Internal Medicine

Non-Hodgkin lymphoma (NHL)


Non-hodgkin lymphoma is a type of lymphoma characterized by the absence of Reed-Sternberg cells.

Lymphomas are a heterogeneous group of malignant tumours of the haematopoietic system and are characterized by the aberrant proliferation of mature lymphoid cells or their precursors.

  • Lymphomas can be divided into 2 major entities:
    • Hodgkin’s lymphoma (HL) (10%)
    • Non-Hodgkin’s lymphoma (NHL) (90%)


Non-hodgkin lymphoma (NHL) subtypes:

Characterized by the absence of Reed-Sternberg cells.
  • Follicular lymphoma (F-NHL) (22.0%)
  • Marginal zone lymphoma (MZL) (9.0%)
  • Mantle cell lymphoma (MCL) (6.0%)
  • Diffuse large B-cell lymphoma (DLBCL) (M/C worldwide & India, 35.0%)
  • Burkitt Lymphoma (1.0%)
  • T-cell lymphoma (7.0%)

International Working Group classification (old):

On the basis of morphology and clinical behaviour:
  • Low grade: CLL/SLL, follicular lymphoma
  • Intermediate grade: Mantle cell and marginal cell lymphoma
  • High grade: Diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma
Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204.
  • M/aggressive NHL: DLBCL
  • M/rapidly progressive human tumour: Burkitt’s lymphoma
  • Pediatric NHLs are high grade and aggressive


  • All NHLs are more common in males (except MALT lymphomas)


Genetic mutation:

Lymphoid neoplasmMost characteristic translocation
Mantle-cell lymphomat (11;14)
Follicular lymphomat (14;18)
Diffuse large B-cell lymphomat (14;18)
Burkitt lymphomat (8:14), t (2;8), t (8;22)
MALT lymphomat (11;18)


All Non-Hodgkin’s lymphomas involve white pulp of spleen except:

  • Hairy cell leukemia
  • Hepatosplenic lymphoma

Origin of mature B cell lymphomas:

B cell lymphomas are cancers that develop from the malignant transformation of B lymphocytes at various stages of ontogeny. Most are of mature B cell origin, and revolve around the germinal centre (GC) reaction, a critical step in which B cells are subject to intense proliferation and genomic remodelling processes — namely, somatic hypermutation and class-switch recombination — to generate memory B cells and plasma B cells that produce high-affinity antibodies. From naive B cells to memory B cells, most differentiation steps are associated with a malignant B cell subtype (defined as the cell of origin (COO)) on the basis of classic histological definitions and gene expression profiling. The COO assumes that B cell malignancies are ‘frozen’ at a given B cell differentiation stage arising in a particular location of the B cell follicle. For example, follicular lymphoma (FL) is a follicle-related B cell lymphoma that is considered the malignant counterpart of normal ‘frozen’ GC B cells. Unmutated mantle cell lymphoma (UM-MCL) originates from mantle zone B cells, marginal zone lymphoma (MZL) resembles marginal zone B cells whereas Burkitt lymphoma (BL) resembles dark zone B cells. Based on the COO, distinct diffuse large B cell lymphoma (DLBCL) molecular subtypes are defined as not otherwise specified DLBCL (DLBCL NOS), whereas, the GC B cell-like DLBCL corresponds to B cells that are arrested at various stages of the GC transit (from dark zone to light zone B cells) and the activated B cell-like DLBCL seems to derive from GC B cells en route to plasma cell differentiation, resembling plasmablasts. BCR, B cell receptor; FDC, follicular dendritic cell; M-MCL, mutated mantle cell lymphoma; MHC, major histocompatibility complex; TCR, T cell receptor; TFH, follicular T helper. | Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015). Return to ref 44 in article

Clinical features

Painless lymphadenopathy (enlarging over months):

  • M/C sites: Mediastinal/neck nodes (60%) >> splenic > axillary > abdominal > hilar/inguinofemoral
  • Bulky disease: Transverse diameter of tumor mass > 10 cm and confers a poorer prognosis in early-stage patients.


  • Fevers, chills, night sweats or unexplained weight loss >10% of body weight
  • Frequent in patients with advanced-stage or bulky disease
The Calgary Guide |

Extranodal involvement

GIT > skin > CNS

  • Gastrointestinal lymphoma (M/C extranodal NHL, 5–20% cases)
  • Primary cutaneous lymphomas (PCL) (#2 M/C extranodal NHL)
  • Priamry CNS lymphoma

Gastrointestinal lymphoma: Stomach > Small intestine > Colon > Esophagus

  • M/C extranodal site in immunocompromised (except HIV cases):
    • MALTomas: Stomach
    • Follicular lymphoma: Duodenum
    • Burkitt’s lymphoma: Terminal ileum
    • Mantle cell lymphoma: Terminal ileum, Jejunum, Colon
    • Enteropathy-associated T cell lymphoma (EATL): Jejunum

Primary cutaneous lymphomas (PCL)

  • M/C type: Mycosis fungoides (MF) > Sezary syndrome

Central Nervous system:

  • M/C extranodal site in HIV
  • M/C histological subtype in HIV: Diffuse large B cell lymphoma (DLBCL)
  • Primary CNS lymphoma (histologically, DLBCL) is one of the AIDS-defining malignancies


Tumour lysis syndrome (TLS) (in aggressive tumours):

Potential complication of therapy due to rapid growth rates of tumour cells caused by release of cellular products overwhelming the kidneys’ excretory capacity.
  • Kidney damage → Electrolyte imbalances (hyperkalemia, hyperphosphatemia, hyperuricemia) → Kidney failure
  • : IV hydration, hypouricemic agents (allopurinol, rasburicase) & dialysis (if indicated)


Core-needle/excisional biopsy (no FNAC):


B cell precursors Derived lymphomas/leukaemia Immunophenotype
Pro-B cell Pro-B cell ALL CD34, CD19, CD79a
Pre-B cell Pre-B cell ALL CD19, CD79a, CD10, Tdt, Cytoplasmic Ig
Mature B cell CLL/SLL CD19, CD79a,CD 20, CD21, CD22, surface IgM, CD 23, CD5
Mantle zone Mantle zone lymphoma CD19, CD79a,CD 20, CD21, CD22, surface IgM, CD5
Germinal center/Follicular center Follicular lymphoma



Diffuse large B-cell lymphoma

Burkitt lymphoma

CD 79a, CD 79b, CD 19, CD 20, CD,21,CD22, CD10, CD 23, Bcl-2


CD10, Cd23, Bcl-6

CD19, CD20, CD22, CD79a, CD10, Bcl-6

Memory B cells Extranodal marginal zone lymphoma CD19, CD79a,CD 20, surface Ig

Ann Arbor staging system with Cotswolds modification:

Staging system for lymphomas, both in Hodgkin’s lymphoma (formerly designated Hodgkin’s disease) and non-Hodgkin lymphoma (abbreviated NHL)
  • Principal stages (determined by location):
    • Stage I: Single site (nodal/extranodal)
    • Stage II: ≥ 2 LN on same side of diaphragm (number of anatomic sites should be indicated in a suffix: e.g. II2)
    • Stage III: LN/structures on both sides of diaphragm:
      • III1: With/without splenic, hilar, celiac or portal nodes
      • III2: With paraaortic, iliac or mesenteric nodes
    • Stage IV: Diffuse, disseminated, several extranodal ± nodal involvement
  • Modifiers (can be appended to some stages):
    • A: No B symptoms
    • B: B symptoms present
    • S (spleen)
    • “extranodal”
    • (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)

St.Jude’s/Murphy classification: Pediatric NHL

  • I: Single tumour site/node extending to GI/mediastinum
  • II: Multiple LN involvement (on one side of diaphragm), single GI lesion
  • III: Extensive GI involvement (non-resectable) with mediastinal involvement, paraspinal/epidural tumour
  • IV: Stage III + CNS/bone marrow involvement



  • Indolent cancer: ABVD regimen
    • Adriamycin (adv. effect: cardiomyopathy)
    • Bleomycin (adv. effect: pulmonary fibrosis)
    • Vincristine (adv. effect: peripheral neuropathy)
    • Dacarbazine (adv. effect: myelosuppression)
  • Aggressive cancer: R-CHOP regimen
    • Rituximab
    • Cyclophosphamide (adv effect: hemorrhagic cystitis)
    • Doxorubicin
    • Vincristine (adv. effect: peripheral neuropathy)
    • Prednisone

NHL in pregnancy:

  • 1st trimester: Termination
  • 2nd trimester: CHOP chemotherapy


International prognostic index (IPI):

  • Age > 60 years
  • ↑ Serum lactate dehydrogenase (LDH)
  • Performance status ≥ 2 (ECOG) or ≤70 (Karnofsky)
  • Ann Arbor Stage III/IV
  • ≥ 2 sites of extranodal involvement

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