Non-Hodgkin's Lymphoma Disease Background

Last updated: 16 July 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.



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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 developed by the American Joint Committee on Cancer: Ann Arbor Staging Classification and the Cotswold Modifications.


Stage Features
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
III Involvement of lymph regions or structures on both sides of the diaphragm
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 2016 classification is based on the World Health Organization (WHO) modification of the Revised European American Lymphoma (REAL) classification. These are further subdivided into precursor and mature subtypes.  

B-cell Lymphomas  

Precursor

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

Mature

  • Diffuse large B-cell lymphoma (DLBCL): Most common histologic subtype
  • Follicular lymphoma (FL): The second most frequent NHL subtype
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL): The most common leukemia among adults
  • B-cell prolymphocytic leukemia (B-PLL)
  • Lymphoplasmacytic lymphoma/immunocytoma
  • Mantle cell lymphoma (MCL)
  • Burkitt lymphoma (BL)
  • Hairy cell leukemia (HCL)
  • Plasmacytoma/plasma cell myeloma
  • AIDS-related B-cell lymphoma
  • Primary cutaneous B-cell lymphoma (PCBCL)
  • Marginal zone lymphoma (MZL)
    • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
    • Nodal MZL
    • Splenic MZL

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

Precursor

  • Acute lymphoblastic leukemia/LBL


Mature

  • T-cell prolymphocytic leukemia (T-PLL)
  • T-cell chronic lymphocytic leukemia
  • T-cell large granular lymphocytic leukemia (T-LGLL)
  • Mycosis fungoides (MF)/Sézary syndrome (SS)
  • Enteropathy-type intestinal T-cell lymphoma (EATL)
  • Adult T-cell lymphoma/leukemia (ATLL)
  • Anaplastic large cell lymphoma (ALCL), primary systemic type
  • Angioimmunoblastic T-cell lymphoma (AITL)
  • ALCL, primary cutaneous type
  • Aggressive NK-cell leukemia (ANKL)
  • Peripheral T-cell lymphoma (PTCL)
  • Hepatosplenic gamma/delta T-cell lymphoma (HSTCL)
  • Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)
  • Extranodal T-/NK-cell lymphoma, nasal type (ENKL)
  • Nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype (nodal PTCL, TFH)
  • Follicular T-cell lymphoma (FTCL)
  • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)