Non-Hodgkin's lymphoma is a heterogeneous group of lymphoproliferative malignancies.
It is the most common hematologic cancer.
The most common subtypes are the diffuse large B-cell and follicular lymphoma. The subtypes are based on the malignant cell's morphology, genetic features, immunohistological characteristics, and stage of maturation.


Physical Examination
  • Node-bearing areas
  • Spleen, liver enlargement especially in follicular lymphoma (FL), hairy cell lymphoma (HCL), Mycosis fungoides (MF)/Sézary syndrome (SS), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL)
  • Examination of the testicles suggested in extranodal natural killer/T-cell lymphoma (ENKL)
  • Skin examination
    • Inclusion of Waldeyer’s ring in ENKL
    • Identification of type of skin lesion in patients with SS

Laboratory Examinations

  • Complete blood count, with differential & platelet count
    • Peripheral monoclonal B lymphocyte count ≥5x109/L - CLL
    • B lymphocytes ≤5x109/L with lymphadenopathy &/or splenomegaly may indicate SLL
  • Metabolic panel, including LDH levels & serum beta-2-microglobulin
  • Serum uric acid levels
  • Hepatitis B screening is recommended for patients with FL, HCL, MCL, DLBCL, BL
  • Testing for hepatitis C is also suggested
  • Viral etiology of NHL should also be examined (eg human T-cell lymphoma virus [HTCLV], Epstein Barr virus [EBV], HIV)
    • ENKL patients with ≥6.1x107 copies/mL may suggest inferior disease-free survival rates
    • HIV testing is suggested for patients with AIDS-related BCL & BL


  • Optional diagnostic test when diagnosis cannot be established with flow cytometry alone

Lymph node biopsy

  • Indicated for nodes >1.5 cm diameter, firm, irregular, clustered, fixed palpable nodes
  • Also used for suspected SLL patients with lymphadenopathy &/or splenomegaly, & abnormal peripheral blood count
  • Excisional biopsies are preferred

Core needle biopsy

  • Suggested when lymph nodes are not accessible

Bilateral core biopsy

  • Recommended before initiation of radioimmunotherapy (RIT)

Bone marrow biopsy

  • Bone marrow aspiration & trephine biopsy are recommended
  • Indicated for specimens >1.6 cm & clinical stage I-II FL
  • Bone marrow aspiration is utilized in cases where lymph nodes are unaccessible for biopsy

Skin Biopsy

  • Indicated for cutaneous B-cell lymphoma
    • Incisional/excisional/punch biopsy preferred over shave biopsy
  • May also be performed for diagnosis of acute T-cell lymphoma/leukemia


Computed Tomography (CT)
  • CT scan of the chest, abdomen & pelvic area are recommended for patients with suspected/diagnosed FL, HCL, MF/SS, MCL, BL, cutaneous BCL, ENKL
  • CT scan of the neck is suggested in FL, primary T-cell lymphoma, MF/SS, MCL & BL
  • Head CT may be performed for patients with possible CNS involvement esp in PTCL, BL & ATLL
  • Use of contrast medium is recommended for patients with FL, HCL & ENKL
  • More sensitive & specific when combined with PET
Magnetic Resonance Imaging (MRI)
  • Indicated for FL, ATLL
  • MRI of the nasal cavity, hard palate, anterior fossa & nasopharynx are recommended for ENKL
Positron Emission Tomography (PET)
  • Recommended for localized diseases & to identify occult sites of the disease or histologic transformation
  • Aids in evaluating patient response to treatment
  • Indicated in FL, DLBCL, BL, MCL, cutaneous BCL, ENKL
Endoscopy/Endoscopic Ultrasound (EU)
  • May be performed as endoscopy alone or via ultrasound-guided endoscopy
  • Suggested for patients with suspected gastric mucosa-associated lymphatic tissue (MALT), MCL, ATLL (upper GI endoscopy)
Echocardiogram &/or Multi-Gated Acquisition (MUGA) Scan
  • Performed when Anthracycline/Anthracenedione treatment is anticipated
  • Indicated for FL, PTCL, BL, ENKL

Molecular & Genetic Analysis

  • Effectively differentiates NHL subtypes by identifying the specific cell lineage using antibodies
  • Lymph node & spleen tissue samples are preferred over bone marrow tissue samples for cytogenic analysis
  • Detects immunoglobulin heavy chain variable (IGHV) mutational status
Immunophenotyping by Flow Cytometry
  • Fast & reliable method of identifying single cell populations of surface antigens
  • Uses antibodies/markers to identify the presence & proportion of surface antigens by using antibodies/markers
  • Used in FL, prolymphocytic T-cell lymphoma, MF/SS (expanded CD4 & cells with increased CD4/CD8 ratio), BL (bcl2 via cerebrospinal fluid analysis)
  • Suggested for confirmation of clonality of B cells in CLL/SLL
Fluorescence in situ hybridization (FISH)
  • Detects chromosomal abnormalities (11q,13q, 17p deletion, trisomy 12) & highly sensitive for known detectable translocation during initial diagnosis
  • Used in FL (t[14;18], bcl2 & bcl6 rearrangements), MCL (t[11;14] translocation), chronic lymphocytic leukemia (CLL) (t[11;14] translocation with specific CCND1/IGH probes or CCND1 break-apart probe); DLBCL (MYC gene arrangements)
  • Recommended for diagnosis of BL (t[8;14])
Immunohistochemistry (IHC) Panel
  • Aids in identification & characterization of the immunophenotype of most lymphomas
  • Some identified lymphoma foci via IHC panel identification:
    • BCL2 - FL
    • CD10 - BL
    • CD5/CD23 - CLL
    • CD5 - B-cell prolymphocytic leukemia (B-PLL)
    • CD30 - anaplastic large cell lymphomas (ALCL)
    • Ki-67 - FL, MCL, BL (>95%), Cutaneous BCL
    • Pan T-cell markers & T-cell lymphoid antibodies
Polymerase Chain Reaction (PCR)
  • Detects specific abnormal DNA translocations & T cell receptor clonality & B cell clonality that may be the origin of leukemic cells
  • bcl gene rearrangements: B-cell lymphoma, FL, DLBCL
  • T-cell receptor gene rearrangements: MF/SS, MCL (CCND2 gene - 55%)
  • MYC gene rearrangements: DLBCL (2-11%)

Other Procedures

Lumbar puncture
  • Used for patients with possible CNS involvement with overt symptoms
  • Indicated for DLBCL patients with paranasal sinus, testicular, epidural, HIV-associated, bone marrow with large cells, >2 extranodal sites & elevated LDH levels

Hepatitis B Testing

  • Recommended to identify increased risk of viral reactivation prior to treatment initiation


Classification According To Staging
  • Developed by the American Joint Committee on Cancer: Ann Arbor Staging Classification & 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 two or more 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 extranodal site(s) beyond that designated E
    For All Stages
    A No symptoms
    B Fever (>38°C [100.4° F]), drenching sweats, weight loss (10% body weight over 6 month)
    For Stages I-III
    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 (e.g., 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 & 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

  • Current classification based on the World Health Organization (WHO) modification of the Revised European American Lymphoma (REAL) classification
  • Further subdivided into precursor & mature subtypes
B-cell Lymphomas
  • Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL)
  • B-cell prolymphocytic leukemia (B-PLL)
  • Lymphoplasmacytic lymphoma/immunocytoma
  • Mantle cell lymphoma (MCL)
  • Follicular lymphoma (FL)
  • Burkitt lymphoma (BL)
  • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
  • Marginal zone lymphoma (MZL)
    • Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
    • Nodal MZL
    • Splenic MZL
  • Hairy cell leukemia (HCL)
  • Plasmacytoma/plasma cell myeloma
  • Diffuse large B-cell lymphoma (DLBCL)
  • AIDS-related B-cell lymphoma
  • Primary cutaneous B-cell lymphoma (PCBCL)
T-cell/Natural Killer (NK)-cell Lymphomas
  • Acute lymphoblastic leukemia/LBL
  • T-cell prolymphocytic leukemia (T-PLL)
  • T-cell chronic lymphocytic leukemia
  • T-cell large granular lymphocytic leukemia
  • Mycosis fungoides (MF)/Sézary syndrome (SS)
  • Enteropathy-type intestinal T-cell lymphoma
  • Adult T-cell lymphoma/leukemia (ATLL)
  • Anaplastic large cell lymphoma, primary systemic type
  • Anaplastic large cell lymphoma, primary cutaneous type
  • Aggressive NK-cell leukemia
  • Peripheral T-cell lymphoma (PTCL)
  • Hepatosplenic gamma/delta T-cell lymphoma
  • Subcutaneous panniculitis-like T-cell lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Extranodal T-/NK-cell lymphoma, nasal type (ENKL)
Classification According to Prognostic Group
  • Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia)
  • Splenic MZL
  • Primary cutaneous anaplastic large cell lymphoma
  • Follicular lymphoma
  • Marginal zone lymphoma
  • Diffuse large B-cell lymphoma
  • Follicular large cell lymphoma
  • Anaplastic large cell lymphoma
  • Extranodal NK-/T-cell lymphoma
  • Lymphomatoid granulomatosis
  • Lymphoblastic lymphoma
  • Burkitt lymphoma/diffuse small noncleaved-cell lymphoma
  • Enteropathy-type intestinal T-cell lymphoma
  • Polymorphic post-transplantation lymphoproliferative disorder
  • Mediastinal large B-cell lymphoma (primary mediastinal large B-cell lymphoma)
  • Intravascular large B-cell lymphoma (intravascular lymphomatosis)
  • Adult T-cell leukemia/lymphoma
  • Mantle cell lymphoma
  • True histiocytic lymphoma
  • Primary effusion lymphoma
  • Angioimmunoblastic T-cell lymphoma
  • Peripheral T-cell lymphoma
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