Non-Hodgkin's Lymphoma Disease Background

Last updated: 24 October 2025
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Introduction

Non-Hodgkin’s lymphoma is a heterogeneous group of lymphoproliferative malignancies formed by either B-cells or T-cell/natural killer (NK) cells. B-cell NHLs are 80-85% more common than T-cell/NK cell NHLs (15-20%). 

Epidemiology

Non-Hodgkin’s lymphoma is the 11th most common neoplasm in the world.  This is the most common hematologic cancer. NHL accounts for 90% of all malignant lymphomas.  The incidence of NHL increases with age, with most patients being >60 years old. Men have a higher rate of incidence and mortality globally and seen in almost all subtypes of NHL.  

Asia and Africa have lower incidence rates compared to Western and European countries.  However, the incidence of NHL is rising in some parts of Asia, with the greatest observed increase in East Asia. 

Etiology

The causes of non-Hodgkin’s lymphoma are:

  • Genetic aberrations and lesions of: 
    • p53 tumor suppressor gene deletions/alterations (eg Burkitt lymphoma [BL], follicular lymphoma [FL], mantle cell lymphoma [MCL])
    • Chromosomal deletions (eg chromosome 6q, chromosome 13q14)
    • Chromosomal translocations (eg FL - t[14;18][q32;q21], MCL - t[11;14][q13;q32])
  • Oncogenic viruses (eg Epstein-Barr virus, human T-cell lymphotropic virus I, human herpesvirus-8)

Advances in molecular genetics allowed better understanding of pathophysiology and further identification of the different subtypes of NHL. NHL subtypes are based on the malignant cell’s morphology, genetic features, immunohistological characteristics, and stage of maturation.



Non-Hodgkins Lymphoma_Disease BackgroundNon-Hodgkins Lymphoma_Disease Background
 

Risk Factors

The risk factors of non-Hodgkin’s lymphoma are the as follows: 

  • Acquired immunosuppression (previous organ/bone marrow/stem cell transplant, human immunodeficiency virus [HIV], acquired immunodeficiency syndrome [AIDS])
  • Congenital immunodeficiency syndromes
  • Old age
  • Positive family history of NHL
  • Positive medical history of Hodgkin lymphoma
  • Chemical exposures (pesticides, wood dust, epoxy glue, organic solvents, medication [eg Methotrexate, TNF-α inhibitors])
  • Radiation exposure

Classification

CLASSIFICATION ACCORDING TO STAGING  

The classification of non-Hodgkin’s lymphoma is based on the Lugano Modification of Ann Arbor Staging System.


Stage Features
Limited 
I Involvement of a single lymph node region or lymphoid structure (eg spleen, thymus, Waldeyer’s ring)
II* Involvement of ≥2 lymph node regions on the same side of the diaphragm
II bulky  Stage II with bulky disease 
 Advanced
III Involvement of lymph regions or structures on both sides of the diaphragm; lymph node region above the diaphragm with spleen involvement
IV Involvement of ≥1 extranodal site(s) beyond that designated E
For Stages I-II
E Involvement of a single extranodal site contiguous or proximal to known nodal site
Cotswold Modifications
(i) Suffix X to designate bulky disease as more than one third widening of the mediastinum or >10-cm maximum dimension of nodal mass
(ii) The number of anatomic regions involved should be indicated by a subscript (eg 113)
(iii) Stage III may be subdivided into: III1, with or without splenic, hilar, celiac, or portal nodes; III2, with para-aortic, iliac, mesenteric nodes
(iv) Staging should be identified as clinical stage or pathological stage
(v) Staging should be identified as clinical stage or pathological stage A new category of response to therapy, unconfirmed/uncertain complete remission should be introduced because of the persistent radiologic abnormalities of uncertain significance
*Divided into Stage II and Stage II bulky based on the Lugano Modification of Ann Arbor Staging System for primary nodal lymphomas
Stage II bulky defined as Stage II with bulky disease

CLASSIFICATION ACCORDING TO HISTOLOGIC TYPES  

The 2024 classification is based on the World Health Organization (WHO) classification of hematolymphoid tumors lymphoid neoplasms (5th edition) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms. It is further divided into precursor and mature subtypes. 

B-cell Lymphomas  

Precursor

  • Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL)

Mature

  • Large B-cell lymphomas
    • Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS): Most common histologic subtype
    • DLBCL/high-grade B-cell lymphomas with MYC and BCL2 rearrangements
    • High-grade B-cell lymphoma, NOS
    • T-cell/histiocyte-rich large B-cell lymphoma (LBCL)
    • ALK-positive LBCL
    • LBCL with IRF4 rearrangement
    • High-grade B-cell lymphoma with 11q aberrations
    • EBV-positive DLBCL
    • DLBCL associated with chronic inflammation
    • Fibrin-associated LBCL
    • Fluid overload-associated LBCL
    • Lymphomatoid granulomatosis
    • Primary LBCL of immune-privileged sites: Primary LBCL of the CNS, primary LBCL of the vitreoretina, primary LBCL of the testis
    • Primary cutaneous DLBCL, leg-type
    • Intravascular LBCL
    • Primary mediastinal LBCL
    • Mediastinal grey zone lymphoma
  • Follicular lymphoma (FL): The second most frequent NHL subtype
    • Classic FL (cFL)
    • Follicular large B-cell lymphoma (FLBCL)
    • FL with unusual cytological features (ucFL)
    • In situ follicular B-cell neoplasm
    • Duodenal-type FL
    • Pediatric-type FL
    • FL with predominantly diffuse growth pattern (dFL)
  • Kaposi’s sarcoma herpesvirus/human herpesvirus-8- (KSHV/HHV8)-associated B-cell lymphoid proliferations and lymphomas
    • Primary effusion lymphoma
    • KSHV/HHV8-positive DLBCL
    • KSHV/HHV8-positive germinotropic lymphoproliferative disorder
  • Pre-neoplastic and neoplastic small lymphocytic proliferations
    • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL): The most common leukemia among adults (Please see Chronic Lymphocytic Leukemia disease management chart)
    • Monoclonal B-cell lymphocytosis
  • Lymphoplasmacytic lymphoma/immunocytoma
  • Mantle cell lymphoma (MCL): In situ mantle cell neoplasms. leukemic non-nodal MCL
  • Burkitt lymphoma (BL)
  • Splenic B-cell lymphomas and leukemias:
    • Hairy cell leukemia (HCL)
    • Splenic marginal zone lymphoma (MZL)
    • Splenic diffuse red pulp small B-cell lymphoma
    • Splenic B-cell lymphoma/leukemia with prominent nucleoli
  • Primary cutaneous B-cell lymphoma (PCBCL)
  • Plasmacytoma/plasma cell myeloma
  • AIDS-related B-cell lymphoma
  • Marginal zone lymphoma (MZL)
    • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
    • Nodal MZL
    • Primary cutaneous MZL
    • Pediatric nodal MZL
  • Transformations of indolent B-cell lymphomas
  • Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation
    • Hyperplasias arising in immune deficiency/dysregulation
    • Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation
    • EBV-associated mucocutaneous ulcer
    • Lymphomas arising in immune deficiency/dysregulation
    • Inborn error of immunity-associated lymphoid proliferations and lymphomas
  • Tumor-like lesions with B-cell predominance
    • Reactive B-cell rich lymphoid proliferations that can mimic lymphoma
    • IgG4-related disease
    • Unicentric Castleman disease
    • Idiopathic multicentric Castleman disease
    • Kaposi’s sarcoma-associated herpesvirus-associated multicentric Castleman disease

T-cell/Natural Killer (NK)-cell Lymphomas  

Precursor

  • Acute lymphoblastic leukemia/LBL

Mature

  • T-cell prolymphocytic leukemia (T-PLL)
  • T-cell large granular lymphocytic leukemia (T-LGLL)
  • NK-large granular lymphocytic leukemia (chronic lymphoproliferative disorder of NK cells)
  • Mycosis fungoides (MF)/Sézary syndrome (SS)
  • Adult T-cell lymphoma/leukemia (ATLL)
  • Anaplastic large cell lymphoma (ALCL): ALK-positive ALCL, ALK-negative ALCL, breast implant-associated ALCL
  • ALCL, primary cutaneous type
  • Aggressive NK-cell leukemia (ANKL)
  • Peripheral T-cell lymphoma (PTCL)
  • Hepatosplenic T-cell lymphoma (HSTCL)
  • Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
  • EBV-positive NK-cell and T-cell lymphomas: EBV-positive nodal T- and NK-cell lymphoma, extranodal T-/NK-cell lymphoma, nasal type (ENKL)
  • Nodal T-follicular helper (TFH) cell lymphoma: Angioimmunoblastic-type, follicular-type, NOS
  • Follicular T-cell lymphoma (FTCL)
  • Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas
    • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
    • Enteropathy-associated T-cell lymphoma (EATL)
    • Intestinal T-cell lymphoma, NOS
    • Indolent T-cell lymphoma of the gastrointestinal (GI) tract (indolent clonal T-cell lymphoproliferative disorder of the GI tract)
    • Indolent NK-cell lymphoproliferative disorder of the GI tract