Non-Hodgkins Lymphoma

Overview

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies arising from B cells, T cells, or natural killer (NK) cells, characterised by clonal proliferation of lymphocytes at different stages of differentiation. It accounts for approximately 4–5% of all cancers worldwide, with incidence increasing with age and a median diagnosis in the sixth to seventh decade. B-cell lymphomas represent ~85–90% of cases. NHL encompasses a wide clinical spectrum from indolent (e.g., follicular lymphoma) to aggressive (e.g., diffuse large B-cell lymphoma) and highly aggressive subtypes (e.g., Burkitt lymphoma). Risk factors include immunosuppression, infections (EBV, H. pylori, HIV), autoimmune disease, and environmental exposures.

Definition

Lymphoma: Malignancy of lymphocytes arising from lymphoid tissues.
Non-Hodgkin lymphoma: Group of lymphoid malignancies excluding Hodgkin lymphoma, lacking Reed-Sternberg cells.
B-cell lymphoma: Malignancy derived from B lymphocytes (~85–90% of NHL).
Indolent vs aggressive lymphoma: Classification based on growth rate and clinical behaviour.

NHL is a spectrum of diseases, not a single entity.

Anatomy & Physiology

Lymphatic system: Network of lymph nodes, spleen, thymus, and lymphatic vessels responsible for immune surveillance
Lymph node structure: Cortex (B-cell follicles), paracortex (T-cells), medulla (plasma cells, macrophages)
B-cell maturation: Occurs in bone marrow → germinal centre reaction → antibody production
T-cell function: Cell-mediated immunity, immune regulation

Aetiology & Risk Factors

Aetiology

Genetic mutations (e.g., BCL2, MYC, BCL6 rearrangements)
Chronic antigenic stimulation
Viral oncogenesis

Risk Factors

Immunosuppression (HIV, post-transplant)
Infections: EBV, H. pylori, HTLV-1, hepatitis C
Autoimmune diseases (RA, Sjögren’s)
Environmental exposures (radiation, chemicals)
Increasing age

Chronic immune stimulation → increased risk of malignant transformation.

Pathophysiology

Genetic mutation in lymphocyte → clonal expansion
Dysregulated apoptosis (e.g., BCL2 overexpression)
Accumulation in lymph nodes and extranodal tissues
Disruption of normal immune function
Bone marrow infiltration → cytopenias

Clinical Manifestations

Painless, firm lymphadenopathy
B symptoms:
Fatigue and malaise
Splenomegaly or hepatomegaly
Extranodal disease:
- GI tract → abdominal pain, bleeding, obstruction
- CNS → headache, seizures, neurological deficits
- Skin → rash, nodules or plaques
- Testes → painless swelling
Compression symptoms from bulky lymphadenopathy
- Mediastinal mass → cough, dyspnoea, chest discomfort
- Superior vena cava obstruction → facial swelling, venous distension
- Abdominal/pelvic nodes → abdominal pain, bowel or urinary obstruction
Symptoms may vary by subtype

Non-Hodgkin lymphoma is more likely than Hodgkin lymphoma to present with extranodal involvement and can have a very variable clinical presentation.

Diagnosis

Diagnostic Criteria (WHO classification 2016+ / ICC 2022):

Histopathological confirmation required
Immunophenotyping + molecular classification essential

Investigations

Excisional lymph node biopsy (gold standard)
Immunohistochemistry (CD markers)
Flow cytometry
PET-CT for staging
Bone marrow biopsy
Blood tests: LDH, FBC

Differential diagnosis

Hodgkin lymphoma
Reactive lymphadenopathy
Leukemia

Excisional biopsy > FNA. Excisional biopsy is preferred over FNA in suspected lymphoma because it preserves lymph node architecture, enabling accurate classification and definitive diagnosis.

Classification

By Cell Type:

B-cell lymphomas
T-cell/NK-cell lymphomas

By Behaviour:

Indolent (slow-growing)
Aggressive
Highly aggressive

Table – Common Subtypes

Subtype	Behaviour	Key Feature
DLBCL	Aggressive	Most common NHL
Follicular lymphoma	Indolent	t(14;18), BCL2
Burkitt lymphoma	Highly aggressive	MYC translocation
Mantle cell lymphoma	Aggressive	Cyclin D1 overexpression

Treatment

Treatment depends on type of NHL and disease burden

Chemotherapy: R-CHOP = rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.
Adjuncts
- Methotrexate (CNS prophylaxis)
- Mesna (high dose cyclophosphamide or ifosfamide are at risk of haemorrhagic cystitis)
Radiotherapy
Targeted therapy (BTK inhibitors, CAR-T)
Stem cell transplant (selected patients)

Always assess risk of tumour lysis syndrome, infection, hepatitis B reactivation, fertility issues, and cardiac function before treatment.

Rituximab is used for CD20-positive B-cell lymphomas.

R-CHOP = rituximab + cyclophosphamide + doxorubicin + vincristine + prednisone.

Treatment Overview
NHL type	Usual first-line approach
Diffuse large B-cell lymphoma (DLBCL)	R-CHOP or similar chemoimmunotherapy; aggressive but potentially curable
Follicular lymphoma, asymptomatic low burden	Watch and wait
Follicular lymphoma, symptomatic/high burden	Anti-CD20 therapy ± chemotherapy, e.g. rituximab-based treatment
Burkitt lymphoma	Urgent intensive multi-agent chemotherapy + CNS prophylaxis
Mantle cell lymphoma	Immunochemotherapy ± BTK inhibitor; transplant considered in fit younger patients
Marginal zone lymphoma	Treat cause if present, e.g. H. pylori eradication in gastric MALT; radiotherapy or rituximab-based therapy if persistent/disseminated
Relapsed/refractory aggressive B-cell NHL	Salvage therapy, CAR-T, bispecific antibodies, or transplant depending on fitness and prior response

Complications & Prognosis

Complications

Bone marrow failure
Infections
Tumour lysis syndrome
CNS involvement

Prognosis

Variable depending on subtype
Indolent lymphomas: long survival, often incurable
Aggressive lymphomas: potentially curable
Poor prognostic factors:
- Age
- Elevated LDH
- Advanced stage
- Poor performance status