Lymphoma (Adult)

1. Overview

Lymphomas are a heterogeneous group of malignancies arising from lymphoid tissue, representing the fifth most common cancer in developed countries. [1] They are broadly classified into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), based on the presence or absence of Reed-Sternberg cells on histology. This fundamental distinction drives profoundly different biological behaviour, staging, treatment approaches, and prognosis. [2]

Hodgkin lymphoma accounts for approximately 10% of all lymphomas and is characterised by the presence of pathognomonic Reed-Sternberg cells within a reactive inflammatory background. It exhibits a bimodal age distribution (peaks at 20-30 years and > 55 years), contiguous lymph node spread, and excellent cure rates exceeding 80% with combination chemotherapy and radiotherapy. [3]

Non-Hodgkin lymphomas are more common, comprising over 90% of lymphomas, and represent a diverse collection of over 60 distinct subtypes with variable aggressiveness. The most common NHL subtype is diffuse large B-cell lymphoma (DLBCL), accounting for 30-40% of cases, followed by follicular lymphoma (20-25%). [4] NHL typically presents with non-contiguous spread and requires immunophenotyping for accurate classification and targeted therapy selection. The introduction of rituximab (anti-CD20 monoclonal antibody) has revolutionised outcomes for B-cell lymphomas. [5]

Early recognition of lymphoma, particularly oncological emergencies such as superior vena cava obstruction, spinal cord compression, and tumour lysis syndrome, is critical for optimal patient outcomes. Distinguishing benign reactive lymphadenopathy from malignant lymphoma and initiating timely biopsy is a core clinical skill across multiple specialties.

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2. Epidemiology

Incidence and Prevalence

Lymphoma is the fifth most common cancer in the UK, with approximately 14,000 new cases diagnosed annually (comprising ~4,000 HL and ~10,000 NHL cases). [1] The age-standardised incidence rate is approximately 20 per 100,000 population for NHL and 3 per 100,000 for HL. [6]

Age Distribution

Hodgkin Lymphoma: Exhibits classical bimodal age distribution with first peak in the third decade (20-30 years, predominantly nodular sclerosing subtype) and second peak after age 55 years (mixed cellularity subtype). [3]

Non-Hodgkin Lymphoma: Incidence increases steadily with age, with median age at diagnosis of 65-70 years for most subtypes. Notable exceptions include:

• Burkitt lymphoma: Children and young adults (median age 30 years)
• Primary mediastinal B-cell lymphoma: Young adults (median age 35 years)
• Mantle cell lymphoma: Older adults (median age 68 years) [4]

Risk Factors

Immunodeficiency States: HIV infection (200-fold increased risk of NHL), iatrogenic immunosuppression (post-transplant lymphoproliferative disorder), and primary immunodeficiencies. [7]

Infectious Agents:

• Epstein-Barr virus (EBV): Associated with endemic Burkitt lymphoma, post-transplant lymphoproliferative disorder, and HL
• Helicobacter pylori: MALT lymphoma of the stomach (70-80% association)
• Human T-lymphotropic virus-1 (HTLV-1): Adult T-cell leukaemia/lymphoma
• Hepatitis C virus: Associated with marginal zone lymphoma and DLBCL [8]

Autoimmune Disorders: Sjögren syndrome (44-fold increased risk of MALT lymphoma), rheumatoid arthritis, systemic lupus erythematosus, and coeliac disease (enteropathy-associated T-cell lymphoma). [9]

Occupational Exposures: Agricultural chemicals, pesticides, herbicides, and organic solvents have been implicated in epidemiological studies, though causative mechanisms remain unclear. [10]

Genetic Predisposition: First-degree relatives of lymphoma patients have 2-3-fold increased risk; specific genetic syndromes include ataxia-telangiectasia, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative syndrome. [11]

Geographic Variation

Hodgkin lymphoma shows higher incidence in developed countries. Endemic Burkitt lymphoma demonstrates geographic clustering in equatorial Africa, linked to EBV infection and malaria co-endemicity. HTLV-1-associated adult T-cell leukaemia/lymphoma is endemic in southwestern Japan, the Caribbean, and parts of Africa. [8]

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3. Aetiology & Pathophysiology

Hodgkin Lymphoma

Cellular Origin

Hodgkin lymphoma is characterised by rare malignant Reed-Sternberg cells and their mononuclear variants (Hodgkin cells), which typically represent less than 1% of the tumour mass. These cells are derived from germinal centre or post-germinal centre B cells that have undergone somatic hypermutation and class-switch recombination. [12]

Reed-Sternberg cells are large (> 20 μm), binucleated or multinucleated cells with prominent eosinophilic nucleoli, creating the pathognomonic "owl's eye" appearance. They are surrounded by a reactive inflammatory background comprising T lymphocytes, eosinophils, plasma cells, histiocytes, and fibroblasts. [3]

Immunophenotype

Classical Hodgkin lymphoma Reed-Sternberg cells express:

• CD30 (100%)
• CD15 (75-85%)
• PAX5 (weak/variable)
• Usually negative for CD20, CD45 (LCA)

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) shows distinct features:

• CD20+ (B-cell marker)
• CD30- and CD15-
• "Popcorn cells" rather than classical Reed-Sternberg cells [12]

Pathophysiological Mechanisms

Reed-Sternberg cells evade immune destruction through multiple mechanisms:

• Overexpression of PD-L1 and PD-L2 (immune checkpoint ligands)
• Secretion of cytokines (IL-5, IL-13, TGF-β) that recruit immunosuppressive cells
• Loss of MHC class I/II expression reducing antigen presentation
• Activation of NF-κB, JAK/STAT, and PI3K/AKT signalling pathways promoting survival [13]

Non-Hodgkin Lymphoma

Pathogenesis

NHL arises from malignant transformation of B cells (85%), T cells (12%), or NK cells (3%) at various stages of differentiation. Pathogenesis involves:

1. Chromosomal Translocations:

   • t(14;18)(q32;q21): BCL2-IGH fusion in follicular lymphoma (85% cases) causing BCL2 overexpression and apoptosis resistance [14]
   • t(11;14)(q13;q32): CCND1-IGH fusion in mantle cell lymphoma causing cyclin D1 overexpression and cell cycle dysregulation
   • t(8;14)(q24;q32): MYC-IGH fusion in Burkitt lymphoma causing MYC overexpression and rapid proliferation

2. Oncogene Activation: MYC, BCL2, BCL6 activation through translocations or mutations

3. Tumour Suppressor Loss: TP53, CDKN2A/B deletion or mutation

4. Immune Evasion: Loss of MHC expression, PD-L1 overexpression, immune checkpoint activation

5. Microenvironment Interactions: Malignant cells interact with follicular dendritic cells, T cells, and stromal cells creating a supportive niche [15]

WHO Classification (2016, Revised 2022)

Mature B-Cell Neoplasms (most common):

• Diffuse large B-cell lymphoma (DLBCL), NOS (30-40%)
• Follicular lymphoma (20-25%)
• Marginal zone lymphoma (extranodal MALT, nodal, splenic) (8-10%)
• Mantle cell lymphoma (6%)
• Burkitt lymphoma (2%)
• Primary mediastinal large B-cell lymphoma (2-3%)
• Lymphoplasmacytic lymphoma (Waldenström macroglobulinaemia) (1%)

Mature T-Cell and NK-Cell Neoplasms (10-15%):

• Peripheral T-cell lymphoma, NOS (4%)
• Angioimmunoblastic T-cell lymphoma (2%)
• Anaplastic large cell lymphoma (ALK+ and ALK-) (2%)
• Extranodal NK/T-cell lymphoma, nasal type (1%)
• Adult T-cell leukaemia/lymphoma (endemic regions) [16]

Molecular Subtypes

DLBCL Cell-of-Origin Classification (gene expression profiling):

• Germinal centre B-cell-like (GCB): Better prognosis, 60% 5-year OS
• Activated B-cell-like (ABC): Worse prognosis, 35% 5-year OS
• Unclassified: Intermediate prognosis [17]

Hans algorithm (immunohistochemistry surrogate):

• CD10, BCL6, MUM1 expression patterns predict GCB vs ABC subtypes

Double-Hit and Triple-Hit Lymphomas: Lymphomas with MYC rearrangement plus BCL2 and/or BCL6 rearrangement (5-10% of DLBCL) have particularly aggressive behaviour and poor prognosis with standard R-CHOP, requiring intensified regimens. [18]

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4. Clinical Presentation

Symptoms

Lymphadenopathy (75-80% of cases)

Hodgkin Lymphoma: Typically presents with painless, progressive enlargement of cervical or supraclavicular lymph nodes (60-70% of cases). Nodes are firm, rubbery, and mobile. Contiguous spread is characteristic—disease extends from one node group to adjacent groups in an orderly fashion. [3]

Non-Hodgkin Lymphoma: Presents with painless lymphadenopathy in varied distributions depending on subtype. Spread is non-contiguous. Common sites:

• Cervical/supraclavicular (50%)
• Axillary (20%)
• Inguinal (15%)
• Mediastinal (PMBCL, lymphoblastic lymphoma)
• Retroperitoneal (follicular lymphoma) [4]

Alcohol-Induced Pain: Rare (less than 5%) but highly specific symptom for Hodgkin lymphoma—patients report pain in affected lymph nodes within minutes of alcohol consumption. Mechanism unknown. [19]

B Symptoms (30-40% of cases)

Constitutionally defined symptoms indicating advanced disease and adverse prognosis, incorporated into Ann Arbor staging as "B" designation:

B symptoms are more common in Hodgkin lymphoma (40%) than NHL (20%), and indicate worse prognosis (lower 5-year survival by ~10-15%). Presence of B symptoms upstages disease (e.g., IIA → IIB) and influences treatment intensity. [20]

Pruritus (15-30% in HL)

Generalised itching without rash, often severe and refractory to antihistamines. More common in Hodgkin lymphoma (particularly nodular sclerosis subtype). Not classified as a B symptom but may indicate active disease. Mechanism involves cytokine release (IL-31, IL-5). [21]

Extranodal Symptoms

Gastrointestinal Involvement (10-15% of NHL):

• Abdominal pain, nausea, early satiety (gastric MALT lymphoma)
• Change in bowel habit, bleeding (intestinal lymphoma)
• B symptoms less common in localised GI lymphomas

Bone Marrow Involvement (20-30% of NHL):

• Cytopenias: Anaemia (fatigue, dyspnoea), thrombocytopenia (bruising, bleeding), neutropenia (infections)
• More common in follicular lymphoma (40-50% have BM involvement at diagnosis)

CNS Involvement (2-5% of aggressive NHL):

• Headache, focal neurological deficits, cranial nerve palsies
• High risk in Burkitt lymphoma, lymphoblastic lymphoma, testicular DLBCL
• CSF analysis and MRI brain/spine essential in high-risk cases [22]

Skin Involvement:

• Mycosis fungoides/Sézary syndrome (cutaneous T-cell lymphomas)
• Secondary skin involvement in systemic lymphoma (5%)

Signs

Lymph Node Examination

Character: Firm, rubbery (lymphoma) vs hard (metastatic carcinoma) vs soft, tender (reactive)

Size: Pathological lymphadenopathy typically > 1 cm; > 2 cm warrants urgent investigation

Distribution: Document all involved sites systematically (cervical, supraclavicular, axillary, epitrochlear, inguinal, femoral)

Mobility: Mobile (early disease) vs fixed/matted (advanced disease or surrounding tissue infiltration)

Overlying Skin: Usually normal; erythema/warmth suggests infection; skin involvement indicates aggressive disease

Waldeyer's Ring Examination

Tonsillar enlargement (particularly unilateral) may indicate lymphoma involvement; oropharyngeal examination essential.

Hepatosplenomegaly

• Hepatomegaly (10-15% of cases): Suggests advanced disease (Stage IV)
• Splenomegaly (30-40% of HL, 10-20% of NHL): Palpable spleen suggests splenic involvement; imaging required for confirmation
• Massive splenomegaly: Characteristic of splenic marginal zone lymphoma [23]

Signs of Oncological Emergencies

Superior Vena Cava Obstruction: Facial/neck swelling, dilated chest wall veins, cyanosis, respiratory distress—requires urgent imaging and treatment

Spinal Cord Compression: Back pain, lower limb weakness, sensory level, sphincter dysfunction—MRI spine within 24 hours and urgent oncology/neurosurgery referral

Tumour Lysis Syndrome: Acute kidney injury, hyperkalaemia, hyperphosphataemia, hypocalcaemia—preventable with hydration and allopurinol/rasburicase prophylaxis

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5. Differential Diagnosis

Lymphadenopathy has a broad differential diagnosis; systematic evaluation is essential to avoid missing malignancy or serious infection.

Red Flags Warranting Urgent Investigation

• Lymph nodes > 2 cm persisting > 4-6 weeks
• Supraclavicular lymphadenopathy (Virchow's node)
• Hard, fixed, or rapidly enlarging nodes
• Associated B symptoms
• Unexplained splenomegaly
• Generalised lymphadenopathy with cytopenias

NICE Guidelines (NG12): Refer urgently (suspected cancer pathway, appointment within 2 weeks) for unexplained lymphadenopathy. [24]

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6. Investigations

First-Line Investigations

Complete Blood Count (FBC)

• Anaemia: Normocytic normochromic anaemia of chronic disease (30-40%); autoimmune haemolytic anaemia (5% of HL, positive DAT)
• Thrombocytopenia: Bone marrow involvement or immune-mediated destruction
• Neutropenia: Bone marrow involvement or chemotherapy effect
• Lymphocytosis: May suggest CLL rather than lymphoma; circulating lymphoma cells rare except in leukaemic phase (mantle cell, Burkitt)
• Eosinophilia: Classic association with Hodgkin lymphoma (10-15% of cases) [25]

Biochemistry

• Lactate Dehydrogenase (LDH): Elevated in aggressive lymphomas (Burkitt, DLBCL); reflects tumour burden and cell turnover; independent adverse prognostic factor
• Albumin: Low albumin indicates advanced disease and poor prognosis
• Uric Acid: Elevated in high-grade lymphomas; risk factor for tumour lysis syndrome
• Renal Function: Baseline essential; may be impaired by tumour infiltration, hypercalcaemia, or urate nephropathy
• Liver Function Tests: Hepatic involvement (elevated ALP, GGT); hyperbilirubinaemia may indicate bile duct compression
• Calcium: Hypercalcaemia in aggressive NHL (Burkitt, DLBCL) or bony involvement
• Beta-2 Microglobulin: Prognostic marker; elevated in aggressive disease [26]

Inflammatory Markers

• ESR: Elevated in Hodgkin lymphoma (included in Hasenclever prognostic index)
• CRP: Elevated in aggressive disease; non-specific but useful for monitoring

Serology

• HIV Test: Mandatory in all lymphoma patients (consent required); HIV-associated lymphomas are aggressive and require modified treatment
• Hepatitis B and C Serology: Hepatitis B reactivation risk with rituximab and chemotherapy; prophylactic antivirals required if HBsAg or anti-HBc positive
• EBV Serology: May be useful in suspected EBV-associated lymphomas

Diagnostic Investigations

Lymph Node Biopsy (Gold Standard)

Excisional Biopsy (preferred):

• Entire lymph node removed (> 1 cm preferred)
• Preserves architecture essential for diagnosis
• Superior to core biopsy or FNA for initial diagnosis
• Allows comprehensive histology, immunohistochemistry, flow cytometry, and molecular studies [27]

Core Needle Biopsy:

• Acceptable alternative if excisional biopsy not feasible
• Multiple cores (4-6) required
• Useful for deep-seated nodes (retroperitoneal, mediastinal) under CT or ultrasound guidance

Fine Needle Aspiration (FNA):

• NOT recommended for initial lymphoma diagnosis—insufficient material for subtyping
• May be useful for confirming relapse in patients with known lymphoma

Histopathological Analysis

Hodgkin Lymphoma:

• Presence of Reed-Sternberg cells (large binucleated cells with prominent nucleoli)
• Reactive inflammatory background (T cells, eosinophils, histiocytes)
• Immunophenotype: CD30+, CD15+, PAX5 (weak), CD20- (usually), CD45-
• Subclassification: Nodular sclerosis (70%), mixed cellularity (20%), lymphocyte-rich (5%), lymphocyte-depleted (5%)
• NLPHL: "Popcorn cells," CD20+, CD15-, CD30- [12]

Non-Hodgkin Lymphoma:

• Architecture: Follicular vs diffuse growth pattern
• Cell morphology: Small vs large cell; cleaved vs non-cleaved nuclei
• Immunophenotyping (essential): CD20, CD3, CD5, CD10, BCL2, BCL6, MUM1, Ki-67
• Flow cytometry: Clonality (kappa/lambda light chain restriction)
• Molecular studies:
  • "FISH for translocations: t(14;18) BCL2, t(11;14) CCND1, t(8;14) MYC"
  • MYC/BCL2/BCL6 rearrangements (double/triple-hit status in DLBCL)
  • IgH gene rearrangement (clonality confirmation) [16]

Staging Investigations

CT Chest, Abdomen, Pelvis (CT CAP)

• Contrast-Enhanced CT: Standard staging modality for all lymphomas
• Assesses:
  • Lymph node involvement (cervical, mediastinal, axillary, abdominal, pelvic, inguinal)
  • Extranodal disease (liver, spleen, lung, kidneys, bone)
  • Complications (SVC obstruction, ureteric obstruction, bowel obstruction)
• Measurable disease documented for response assessment (RECIST criteria)

PET-CT (FDG-PET)

• Standard for Hodgkin Lymphoma and Aggressive NHL: Superior to CT alone for staging and response assessment
• Advantages:
  • Detects metabolically active disease (higher sensitivity than CT)
  • Differentiates active disease from residual masses post-treatment
  • Interim PET after 2-4 cycles chemotherapy guides treatment adaptation (Deauville criteria)
  • End-of-treatment PET determines complete metabolic response [28]
• Deauville 5-Point Scale (PET response assessment):
  • "Score 1-3: Negative (complete metabolic response)"
  • "Score 4: Probably positive"
  • "Score 5: Positive (active disease)"
• Not routinely used: Indolent lymphomas (follicular, marginal zone) due to low FDG avidity

Bone Marrow Biopsy

Indications:

• Staging of NHL (particularly follicular, mantle cell, marginal zone)
• Unexplained cytopenias
• Not routinely required in Hodgkin lymphoma if PET-CT negative [29]

Technique:

• Posterior iliac crest aspiration and trephine biopsy
• Immunohistochemistry and flow cytometry if infiltration suspected

Lumbar Puncture (CSF Analysis)

Indications (CNS prophylaxis/staging):

• Burkitt lymphoma (mandatory)
• Lymphoblastic lymphoma (mandatory)
• DLBCL with high-risk features:
  • Testicular involvement
  • Paranasal sinus involvement
  • Breast involvement
  • Epidural involvement

  • 1 extranodal site + elevated LDH

  • High IPI score (4-5) [22]

CSF Studies:

• Cell count, cytology, flow cytometry, protein, glucose
• Positive if malignant cells identified or lymphocytosis with clonal population

Additional Investigations

Echocardiogram/MUGA Scan: Baseline cardiac function assessment before anthracycline chemotherapy (doxorubicin cardiotoxicity risk)

Pulmonary Function Tests: Baseline before bleomycin (pulmonary fibrosis risk)

Fertility Counselling: Sperm banking/oocyte preservation before gonadotoxic chemotherapy in patients of reproductive age

Virology Screening: HIV, hepatitis B/C (mandatory before rituximab or chemotherapy)

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7. Staging (Ann Arbor Classification)

The Ann Arbor staging system (Cotswolds modification) is used for both Hodgkin and non-Hodgkin lymphomas. Stage is determined by anatomical extent of disease and presence/absence of B symptoms.

Modifiers:

• A: Absence of B symptoms
• B: Presence of B symptoms (fever > 38°C, unintentional weight loss > 10% in 6 months, drenching night sweats)
• E: Contiguous extranodal extension from nodal site
• X: Bulky disease (> 10 cm mass or mediastinal mass >⅓ thoracic diameter on CXR)
• S: Splenic involvement

Examples:

• Stage IIA: Two lymph node regions same side of diaphragm, no B symptoms
• Stage IIIB: Lymph nodes both sides of diaphragm with B symptoms
• Stage IVB: Bone marrow involvement with B symptoms [30]

Prognostic Scores

International Prognostic Score (IPS) for Hodgkin Lymphoma

Seven adverse factors (1 point each):

1. Albumin less than 40 g/L
2. Haemoglobin less than 105 g/L
3. Male sex
4. Age ≥45 years
5. Stage IV disease
6. White cell count ≥15×10⁹/L
7. Lymphocyte count less than 0.6×10⁹/L or less than 8% of WCC

Interpretation:

• Score 0-2: 5-year freedom from progression (FFP) ~80%
• Score 3-4: 5-year FFP ~60%
• Score ≥5: 5-year FFP ~40% [31]

International Prognostic Index (IPI) for Aggressive NHL (DLBCL)

Five adverse factors (1 point each):

1. Age > 60 years
2. Stage III or IV disease
3. Elevated serum LDH (above upper limit of normal)
4. ECOG performance status ≥2

5. 1 extranodal site

Interpretation (in rituximab era, R-IPI):

• Low risk (0-1): 5-year OS ~90%
• Low-intermediate risk (2): 5-year OS ~80%
• High-intermediate risk (3): 5-year OS ~60%
• High risk (4-5): 5-year OS ~50% [32]

Follicular Lymphoma International Prognostic Index (FLIPI)

Five adverse factors (1 point each):

1. Age > 60 years
2. Stage III-IV
3. Haemoglobin less than 120 g/L
4. Elevated serum LDH

5. 4 nodal areas involved

Interpretation:

• Low risk (0-1): 10-year OS ~70%
• Intermediate risk (2): 10-year OS ~50%
• High risk (≥3): 10-year OS ~35% [33]

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8. Management

Hodgkin Lymphoma

Early-Stage Favourable (IA, IIA without risk factors)

Standard Treatment:

• ABVD × 2 cycles + Involved-Field Radiotherapy (IFRT) 20 Gy [34]

ABVD Regimen (administered every 14 days):

• Adriamycin (doxorubicin) 25 mg/m² IV day 1, 15
• Bleomycin 10 units/m² IV day 1, 15
• Vinblastine 6 mg/m² IV day 1, 15
• Dacarbazine 375 mg/m² IV day 1, 15

Risk Factors (determine "favourable" vs "unfavourable"):

• Bulky mediastinal mass (>⅓ thoracic diameter)
• Age ≥50 years
• Elevated ESR (≥50 without B symptoms, ≥30 with B symptoms)
• ≥3 nodal areas involved

Early-Stage Unfavourable (IA, IIA with risk factors, IIB)

Standard Treatment:

• ABVD × 4 cycles + IFRT 30 Gy [34]

Alternative (selected patients):

• BEACOPP (Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Oncovin, Procarbazine, Prednisolone): More intensive; used in some European centres for unfavourable early-stage disease

Advanced-Stage (IIB with bulky disease, III, IV)

Standard Treatment:

• ABVD × 6 cycles [35]
• PET-Guided Approach (RATHL trial): Interim PET after 2 cycles:
  • "PET-negative (Deauville 1-3): Continue ABVD or AVD (omit bleomycin to reduce pulmonary toxicity)"
  • "PET-positive (Deauville 4-5): Escalate to BEACOPP or BrECADD"

Escalated BEACOPP (for high-risk disease):

• More intensive regimen with higher cure rates but greater toxicity
• Used in young patients with high IPS scores or PET-positive interim scans
• 5-year FFP ~90% vs 85% with ABVD [36]

Radiotherapy Consolidation:

• Considered for PET-positive residual masses after chemotherapy
• IFRT 30-36 Gy to residual disease

Relapsed/Refractory Hodgkin Lymphoma

Second-Line Chemotherapy:

• ICE (Ifosfamide, Carboplatin, Etoposide)
• DHAP (Dexamethasone, High-dose Ara-C, Platinum)
• GDP (Gemcitabine, Dexamethasone, Platinum)

Autologous Stem Cell Transplantation (ASCT):

• Standard of care for relapsed/refractory HL with chemosensitive disease
• High-dose chemotherapy (BEAM: BCNU, Etoposide, Ara-C, Melphalan) followed by stem cell rescue
• 5-year OS ~60-70% [37]

Novel Agents:

• Brentuximab Vedotin (anti-CD30 antibody-drug conjugate): Response rate ~75% in relapsed/refractory HL; approved post-ASCT or in ASCT-ineligible patients [38]
• PD-1 Inhibitors (Nivolumab, Pembrolizumab): Response rate ~65-70%; particularly effective in classical HL due to PD-L1 amplification (9p24.1) [39]

Non-Hodgkin Lymphoma

Diffuse Large B-Cell Lymphoma (DLBCL)

Standard First-Line Treatment:

• R-CHOP × 6 cycles (administered every 21 days) [40]

R-CHOP Regimen:

• Rituximab 375 mg/m² IV day 1
• Cyclophosphamide 750 mg/m² IV day 1
• Hydroxydaunorubicin (Doxorubicin) 50 mg/m² IV day 1
• Oncovin (Vincristine) 1.4 mg/m² IV day 1 (max 2 mg)
• Prednisolone 100 mg PO days 1-5

CNS Prophylaxis (intrathecal methotrexate or high-dose systemic methotrexate):

• Testicular, paranasal sinus, breast, epidural DLBCL

• 1 extranodal site + elevated LDH

• High IPI score (4-5) [22]

Consolidation Radiotherapy:

• IFRT to initial bulky sites (> 10 cm) or PET-positive residual masses
• 30-36 Gy

Limited-Stage DLBCL (Stage I-II):

• R-CHOP × 3-4 cycles + IFRT 30-40 Gy (preferred)
• R-CHOP × 6 cycles alone (alternative if radiotherapy contraindicated)

Advanced-Stage DLBCL (Stage III-IV):

• R-CHOP × 6 cycles (standard)
• Interim PET after 3-4 cycles guides prognosis but not routinely treatment modification

Double-Hit/Triple-Hit Lymphomas:

• R-CHOP inadequate (5-year OS ~30%)
• Intensified regimens: DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) [18]

Relapsed/Refractory DLBCL

Second-Line Chemotherapy (salvage):

• R-ICE, R-DHAP, R-GDP (rituximab + platinum-based regimens)

Autologous Stem Cell Transplantation:

• Standard of care for chemosensitive relapsed DLBCL
• 3-year OS ~50% [41]

CAR-T Cell Therapy:

• Axicabtagene Ciloleucel (Axi-cel) and Tisagenlecleucel (Tisa-cel): Anti-CD19 CAR-T cell therapies
• Approved for relapsed/refractory DLBCL after ≥2 prior lines
• Response rate ~50-80%; durable remissions in 30-40%
• Toxicities: Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) [42]

Bispecific Antibodies:

• Glofitamab (CD20×CD3 bispecific): Response rate ~50% in heavily pre-treated DLBCL [43]

Follicular Lymphoma (Indolent NHL)

Management Strategy: Risk-adapted; observation vs treatment based on tumour burden and symptoms.

Watch-and-Wait (Asymptomatic, Low Tumour Burden):

• Observation without immediate treatment
• Median time to treatment ~3 years
• No survival disadvantage compared to early treatment [44]

Indications for Treatment (GELF/BNLI Criteria):

• Symptomatic disease (B symptoms, pruritus)
• Bulky disease (> 7 cm)
• Rapidly progressive disease
• Cytopenias (Hb less than 100 g/L, platelets less than 100×10⁹/L)
• Threatened end-organ function (ureteric obstruction, spinal cord compression)

First-Line Treatment (Limited Stage I-II):

• Involved-Site Radiotherapy (ISRT) 24-30 Gy: Potentially curative (20-30% long-term disease-free survival)

First-Line Treatment (Advanced Stage III-IV or Symptomatic):

• Bendamustine-Rituximab (BR) × 6 cycles: Preferred in elderly/frail patients; lower toxicity [45]
• R-CVPP (Rituximab, Cyclophosphamide, Vinblastine, Procarbazine, Prednisolone)
• R-Chlorambucil: Older, less fit patients

Maintenance Rituximab:

• Rituximab 375 mg/m² every 2-3 months for 2 years post-induction
• Prolongs progression-free survival (PFS) by ~4 years
• Recommended after chemotherapy induction [46]

Relapsed Follicular Lymphoma:

• Repeat rituximab-based regimen (if first remission > 2 years)
• Obinutuzumab (anti-CD20 glycoengineered antibody) + chemotherapy
• Lenalidomide-Rituximab (oral immunomodulatory agent)
• Radioimmunotherapy: Yttrium-90 or Iodine-131-labelled anti-CD20 antibodies (reserved for specific cases)
• Autologous SCT: Considered in young, fit patients with early relapse

Transformation to Aggressive Lymphoma (Richter transformation):

• Occurs in 2-3% per year (cumulative 30% at 10 years)
• Suspected if: Rapid lymph node enlargement, B symptoms, elevated LDH, PET-avid lesion (SUV > 10)
• Requires re-biopsy
• Treated as DLBCL (R-CHOP); poor prognosis (median OS ~1 year) [47]

Mantle Cell Lymphoma

First-Line Treatment (Fit Patients less than 65 years):

• Intensive induction: R-HyperCVAD (Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, Dexamethasone alternating with Methotrexate, Cytarabine) or Nordic protocol
• Autologous SCT consolidation in first remission
• Rituximab maintenance for 3 years: Prolongs PFS [48]

First-Line Treatment (Older/Unfit Patients):

• Bendamustine-Rituximab (BR) × 6 cycles + rituximab maintenance

Novel Agents:

• Ibrutinib (Bruton tyrosine kinase inhibitor): Response rate ~65% in relapsed/refractory MCL; approved first-line in combination with rituximab [49]
• Acalabrutinib (second-generation BTK inhibitor): Better tolerability
• Venetoclax (BCL2 inhibitor): Active in relapsed MCL

Burkitt Lymphoma

Treatment: Intensive multi-agent chemotherapy with CNS prophylaxis

• CODOX-M/IVAC (Cyclophosphamide, Vincristine, Doxorubicin, Methotrexate alternating with Ifosfamide, Etoposide, Cytarabine)
• Hyper-CVAD + Rituximab
• Intrathecal chemotherapy (methotrexate, cytarabine) with every cycle
• 5-year OS ~70-80% in adults [50]

Tumour Lysis Syndrome Prophylaxis (mandatory):

• Aggressive hydration (3 L/m²/day)
• Allopurinol 300 mg daily (or rasburicase 0.2 mg/kg if high risk)
• Monitor electrolytes (K⁺, PO₄³⁻, Ca²⁺), uric acid, creatinine every 6-12 hours

Supportive Care

Infection Prophylaxis

• Pneumocystis jirovecii Prophylaxis: Co-trimoxazole 960 mg three times weekly during and for 6 months post-chemotherapy (particularly with fludarabine, bendamustine, or steroids)
• Antiviral Prophylaxis: Aciclovir 400 mg BD if herpes zoster risk or history
• Antifungal Prophylaxis: Fluconazole if prolonged neutropenia expected
• Hepatitis B Reactivation Prophylaxis: Lamivudine or entecavir if HBsAg+ or anti-HBc+ receiving rituximab [51]

Haemopoietic Growth Factors

• G-CSF (Filgrastim, Pegfilgrastim): Primary prophylaxis if febrile neutropenia risk > 20% (BEACOPP, dose-dense regimens)

Antiemetics

• 5-HT3 Antagonists (Ondansetron 8 mg TDS) + NK1 Antagonists (Aprepitant) + Dexamethasone for highly emetogenic chemotherapy (ABVD, R-CHOP)

Fertility Preservation

• Sperm Banking: Offered to all male patients pre-chemotherapy
• Oocyte/Embryo Cryopreservation: Offered to female patients if feasible (may delay treatment 2-3 weeks)
• GnRH Agonists: Limited evidence for ovarian protection

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9. Complications

Treatment-Related Complications

Disease-Related Complications

Superior Vena Cava Obstruction (2-3% of cases):

• Mediastinal lymphoma (PMBCL, lymphoblastic, DLBCL)
• Facial/neck swelling, dyspnoea, chest wall venous distension
• Urgent CT chest, tissue diagnosis (biopsy if not previously confirmed), chemotherapy or radiotherapy

Spinal Cord Compression (1-2% of cases):

• Back pain, lower limb weakness, sensory level, bowel/bladder dysfunction
• MRI spine within 24 hours
• High-dose dexamethasone 16 mg daily, urgent radiotherapy or surgical decompression [52]

Hyperviscosity Syndrome (rare in lymphoma):

• Waldenström macroglobulinaemia (lymphoplasmacytic lymphoma)
• Blurred vision, headache, bleeding, confusion
• Urgent plasmapheresis

Autoimmune Cytopenias (5-10%):

• Autoimmune haemolytic anaemia (AIHA): Positive DAT, spherocytes, reticulocytosis; treat with corticosteroids ± rituximab
• Immune thrombocytopenia (ITP): Isolated thrombocytopenia; treat underlying lymphoma

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10. Prognosis

Hodgkin Lymphoma

Hodgkin lymphoma is one of the most curable cancers, with overall cure rates exceeding 80%. [3]

Adverse Prognostic Factors (International Prognostic Score):

• High IPS score (≥4) associated with 5-year FFP ~40-50%
• Bulky mediastinal disease
• B symptoms
• PET-positive interim scan (Deauville 4-5) after 2 cycles

Long-Term Survivorship Issues:

• Secondary malignancies (breast, lung, thyroid cancer) due to radiotherapy/chemotherapy exposure—10-15% risk at 20 years [53]
• Cardiovascular disease (coronary artery disease, heart failure) due to mediastinal radiotherapy and anthracyclines
• Infertility (particularly with BEACOPP)
• Hypothyroidism (neck radiotherapy)

Follow-Up:

• Clinical review every 3 months for 2 years, then 6-monthly to 5 years, then annually
• Annual thyroid function tests if neck radiotherapy
• Cardiovascular risk assessment and management
• Age-appropriate cancer screening (mammography if chest radiotherapy in women)

Non-Hodgkin Lymphoma

Prognosis varies widely based on histological subtype, stage, IPI score, and molecular features.

Diffuse Large B-Cell Lymphoma (DLBCL)

Cell-of-Origin Impact:

• GCB subtype: 5-year OS ~75%
• ABC subtype: 5-year OS ~55%
• Double/triple-hit lymphomas: 5-year OS ~30% with R-CHOP (improved with DA-EPOCH-R) [17,18]

Follicular Lymphoma

Follicular lymphoma is indolent but incurable. Median overall survival is 15-20 years with modern treatment (rituximab era). [44]

Disease Course:

• Relapsing-remitting pattern; median time to first treatment ~3 years
• Median PFS after first-line rituximab-based therapy ~4-5 years
• Cumulative risk of transformation to aggressive lymphoma (DLBCL) ~30% at 10 years (poor prognosis) [47]

Mantle Cell Lymphoma

Aggressive yet partially chemosensitive; median OS ~5-7 years. [48]

• Intensive therapy + ASCT in young patients: Median OS ~10 years
• Older patients (BR + rituximab maintenance): Median PFS ~4 years

Burkitt Lymphoma

Highly aggressive but potentially curable with intensive chemotherapy.

• 5-year OS ~70-80% in adults with modern regimens (CODOX-M/IVAC, Hyper-CVAD-R)
• Prognosis worse in older patients (> 60 years) and HIV-associated disease [50]

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11. Key Guidelines

1. NICE NG52 (2016): Non-Hodgkin's lymphoma: diagnosis and management. Recommendations on investigation, staging, and treatment pathways. [24]

2. ESMO Clinical Practice Guidelines:

   • Hodgkin Lymphoma (Eichenauer et al., 2018): Evidence-based recommendations for diagnosis, staging, treatment, and follow-up. [34]
   • Diffuse Large B-Cell Lymphoma (Tilly et al., 2015): First-line and relapsed/refractory DLBCL management. [40]

3. NCCN Guidelines: Comprehensive algorithms for all lymphoma subtypes, updated annually.

4. British Society for Haematology (BSH) Guidelines: UK-specific recommendations on lymphoma management.

5. Lugano Classification (2014): Updated staging and response criteria for lymphomas, incorporating PET-CT. [28]

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12. Common Exam Questions

MRCP/FRACP Style Questions

1. "A 25-year-old presents with painless cervical lymphadenopathy and alcohol-induced pain in the neck. What is the most likely diagnosis?"

   • Answer: Hodgkin lymphoma (alcohol-induced pain is rare but highly specific)

2. "What is the most common subtype of non-Hodgkin lymphoma in adults?"

   • Answer: Diffuse large B-cell lymphoma (30-40% of NHL)

3. "A patient with DLBCL has testicular involvement. What additional investigation is mandatory?"

   • Answer: Lumbar puncture (CSF analysis) for CNS staging—testicular DLBCL has high CNS relapse risk

4. "What is the immunophenotype of Reed-Sternberg cells in classical Hodgkin lymphoma?"

   • Answer: CD30+, CD15+, CD20- (usually), CD45-

5. "Which chromosomal translocation is characteristic of follicular lymphoma?"

   • Answer: t(14;18) BCL2-IGH translocation (85% of cases)

6. "What is the first-line treatment for advanced-stage Hodgkin lymphoma?"

   • Answer: ABVD chemotherapy × 6 cycles

7. "A patient with Burkitt lymphoma is about to start chemotherapy. What is the most important preventive measure?"

   • Answer: Tumour lysis syndrome prophylaxis (aggressive hydration, allopurinol/rasburicase, electrolyte monitoring)

8. "What is the role of rituximab in B-cell lymphomas?"

   • Answer: Anti-CD20 monoclonal antibody; standard component of treatment for CD20+ B-cell lymphomas (DLBCL, follicular lymphoma, mantle cell lymphoma)

Viva Points

Opening Statement for Hodgkin Lymphoma: "Hodgkin lymphoma is a lymphoid malignancy characterised by the presence of Reed-Sternberg cells on histology, accounting for approximately 10% of lymphomas. It exhibits a bimodal age distribution with peaks at 20-30 years and > 55 years. The disease typically presents with painless, progressive cervical or supraclavicular lymphadenopathy and demonstrates contiguous spread through lymph node chains. The immunophenotype is CD30+, CD15+, with weak PAX5 expression. First-line treatment is combination chemotherapy with ABVD, with or without radiotherapy depending on stage. Hodgkin lymphoma is highly curable, with 5-year survival exceeding 80-85% across all stages."

Opening Statement for Non-Hodgkin Lymphoma: "Non-Hodgkin lymphomas are a heterogeneous group of lymphoid malignancies comprising over 60 distinct subtypes, classified based on cell of origin (B-cell, T-cell, NK-cell), morphology, immunophenotype, and molecular features. The most common subtype is diffuse large B-cell lymphoma, accounting for 30-40% of cases, which is aggressive but curable with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). NHL demonstrates non-contiguous spread, in contrast to Hodgkin lymphoma. Prognosis varies widely by subtype—aggressive lymphomas like DLBCL are potentially curable, whereas indolent lymphomas like follicular lymphoma are incurable but have prolonged survival measured in decades."

Common Mistakes

❌ Using FNA for initial lymphoma diagnosis: Fine needle aspiration provides insufficient material for subtyping; excisional lymph node biopsy is required.

❌ Missing CNS prophylaxis in high-risk DLBCL: Testicular, paranasal sinus, breast, and epidural DLBCL require intrathecal chemotherapy or high-dose systemic methotrexate to prevent CNS relapse.

❌ Treating follicular lymphoma immediately without indication: Asymptomatic, low-burden follicular lymphoma should be observed ("watch-and-wait") with no survival disadvantage compared to early treatment.

❌ Forgetting hepatitis B screening before rituximab: Rituximab causes HBV reactivation in 20-50% of HBsAg+ patients; antiviral prophylaxis is mandatory.

❌ Missing tumour lysis syndrome prophylaxis in Burkitt lymphoma: Burkitt lymphoma has extremely high cell turnover; aggressive hydration and allopurinol/rasburicase are mandatory before chemotherapy.

❌ Assuming all lymphomas are treated the same: Lymphoma subtypes have vastly different biology and treatment—DLBCL requires intensive chemotherapy (R-CHOP), whereas follicular lymphoma may not require immediate treatment.

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13. Patient/Layperson Explanation

What is Lymphoma?

Lymphoma is a type of cancer that starts in the lymphatic system—the network of glands (lymph nodes) and vessels that helps your body fight infections. White blood cells called lymphocytes become abnormal and grow out of control, forming lumps in lymph nodes or other organs.

Two Main Types

Hodgkin Lymphoma:

• Less common (about 10% of lymphomas)
• Usually very curable—more than 8 out of 10 people are cured
• More common in young adults and older people
• Diagnosed by finding specific abnormal cells (Reed-Sternberg cells) under a microscope

Non-Hodgkin Lymphoma:

• More common (about 90% of lymphomas)
• Many different subtypes with different behaviours
• Some types are aggressive but curable; others grow slowly and can be managed for many years
• Treatment depends on the specific type

Symptoms

The most common symptom is painless swelling of lymph nodes in the neck, armpit, or groin. These lumps don't go away and may slowly get bigger.

Other symptoms may include:

• Unexplained fevers
• Night sweats (soaking the bedsheets)
• Weight loss (losing more than 10% of your body weight without trying)
• Tiredness
• Itching all over the body

Diagnosis

To diagnose lymphoma, a doctor will:

1. Remove a swollen lymph node (biopsy) for examination under a microscope
2. CT or PET scans to see where the lymphoma has spread
3. Blood tests to check your general health

Treatment

Hodgkin Lymphoma:

• Chemotherapy (usually a combination called ABVD)
• Sometimes radiotherapy (focused beams to kill cancer cells)
• Most people are cured with treatment

Non-Hodgkin Lymphoma:

• Depends on the type:
  • "Aggressive types (like DLBCL): Chemotherapy with rituximab (R-CHOP regimen)—potentially curable"
  • "Slow-growing types (like follicular lymphoma): May not need immediate treatment; can be watched closely and treated when symptoms develop"

Side Effects

Chemotherapy can cause:

• Hair loss (temporary—hair grows back after treatment)
• Nausea and vomiting (controlled with anti-sickness medicines)
• Increased infection risk (antibiotics given if needed)
• Tiredness

Outlook

• Hodgkin lymphoma: More than 80% of people are cured
• Aggressive non-Hodgkin lymphomas: 60-70% are cured with chemotherapy
• Slow-growing non-Hodgkin lymphomas: Not curable but people often live for 15-20 years or more with treatment

Support

• Lymphoma Action (UK charity): lymphoma-action.org.uk
• Macmillan Cancer Support: macmillan.org.uk
• Your hospital team will provide information and support throughout treatment

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39. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319. doi:10.1056/NEJMoa1411087

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Medical Disclaimer: MedVellum content is for educational purposes only and does not constitute medical advice. Clinical decisions should be made in consultation with qualified healthcare professionals and with reference to current guidelines and patient-specific factors.