Non-Hodgkin Lymphoma (NHL)

Article Last Updated:15/01/2026

Lymphomas are broadly classified into 1) Hodgkin lymphoma and 2) non-Hodgkin lymphoma:

Hodgkin lymphoma is a distinct lymphoid malignancy (on its own) defined by the presence of Reed-Sternberg cells
Non-Hodgkin lymphoma represents a heterogeneous group of lymphoid malignancies characterised by the absence of Reed-Sternberg cells

Definition

Lymphomas are malignancies arising from lymphoid tissue, most commonly derived from B cells, but also T cells or NK cells.

Main lymphoid tissues affected in Hodgkin and non-Hodgkin lymphoma:

Hodgkin lymphoma	Non-Hodgkin lymphoma
Primarily affects and presents as nodal disease: Lymph node chains (classic) Spleen Extra-nodal involvement is uncommon	Can affect and present as BOTH: Nodal disease (lymph nodes and spleen), or Extra-nodal disease (essentially NOT lymph nodes and spleen) Mucosa-associated lymphoid tissue (MALT) (e.g. stomach, salivary glands, thyroid) Lung Liver Bone and bone marrow

Hodgkin lymphoma

Non-Hodgkin lymphoma

Primarily affects and presents as nodal disease:

Lymph node chains (classic)
Spleen

Extra-nodal involvement is uncommon

Can affect and present as BOTH:

Nodal disease (lymph nodes and spleen), or
Extra-nodal disease (essentially NOT lymph nodes and spleen)
- Mucosa-associated lymphoid tissue (MALT) (e.g. stomach, salivary glands, thyroid)
- Lung
- Liver
- Bone and bone marrow

Lymphoma may be confused with chronic lymphocytic leukaemia (CLL) because both arise from mature lymphocytes.

However, the distinction is based on the predominant site of disease:

Lymphoma is a disease that originates and predominantly presents as a solid tumour in lymphoid tissue
CLL is a disease that originates in and predominantly involves the bone marrow with spillover into the peripheral blood

Classification and Grading

NHLs are classified primarily by cell or origin and biological behaviour (aggressive or not). The following classification and listing is included for completeness (which is still non-exhaustive), exam-relevant ones are in bold, and further discussed below. ^[Ref1]^[Ref2]^[Ref3]

B-cell NHL (~85%)	Low-grade (indolent)	Follicular lymphoma Hairy cell leukaemia Marginal zone lymphomas (includes MALT lymphoma) Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma)



	High-grade (aggressive)	Diffuse large B-cell lymphoma (primary CNS lymphoma is a subtype) Burkitt lymphoma Mantle cell lymphoma Primary mediastinal large B-cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Chronic lymphocytic leukaemia and small lymphocytic lymphoma


T-cell NHL (~15%)	Low-grade (indolent)	Mycosis fungoides (cutaneous T-cell lymphoma) T-cell prolymphocytic leukaemia T-cell granular lymphocytic leukaemia
	High-grade (aggressive)	Enteropathy-associated T-cell lymphoma Adult T-cell leukaemia/lymphoma Anaplastic large cell lymphoma Peripheral T-cell lymphoma Angioimmunoblastic T-cell lymphoma Extranodal NK/T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma

Key information: ^[Ref]

B-cell lymphomas are significantly more common (85-90%) than T-cell or NK-cell lymphoma
Diffuse large B-cell lymphoma (aggressive) is the most common subtype of NHL
Follicular lymphoma (indolent) is the 2nd most common subtype of NHL

Epidemiology

Commonly affects older adults

Incidence rate increases steadily with age and peaks in >65 y/o

In contrast, Hodgkin lymphoma demonstrates a bimodal age distribution, typically affecting younger adults:

First peak in young adults (20-30 y/o)
Second peak in older adults (50-70 y/o)

Shared Clinical Features

Painless lymphadenopathy (often symmetrical / generalised)
Non-contiguous pattern of spread
- The spread “skips” between sites, involved areas are NOT next to each other anatomically
- E.g. cervical lymph nodes and abdominal nodes involved without mediastinal involvement in between
Extra-nodal disease (common and subtype-dependent)
B symptoms (more common in aggressive disease)

It is important to differentiate features suggestive of malignant lymphadenopathy (as seen in Hodgkin lymphoma) from reactive lymphadenopathy.

Feature	Malignant lymphadenopathy	Reactive lymphadenopathy
Mobility	Immobile / fixed to surrounding tissue	Mobile
Consistency	Hard / firm / rubbery	Soft / rubbery
Tenderness	Non-tender	Tender

In contrast, Hodgkin lymphoma has the following characteristic features:

Asymmetrical lymphadenopathy
Contiguous pattern of spread
Extra-nodal disease is uncommon

This is at least true for exams (text-book), but less clean-cut in real practice.

Type-Specific Features and Diagnosis

Definitive diagnosis of lymphoma requires a lymph node tissue biopsy ^[Ref]

Preferred: peripheral lymph node excisional biopsy
Alternative: CT-guided biopsy on internal nodes (e.g. mediastinal nodes)

In NHL, the diagnosis depends on immunophenotyping, morphology alone cannot define the disease (unlike in Hodgkin lymphoma, which can be diagnosed by the presence of Reed Sternberg cells).

Be aware that fine needle aspiration is inadequate to diagnose lymphoma, as the lymph node architecture is lost and immunophenotyping may be incomplete.

If excisional tissue biopsy is not feasible, core biopsy is an alternative (but inferior to excisional biopsy).

Very high-yield gene translocations to be aware of:

MYC t(8;14) → Burkitt lymphoma
BCL t(14;18) → follicular lymphoma

B-Cell NHL

High-grade (aggressive) B-cell NHL:

Diffuse large B-cell lymphoma ^[Ref1]^[Ref2]	Most common type of NHL Risk factors / association Mutations in BCL, p53 genes HIV infection (5-17x risk) Immunosuppression (e.g. organ transplantation) Hep C infection Richter transformation (CLL transforms into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma) Key presentation Rapidly enlarging, painless lymphadenopathy B symptoms (fever, night sweats, weight loss) in some patients Extra-nodal involvement in 30-40% cases Primary CNS lymphoma (an AIDS-defining condition) Primary mediastinal (thymic) lymphoma (often in young female adults)
Burkitt lymphoma ^[Ref1]^[Ref2]	Most common in children and young adults 3 variants Sporadic EBV infection (endemic – most common in Africa) HIV infection (15-100x risk) (immunodeficiency-associated) Key presentation Sporadic → rapidly enlarging abdominal mass (esp. in the ileocolic region) Endemic → rapidly growing tumours of the jaw / periorbital region (abdominal involvement is also common nowadays) Immunodeficiency-associated → nodal + extranodal disease Biopsy: classic “starry sky” pattern Describes macrophages that have engulfed apoptotic debris serving as the “stars”and enlarged, malignant lymphocytes comprising the remainder of the lesion NOT diagnostic alone, and not seen in all cases MYC gene translocation t(8;14)
Mantle cell lymphoma ^[Ref]	Marked male predominance (~70% cases) Key presentation: Generalised lymphadenopathy Splenomegaly is common Advanced-stage disease (stage III/IV at diagnosis in >80% cases) t(11;14) → cyclin D1 overexpression

Low-grade (indolent) B-cell NHL:

Follicular lymphoma ^[Ref1]^[Ref2]	Typical presentation Slowly progressive generalised lymphadenopathy Splenomegaly and bone marrow involvement is common Extra-nodal disease and B symptoms are less common Biopsy: nodular (follicular) growth pattern that resemble normal germinal centres but lack normal architecture BCL2 gene translocation t(14;18)
MALT lymphoma ^[Ref]	MALT lymphoma is a subtype of marginal zone lymphoma Important notes: Chronic H. pylori infection increases the risk of gastric MALT lymphoma Sjogren’s syndrome is strongly associated with salivary gland lymphoma Hashimoto’s thyroiditis increases the risk of thyroid lymphoma (MALT lymphoma and diffuse large B-cell lymphoma)
Hairy cell leukaemia ^[Ref]	Marked male predominance BRAF V600 E mutation Splenomegaly is common, also cytopaenias (esp. monocytopaenia) Characteristic “hairlike” surface projections on blood smear, a “fried-egg” appearance on bone marrow biopsy
Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma) ^[Ref]	MGUS is a precursor condition, with a small annual risk of progression Characterised by the presence of monoclonal IgM in the serum Presentation: Typically present as anaemia, thrombocytopaenia, hepatosplenomegaly, lymphadenopathy IgM-related complications include hyperviscosity syndrome (headache, blurred vision, mucosal bleeding)

T-cell NHL

Mycosis fungoides ^[Ref]	Low-grade (indolent) tumour Clinical presentation (3 stages): patch → plaque → tumour Lesions may be hypopigmented or hyperpigmented and can persist for years before progression Early lesions: erythematous, scaly patches or thin plaques on non-sun exposed areas Advanced lesions: thicker plaques and tumors, sometimes ulcerating
Enteropathy T-cell lymphoma ^[Ref]	High-grade (aggressive tumour) Associated with coeliac disease Clinical presentation is very non-specific Abdominal pain, diarrhoea B symptoms Jejunal obstruction and perforation is common
Adult T-cell leukaemia/lymphoma ^[Ref]	High-grade (aggressive tumour) Caused by chronic infection of HTLV-1 Endemic in Japan, the Caribbean, parts of Africa, and South America Clinical course is very heterogenous

Management

The key management principles largely depend on the disease category: ^[Ref]

Category	Typical subtypes	Mainstay management
Aggressive (high-grade)	Diffuse large B-cell lymphoma, Burkitt lymphoma	Chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin [also known as hydroxydaunorubicin], vincristine [Oncovin], prednisolone)
Indolent (low-grade)	Follicular lymphoma	Asymptomatic → watch and wait Symptomatic → rituximab monotherapy or rituximab + another agent
Infection-driven	Gastric MALT lymphoma	1st line: H. pylori eradication therapy (see the Helicobacter Pylori Infection article)

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