How is non-Hodgkin lymphoma (NHL) classified?

Updated: Feb 25, 2021
  • Author: Sanjay Vinjamaram, MD, MPH; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF) [64]
  • Revised European-American Classification of Lymphoid Neoplasms (REAL) [65]
  • World Health Organization (WHO) classification [66]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J. [1] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [65]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. [66]

National Cancer Institute’s Working Formulation (IWF)

Although considered obsolete, the IWF classification is still used mainly for historical data comparisons. [64]

Low-grade NHL subtypes in the IWF classification are as follows:

  1. Small lymphocytic, consistent with chronic lymphocytic leukemia
  2. Follicular, predominantly small-cleaved cell
  3. Follicular, mixed small-cleaved, and large cell

Intermediate-grade NHL subtypes in the IWF classification are as follows:

D. Follicular, predominantly large cell

E. Diffuse, small-cleaved cell

F. Diffuse mixed, small and large cell

G. Diffuse, large cell, cleaved, or noncleaved cell

High-grade NHL subtypes in the IWF classification are as follows:

H. Immunoblastic, large cell

I. Lymphoblastic, convoluted, or nonconvoluted cell

J. Small noncleaved-cell, Burkitt, or non-Burkitt

World Health Organization classification

The WHO modification of the REAL classification of NHL is based on morphology and cell lineage. Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms. [66]

The WHO classification subtypes for NHL precursors are as follows:

  • Precursor B–lymphoblastic leukemia/lymphoma
  • Precursor T–lymphoblastic lymphoma/leukemia

The WHO classification subtypes for peripheral B-cell neoplasms are as follows:

  • B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
  • B-cell prolymphocytic leukemia
  • Lymphoplasmacytic lymphoma/immunocytoma
  • Mantle cell lymphoma
  • Follicular lymphoma
  • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
  • Nodal marginal zone B-cell lymphoma (± monocytoid B cells)
  • Splenic marginal zone lymphoma (± villous lymphocytes)
  • Hairy cell leukemia
  • Plasmacytoma/plasma cell myeloma
  • Diffuse large B-cell lymphoma (DLBCL)
  • Burkitt lymphoma

The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:

  • T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
  • T-cell granular lymphocytic leukemia
  • Mycosis fungoides/Sézary syndrome
  • Peripheral T-cell lymphoma, not otherwise characterized
  • Hepatosplenic gamma/delta T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Extranodal T-/NK-cell lymphoma, nasal type
  • Enteropathy-type intestinal T-cell lymphoma
  • Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
  • Anaplastic large cell lymphoma, primary systemic type
  • Anaplastic large cell lymphoma, primary cutaneous type
  • Aggressive NK-cell leukemia

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