripheral adenopathy; excellent survival
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Note: The 2022 International Consensus Classification (ICC) has renamed this "nodular lymphocyte-predominant B-cell lymphoma", dropping the "Hodgkin" designation entirely
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EBV not a feature (unlike cHL)
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Grainger & Allison's Diagnostic Radiology; Robbins, Cotran & Kumar Pathologic Basis of Disease
2. Non-Hodgkin Lymphoma (NHL)
- 85-90% are B-cell in origin in the US and Europe
- Incidence increases steadily with age (unlike HL's bimodal pattern)
- Classified by the 2016 WHO classification (integrating genetic data, morphology, immunophenotype, and molecular features)
Classification Framework (2016 WHO Revision)
The WHO classification divides NHL by:
- Cell of origin: B-cell vs. T/NK-cell
- Maturation stage: Precursor (immature) vs. peripheral (mature/post-thymic)
Mature B-Cell Neoplasms (most common)
| Entity | Notes |
|---|---|
| Diffuse large B-cell lymphoma (DLBCL), NOS | ~30% of all NHL worldwide; most common subtype |
| Follicular lymphoma | ~20%; more frequent in North America/Western Europe; indolent |
| Extranodal marginal zone/MALT lymphoma | 5-10%; often gastric (H. pylori-associated) |
| Small lymphocytic lymphoma (SLL/CLL) | Solid-phase equivalent of CLL |
| Mantle cell lymphoma | t(11;14); cyclin D1 overexpression; aggressive |
| Burkitt lymphoma | t(8;14); c-MYC; highly aggressive |
| Primary mediastinal (thymic) large B-cell lymphoma | Young women |
| Lymphoplasmacytic lymphoma / Waldenström's | IgM secretion |
| High-grade B-cell lymphoma (MYC + BCL2/BCL6 rearrangements) | "Double/triple hit"; very poor prognosis |
| Primary effusion lymphoma | HHV-8-associated; HIV patients |
| Plasmablastic lymphoma | HIV/immunosuppression-associated |
Mature T & NK Neoplasms (10-15% of NHL)
| Entity | Notes |
|---|---|
| Peripheral T-cell lymphoma, NOS | Most common T-cell NHL |
| Angioimmunoblastic T-cell lymphoma | |
| Anaplastic large-cell lymphoma (ALCL), ALK+ / ALK- | CD30+; better prognosis when ALK+ |
| Adult T-cell leukemia/lymphoma | HTLV-1 associated |
| Extranodal NK/T-cell lymphoma, nasal type | EBV-associated; endemic Asia |
| Mycosis fungoides / Sézary syndrome | Primary cutaneous T-cell lymphoma |
| Hepatosplenic T-cell lymphoma | Risk with anti-TNF agents |
Special Categories
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Post-transplant lymphoproliferative disorders (PTLD): EBV-driven; 4 broad types
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Lymphomas in HIV: Burkitt, DLBCL, primary effusion lymphoma, plasmablastic
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Goldman-Cecil Medicine, Table 171-4; Grainger & Allison's Diagnostic Radiology
Genetic Hallmarks
| Translocation | Lymphoma |
|---|---|
| t(8;14) | Burkitt lymphoma (MYC activation) |
| t(11;14) | Mantle cell lymphoma (cyclin D1) |
| t(14;18) | Follicular lymphoma (BCL2) |
| t(2;5) | ALCL, ALK+ (NPM-ALK fusion) |
Epidemiology & Risk Factors
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NHL risk is elevated ~20-fold after prior Hodgkin lymphoma treatment
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Associations: EBV (Burkitt, NLPHL, NK/T-cell), HTLV-1 (adult T-cell), H. pylori (gastric MALT), HHV-8 (primary effusion), HIV/immunosuppression
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Environmental: phenoxy herbicides (2,4-D), ionizing radiation, organic solvents, anti-TNF agents (hepatosplenic T-cell lymphoma), breast implants (ALCL)
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Heavy smoking: increased follicular lymphoma risk
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Low vitamin D: associated with recurrent lymphoma and worse outcomes
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Goldman-Cecil Medicine, Non-Hodgkin Lymphoma chapter
A Note on the 2022 Updates
The 2022 5th edition WHO classification and the 2022 International Consensus Classification (ICC) introduced further refinements - notably renaming NLPHL as "nodular lymphocyte-predominant B-cell lymphoma" and reclassifying several entities. Some provisional entities from 2016 have been elevated to full entities, and new molecular subtypes of DLBCL have been formally recognized. A recent review on high-grade B-cell lymphoma diagnosis (PMID: 39689165, 2025) provides updated guidance on the post-2022 diagnostic framework.
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