Non-Hodgkin’s lymphoma (NHL) comprises a heterogeneous group of malignant lymphoid neoplasms arising from B lymphocytes, T lymphocytes, or natural killer (NK) cells. NHLs are characterized by uncontrolled proliferation of lymphoid cells within lymph nodes, extranodal tissues, bone marrow, or other organs.

NHL is classified according to:

• Cell of origin (B-cell, T-cell, or NK-cell)

• Stage of lymphocyte maturation (immature or mature)

• Biological behavior (indolent or aggressive)

• Histological and molecular characteristics

Common subtypes include:

Indolent lymphomas

• Follicular lymphoma

• MALT lymphoma

• Nodal marginal zone lymphoma

• Splenic marginal zone lymphoma

• Small lymphocytic lymphoma

• Mycosis fungoides

Aggressive lymphomas

• Diffuse large B-cell lymphoma (DLBCL)

• Burkitt lymphoma

• Mantle cell lymphoma

• Primary CNS lymphoma

• Peripheral T-cell lymphoma

NHL is generally highly responsive to chemotherapy and radiotherapy, with outcomes varying according to subtype and stage at diagnosis.

Epidemiology

Non-Hodgkin’s lymphoma is among the most common hematological malignancies worldwide.

Epidemiological features include:

• Can occur at any age

• More common in adults than children

• Slight male predominance

• B-cell lymphomas account for approximately 85–90% of cases

• Incidence is increased among immunocompromised individuals

• HIV infection significantly increases risk

Risk factors

Immunodeficiency states

Including:

• HIV infection

• Congenital immunodeficiency disorders

• Post-transplant immunosuppression

Viral infections

Associated infections include:

• Epstein-Barr virus (EBV)

• Human T-cell lymphotropic virus type 1 (HTLV-1)

• Hepatitis B virus

• Hepatitis C virus

• Human herpesvirus 8 (HHV-8)

Chronic infections and inflammation

Examples include:

• Helicobacter pylori infection

• Chronic autoimmune diseases

• Chronic inflammatory disorders

Autoimmune diseases

Including:

• Rheumatoid arthritis

• Sjögren syndrome

• Systemic lupus erythematosus

Environmental and occupational exposures

• Pesticides

• Herbicides

• Industrial chemicals

• Radiation exposure

Genetic factors

Certain inherited and acquired genetic abnormalities contribute to lymphomagenesis.

Pathophysiology

NHL develops from malignant transformation of lymphocytes at different stages of maturation.

Pathogenesis involves:

1. Genetic mutations affecting cell growth and apoptosis

2. Clonal expansion of abnormal lymphoid cells

3. Progressive infiltration of lymph nodes

4. Spread to extranodal organs

5. Bone marrow involvement in advanced disease

The biological behavior varies considerably:

Indolent lymphoma

• Slow-growing

• Often presents with advanced-stage disease

• Long survival but frequent relapse

Aggressive lymphoma

• Rapid growth

• Potentially life-threatening if untreated

• Often curable with intensive treatment

Common extranodal sites include:

• Gastrointestinal tract

• Bone marrow

• Skin

• Central nervous system

• Testes

• Paranasal sinuses

Clinical presentation

Clinical manifestations vary according to subtype, disease burden, and organ involvement.

The most common presentation is painless lymphadenopathy.

Symptoms

Lymph node-related symptoms

• Painless neck swelling

• Axillary swelling

• Inguinal swelling

• Progressive enlargement of lymph nodes

B symptoms

• Unexplained weight loss

• Persistent fever

• Drenching night sweats

Constitutional symptoms

• Fatigue

• Malaise

• Loss of appetite

Symptoms due to extranodal involvement

Gastrointestinal involvement

• Abdominal pain

• Abdominal distension

• Gastrointestinal bleeding

Bone marrow involvement

• Fatigue

• Easy bruising

• Recurrent infections

CNS involvement

• Headache

• Altered mental status

• Cranial nerve deficits

• Seizures

Symptoms of mediastinal disease

• Cough

• Dyspnoea

• Chest pain

Symptoms of superior vena cava obstruction (SVCO)

• Facial swelling

• Neck vein distension

• Dyspnoea

• Cough

Clinical signs

Lymphatic system

• Painless lymphadenopathy

• Cervical lymph node enlargement

• Axillary lymphadenopathy

• Inguinal lymphadenopathy

Abdominal findings

• Hepatomegaly

• Splenomegaly

• Abdominal masses

Skin findings

• Cutaneous plaques

• Nodules

• Erythematous lesions in mycosis fungoides

Signs of advanced disease

• Cachexia

• Pallor

• Peripheral oedema

• Performance status deterioration

Signs of SVCO

• Facial oedema

• Upper limb swelling

• Dilated chest wall veins

Differential diagnosis

• Hodgkin lymphoma

• Tuberculous lymphadenitis

• Chronic lymphocytic leukemia

• Metastatic carcinoma

• Reactive lymphadenopathy

• Infectious mononucleosis

• HIV-associated lymphadenopathy

• Sarcoidosis

• Leukemia

• Castleman disease

Diagnostic criteria

Non-Hodgkin’s lymphoma should be suspected in patients presenting with:

• Persistent painless lymphadenopathy

• Hepatomegaly or splenomegaly

• B symptoms

• Mediastinal mass symptoms

• Unexplained constitutional symptoms

Diagnosis requires:

• Histopathological confirmation from tissue biopsy

• Immunophenotypic characterization using immunohistochemistry

Investigations

Laboratory investigations

Full blood count (FBC), differential count and peripheral blood film

Used to assess:

• Anaemia

• Leukocyte abnormalities

• Thrombocytopenia

Lactate dehydrogenase (LDH)

Important prognostic marker and indicator of tumour burden.

Renal function tests

• Urea

• Electrolytes

• Creatinine

Liver function tests

• Albumin

• AST

• Bilirubin

• Alkaline phosphatase

Serum calcium

May be elevated in advanced disease.

Serum uric acid

Assesses tumour burden and risk of tumour lysis syndrome.

Pregnancy test

Recommended in females of child-bearing age before chemotherapy.

Viral screening

• Hepatitis B

• Hepatitis C

• HIV

Imaging investigations

Chest X-ray (CXR)

Evaluates mediastinal involvement.

CT scan of chest, abdomen and pelvis

Assesses:

• Nodal disease

• Organ involvement

• Disease staging

PET/CT

Useful for:

• Staging

• Treatment response assessment

• Detection of residual disease

Bone marrow assessment

Bone marrow aspirate and trephine biopsy

Used to determine:

• Bone marrow involvement

• Disease stage

Histopathological investigations

Tissue biopsy

Required for definitive diagnosis and subtype classification.

Immunohistochemistry (IHC)

Used to determine:

• Cell lineage

• CD20 status

• Prognostic markers

Cardiac assessment

MUGA scan or echocardiography

Recommended before anthracycline-based chemotherapy.

Central nervous system evaluation

Lumbar puncture and CSF cytology

Indicated in:

• Suspected CNS involvement

• Testicular lymphoma

• Paranasal sinus lymphoma

• Extradural or paraspinal disease

• High-risk CNS relapse

Staging

Non-Hodgkin’s lymphoma is staged using the Ann Arbor Classification.

Stage I

Involvement of a single lymph node region or single extranodal site.

Stage II

Involvement of two or more lymph node regions on the same side of the diaphragm.

Stage III

Lymph node involvement on both sides of the diaphragm.

Stage IV

Diffuse involvement of extranodal organs such as:

• Bone marrow

• Liver

• Central nervous system

Systemic symptoms are designated by:

• A = absence of B symptoms

• B = presence of B symptoms

Management

Management depends on:

• Histological subtype

• Stage of disease

• CD20 status

• Performance status

• Presence of extranodal involvement

Treatment modalities include:

• Chemotherapy

• Immunotherapy

• Radiotherapy

• Surgery in selected cases

• Supportive care

Non-pharmacological treatment

Radiotherapy

NHL is highly radiosensitive.

Indications include:

• Stage IA disease

• Stage IIA disease

• Consolidation following chemotherapy

• Localized residual disease

• Palliation

Mantle or inverted-Y radiotherapy

• 40 Gy in 20 fractions over 4 weeks

Critical organs should be appropriately shielded.

Involved-field radiotherapy (IFRT)

• 46 Gy in 23 fractions over 4.5 weeks

Splenectomy

Recommended in selected patients with:

• Splenic marginal zone lymphoma

• Symptomatic splenomegaly

Supportive care

Includes:

• Infection prevention

• Nutritional support

• Blood transfusion when indicated

• Management of tumour lysis syndrome

• Psychosocial support

Pharmacological treatment

Indolent lymphoma

Stage I and Stage II disease

Treatment options include:

• Involved-node radiotherapy

• R-CHOP followed by radiotherapy

• R-CVP followed by radiotherapy

R-CHOP regimen

Rituximab – 375 mg/m² – intravenous infusion over 3 hours – day 1

AND

Cyclophosphamide – 750 mg/m² – intravenous infusion over 1 hour – day 1

AND

Doxorubicin – 50 mg/m² – intravenous infusion over 15 minutes – day 1

AND

Vincristine – 1.4 mg/m² (maximum 2 mg) – intravenous infusion over 10 minutes – day 1

AND

Prednisolone – 100 mg – oral – once daily – days 1–5

Frequency:

• Every 21 days

Duration:

• 6–8 cycles

Aggressive CD20-positive lymphoma

Includes:

• Diffuse large B-cell lymphoma

• Mantle cell lymphoma

• Burkitt lymphoma

• Primary CNS lymphoma

• Aggressive T-cell lymphomas

Recommended regimen

R-CHOP regimen

Rituximab – 375 mg/m² – intravenous infusion over 3 hours – day 1

AND

Cyclophosphamide – 750 mg/m² – intravenous infusion over 1 hour – day 1

AND

Doxorubicin – 50 mg/m² – intravenous infusion over 15 minutes – day 1

AND

Vincristine – 1.4 mg/m² (maximum 2 mg) – intravenous infusion over 10 minutes – day 1

AND

Prednisolone – 100 mg – oral – once daily – days 1–5

Frequency:

• Every 21 days

Duration:

• 6–8 cycles

Primary CNS lymphoma

Standard CHOP-based regimens have poor penetration across the blood-brain barrier.

Methotrexate regimen

Methotrexate – 8 mg/m²/day – intravenous – twice weekly until remission is achieved

Cutaneous T-cell lymphoma (Mycosis fungoides)

Localized disease

• Topical corticosteroids

Advanced disease or Sézary syndrome

• Systemic therapy according to specialist oncology protocols

Management according to underlying subtype

Follicular lymphoma

• Radiotherapy for localized disease

• R-CHOP or R-CVP for advanced disease

MALT lymphoma

• Helicobacter pylori eradication if gastric involvement is present

• Radiotherapy or systemic therapy when indicated

Splenic marginal zone lymphoma

• Splenectomy may be beneficial

• Systemic therapy for advanced disease

Diffuse large B-cell lymphoma

• R-CHOP remains the standard first-line regimen

Primary CNS lymphoma

• High-dose methotrexate-based treatment

• CNS-directed therapy

Mycosis fungoides

• Topical corticosteroids

• Radiotherapy

• Systemic therapy for advanced disease

Referral

All patients with suspected or confirmed NHL should be referred to specialized hematology or oncology centres.

Urgent referral indications

• Superior vena cava obstruction

• Airway compromise

• Spinal cord compression

• CNS involvement

• Rapidly enlarging lymph nodes

• Tumour lysis syndrome

• Severe cytopenias

Complications

Disease-related complications

• Bone marrow failure

• Superior vena cava obstruction

• CNS involvement

• Organ infiltration

• Tumour lysis syndrome

• Recurrent infections

Treatment-related complications

Chemotherapy

• Neutropenia

• Febrile neutropenia

• Anaemia

• Thrombocytopenia

• Cardiotoxicity

• Peripheral neuropathy

Radiotherapy

• Mucositis

• Skin toxicity

• Secondary malignancies

Prognosis

Prognosis depends on:

• Histological subtype

• Disease stage

• International Prognostic Index (IPI)

• LDH level

• Age

• Performance status

• Response to therapy

Indolent lymphomas generally have prolonged survival but frequent relapse. Aggressive lymphomas may be curable with appropriate treatment, particularly when diagnosed early.

Prevention

Primary prevention

• Early treatment of chronic infections

• HIV prevention and treatment

• Reduction of occupational chemical exposure

• Appropriate management of autoimmune diseases

Secondary prevention

• Early evaluation of persistent lymphadenopathy

• Prompt investigation of B symptoms

• Screening for viral infections before immunosuppressive therapy

Tertiary prevention

• Regular follow-up after treatment

• Monitoring for relapse

• Prevention and management of treatment-related complications