Non-Hodgkin lymphoma (NHL) is a malignant proliferation of lymphocytes (B and T cells). Like Hodgkin lymphoma, NHL often presents with constitutional signs; however, NHL is associated with painless lymphadenopathy. B cell NHL’s include Burkitt lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, and marginal zone lymphoma. T cell NHL’s include adult T cell lymphoma and mycosis fungoides. Management is primarily through chemotherapy.

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burkitt lymphoma histopathology

Image: “Malignant B cell lymphocytes seen in Burkitt lymphoma, stained with hematoxylin and eosin (H&E) stain.” License: Public Domain

Epidemiology and Etiology

Lymphoma is a neoplastic proliferation of lymphoid cells. 

  • Non-Hodgkin lymphoma (60%)
  • Hodgkin lymphoma (40%)


  • Accounts for 4% of all cancers
    • Most common hematopoietic cancer
  • Occurs in both children and adults
  • Risk of developing NHL increases with age
    • > 50% of cases are in those > 65 years old


Malignant proliferation of mature or progenitor B cell, T cells, and (rarely) natural killer cells associated with

  • Genetic translocations that result in the overexpression of transcription factors
    • t(14;18) causes ↑ Bcl-2
    • t(8;14) causes ↑ c-myc
    • t(11;14) causes ↑ Cyclin D1
  • Infections
    • Epstein-Barr virus (EBV)
    • Human T cell leukemia virus (HTLV)
    • H. pylori 
  • Chronic inflammatory conditions
    • Hashimoto thyroiditis
    • Sjögren syndrome
    • Chronic gastritis

Video Gallery

Non-hodgkin Lymphomas – Lymphoma by Paul Moss, PhD
Lymphoma in Children by Brian Alverson, MD

Clinical Presentation and Types of NHL

The clinical presentation varies depending on the type of lymphoma. The hallmark symptom of Non-Hodgkin lymphoma is painless lymphadenopathy.

Indolent lymphomas, insidious onset of 

  • Lymphadenopathy 
  • Hepato or splenomegaly
  • Cytopenias
    • Anemia
    • Neutropenia
    • Thrombocytopenia

Aggressive lymphomas

  • Constitutional, “B” symptoms
    • Low-grade fever
    • Night sweats
    • Weight loss
  • Rapidly growing mass
    • May result in SVC obstruction
      • Facial swelling and congestion
      • Venous distension in the upper limbs/neck 
      • Pleural effusion
  • Elevated LDH and uric acid

Common Non-Hodgkin lymphomas

Type Risk Factors and Genetics Notes
B cell origin


Follicular lymphoma Driven by

  •  t(14;18)
  • Overexpression of Bcl-2
Population: late adulthood

Classic presentation:

  • Indolent onset/course
  • Painless lymphadenopathy

Complications: progression to diffuse large B cell lymphoma

Diffuse large  B cell lymphoma

(most common NHL)

Arrises sporadically or from transformation of low-grade lymphoma (e.g., follicular lymphoma) Population: late adulthood

Classic presentation:

  • Enlarging lymph node or extranodal mass
  • Extremely aggressive
Burkitt lymphoma Associated with

  • EBV

Driven by 

  • t(8;14)
  • Overexpression of c-myc
Population: adolescents or young adults

Classic presentation: extranodal mass

  • African form: jaw mass
  • Sporadic form: abdominal mass
  • Aggressive

Histology: “Starry sky” appearance

Mantle cell lymphoma Driven by

  • t(11;14) 
  • Overexpression of Cyclin D1
Population: late adulthood, males

Classic presentation:

  • Painless lymphadenopathy 
  • Highly aggressive, often presents in late-stage disease
Marginal zone lymphoma  Associated with

    • Hashimoto thyroiditis
    • Sjögren syndrome
  • H. pylori
Population: adults with chronic inflammatory conditions

Clinical presentation:

  • Indolent onset
  • Painless lymphadenopathy

MALToma: marginal zone lymphoma of mucosal sites

  • Symptoms may mimic gastritis
  • Gastric MALToma may regress with treatment of H. pylori
T cell origin


Adult T cell lymphoma Associated with

  • HTLV
Population: adults

Geographic location: Japan, West Africa, Caribbean

Clinical presentation:

  • Cutaneous lesions
  • Lytic bone lesions
  • Hypercalcemia
Mycosis fungoides Associated with 

  • Staphylococcus aureus
  • Borrelia species 
Population: adults

Clinical presentation:

  • Skin patches/plaques

Histology: atypical CD4+ cells with cerebriform nuclei

Complications: progression to T cell leukemia

Video Gallery

Lymphadenopathy: Non-Hodgkin Lymphoma (NHL) – White Blood Cell Pathology by Carlo Raj, MD
Lymphadenopathy: Follicular Lymphoma and Lymphoid Hyperplasia – White Blood Cell Pathology by Carlo Raj, MD
Lymphadenopathy: Burkitt Lymphoma – White Blood Cell Pathology by Carlo Raj, MD

Diagnostics and Staging


  • Excisional lymph node biopsy
    • Can be excised or core-needle
    • Histology is key.
  • Initial laboratory work-up
    • CBC with white cell differential and platelet count
    • Electrolytes, BUN, and Cr
    • LFTs
    • LDH
    • Uric acid
  • Imaging: CT and PET
    • Staging 
    • Guided biopsy
    • Measuring response to therapy
  • Unique circumstances
    • Endoscopy/gastroscopy
      • If suspected MALToma
    • Lumbar Puncture 
      • If CNS symptoms
    • Thoraco or paracentesis
      • If suspected pleural effusion or ascites
    • Bone Marrow biopsy 
      • If aggressive lymphoma suspected


  • Has limited importance for treatment of NHL
  • More important for targeting therapies for Hodgkin lymphoma
  • Subclasses: E: extranodal extension
    1. Involvement of 1 lymph node group
    2. Involvement of 2 or more lymph node groups on the same side of the diaphragm
    3. Involvement of lymph node groups on both sides of the diaphragm
    4. Disseminated, widespread disease

Image: Hodgkin disease staging. By Lecturio.


Treatment is based on many factors including histological subtype, stage, and patient comorbidities.

  • For localized disease (stage I or II)
    • Local radiation
    • Small course of chemotherapy
  • For advanced disease (stage III, IV, or “B” symptoms)
    • Rituximab and CHOP
      • C – cyclophosphamide
      • H – adriamycin (hydroxydaunorubicin)
      • O – vincristine (oncovin)
      • P – prednisone
  • Before beginning treatment, patients may need a baseline evaluation of their
    • Cardiac function
    • Pulmonary function
    • Fertility goals (if childbearing age)


  • International prognostic index (IPI) for NHL assigns 1 point for each of the following:
    • Age > 60 years
    • Stage III or IV disease
    • Elevated serum LDH
    • Performance status
    • More than 1 extranodal site

IPI Scoring

Risk Points 5-year survival
Low 0—1 73 %
Low-intermediate 2 51 %
High-intermediate 3 43 %
High 4—5 26 %

Clinical Relevance

  • Hodgkin Lymphoma: Neoplastic proliferation of Reed-Sternberg cells (B cells) within the lymph nodes that classically presents with “B” symptoms. Histology is positive for CD15 and CD30. 
  • Multiple Myeloma: The most common primary tumor of the bone in people aged 40–50 years old; occurs secondary to monoclonal plasma cell proliferation. Associated with monoclonal M protein spike, hypercalcemia, lytic bone lesions/back pain, renal involvement, and blood smear showing rouleaux formation.
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